Cervical Cancer

what are the changes in staging for cervical cancer

see notes

● These subtypes have been well characterized as causative agents for cervical cancer:

○ HPV-16 ○ HPV- 18 ○ as well as a long list of other, less frequent subtypes, including but not limited to: ■ HPV types 31, 33, 35, 39, 45, 51, 52, 56, and 58, , with some geographic variation ■ 31 and 45 responsible for 10% of Ca; 90% = 16 and 18

Cell Cycle and Cellular Oncogenes in cervical cancer ● mutations of the Ki-ras gene

○ have been detected in a small percentage of cervical adenocarcinomas but ○ have NOT BEEN significantly associated with stage, grade, or survival

Cell Cycle and Cellular Oncogenes in cervical cancer ● Both specific point mutations and amplification of ras genes have been noted. ● Overexpression of the ras gene p21 product

○ is associated with a POOR PROGNOSISand increased frequency of LYMPH NODE INVOLVEMENT

○ comprises approximately 2% primary cervical adenocarcinomas ○ is believed to arise in mesonephric remnants. ○ These tumors are submucosal, composed of clear and "hobnail" cells, and may grow in a tubular, glandular, papillary, or solid pattern. ○ They appear at any age, with one-third occurring in women younger than 30 years of age ○ The clear cell is characterized by a voluminous cytoplasm filled with glycogen and the hobnail cell by single-cell apical projections into the neoplastic lumina. ○ These tumors tend to be deeply positioned, with the bulk of the lesion on the stroma forming tubular structures, diffusely infiltrating the cervical stroma.

● Clear cell carcinoma(mesonephric), not related to DES exposure

Tumor Factors in cervical cancer: Treatment Duration

● In patients treated with radiation therapy, overall treatment time (OTT) should be as SHORT AS POSSIBLE, and any planned or unplanned interruptions or delays should be AVOIDED. ● Timely integration of external beam and intracavitary irradiation in patients with carcinoma of the uterine cervix is an important factor in improving pelvic tumor control (Fig. 73.8) ● Several studies described lower pelvic tumor control and survival rates in invasive carcinoma of the uterine cervix when the overall time in a course of irradiation is prolonged

PATHOLOGIC CLASSIFICATION of cervical cancer

● More than 90% of tumors are squamous cell carcinoma ● Approximately 7% to 10% are classified as adenocarcinoma ● 1% to 2% are the clear cellmesonephric type

○ have been occasionally described ○ primary or secondary in the cervix, have been sporadically reported ○ They should be treated like other lymphomas ○ is similarly extremely rare and difficult to cure despite attempts at radical surgery.

● Primary sarcomas of the cervix(e.g., leiomyosarcoma, rhabdomyosarcoma, stromal sarcoma, carcinosarcoma). ● Malignant lymphomas ● Melanomaof the cervix

● Several retrospective analyses suggest that prolonged RT treatment duration has an adverse effect on outcome.292-296 Extending the overall treatment beyond 6 to 8 weeks can result in approximately a ______ decrease in pelvic control and cause specific survival for each extra day of overall treatment time. Thus, although no prospective randomized trials have been performed, it is generally accepted that the entire RT course (including both EBRT and brachytherapy components) should be completed in a timely fashion (within 8 weeks); delays or splits in the radiation treatment should be avoided whenever possible.

0.5% to 1%

● Of patients diagnosed with cervical intraepithelial neoplasia (CIN) type1: ○ ______have regression of the lesion ● Of those with CIN2 ○ _____ regress ● Higher levels of dysplasia are more likely to progress to cancer, particularly in the presence of cofactors such as smoking or impaired immunity ● Although progression typically takes 10 to 20 yearsin some instances, a rapid development of carcinoma may be associated with aggressive disease

60% 40%

● The neutrophil-to-lymphocyte ratio has been shown to be prognostic ○ with an NLR ______ associated with a worse OS (HR 1.65, P < .001) and EFS (HR 1.57, P < .001).

> 2.95

Tumor Factors in cervical cancer: Lymph Node Ratio ● In a review of 95 patients with stage I to II cervical cancer treated with a radical hysterectomy and pelvic and/or para-aortic lymphadenectomy ○ the ratio of involved lymph nodes was associated on multivariate analysis with worse survival ○ A ratio of positive to negative of _____ had an HR of 3.96(P = .01)

>7.6%

● The uterus ○ is partially covered by peritoneumin its __________portions; ○ its anterior and lateral surfaces are related to the bladder and the broad ligaments, respectively. ○ attached to the surrounding structures in the pelvis by two pairs of ligaments:

FUNDALand POSTERIOR ■ the broad ligament ● a double layer of peritoneum extending from the lateral margin of the uterus to the lateral wall of the pelvis ● contains the fallopian tubes ● The two layers of peritoneum forming the broad ligament enclose the parametriumas it reaches the uterus ● Inferiorly, the broad ligament follows the plane of the pelvic floor and ends medially in the upper portion of the vagina. ■ Round ligaments ● a band of smooth muscle and connective tissue that contains small vessels and nerves ● extends forward horizontally from its attachment in the anterolateral portion of the uterus to the lateral pelvic wall ● The cord ascending from the lateral wall of the true pelvis crosses the pelvic brim and extends laterally to reach the abdominoinguinal ring, THROUGH which it leaves the abdomen to traverse the inguinal canal and terminates in the superficial fascia.

● Kristensen et al ○ in a study of 465 patients with invasive carcinoma of the uterine cervix on whom DNA index and S-phase fraction studies were performed ○ observed that _________ had prognostic significance

NEITHER ploidy level nor S-phase fraction

True or False ● Survival rates are WORSE with supraclavicular nodal PET positivity ● PALN metastases portend a survival rate between those of pelvic node and supraclavicular positivity

True

True or false ● PET has a higher sensitivity than CT and higher specificity than MR in detecting BONE METASTASES

True

● On a CT scan, the cervical tumor may be seen as ● Parametrial regions appear ● Lymph nodes appear enlarged, with most >1 cm on axial dimension considered pathologic. ● The overall accuracy of CT scanning:

an enlarged, irregular, hypoechoic cervix or as a mass with ill-defined margins dense when involved, and uterosacral involvement may be seen ○ in staging cervical cancer ranges from 63% to 88% ○ In the detection of lymph node abnormalities is 77% to 85%, with sensitivity of 44% and specificity of 93%.

● The integration pattern of HPVis a strong prognostic factor for _______ survival after radiation therapy in cervical cancer:

disease-free ○ episomal (BEST) ○ single-copy ○ multiple-copy tandem repetition

Squamous Cell Carcinoma Antigen and Carcinoembryonic Antigen in cervical cancer

o CEA) levels of >5 ng/mL o noted a correlation with larger tumor size, deeper cervical invasion, and lymphovascular invasion(P < .001) o Increased CEA and CA 19.9 levelswere found with: § MORE ADVANCED stages of the disease § in patients with adenocarcinomacompared with squamous cell carcinoma ○ noted an ELEVATION of squamous cell carcinoma antigen (SCC-Ag) before treatment in 53% of 103 patients, increasing with ADVANCING tumor stageat diagnosis ○ noted that the preirradiation SCC-Ag LEVEL strongly correlated with disease stage ○ A PERSISTENTLY elevated SCC-Ag level 3 months after RT was a stronger predictor for TREATMENT failurethan residual induration by pelvic examination ■ it was associated with a HIGHER incidence of distant metastasis. ○ Patients with an SCC-Ag of <7.2 U/mL ■ had BETTER tumor responsethan those with higher levels

● Results from a large-scale cervical cancer screening trial, conducted over a span of 15 years from Mumbai, India, were reported ○ Over 75,000 women were screened every 2 years using visual inspection and acetic acid vinegar ○ There was a _________ in the screening group, compared with the control group

significant 31% reduction in cervical cancer mortality ○ The 7% reduction in all-cause mortality in the screening group did not reach significance ○ These results suggest acetic acid screening can be utilized in places that lack standard Pap smear screening and treatment resources

● The main artery supplying the uterus is the ________, which originates from the ________ division of the hypogastric artery

uterine artery anterior

HPV vaccination coverage

§ For girls and boys aged 9-14 years § a two-dose schedule (0.5 mL at 0 and 5-13 months) is recommended § If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose is recommended § For those aged 15 years and above, and for immunocompromised patients irrespective of age § the recommendation is for three doses (0.5 mL at 0, 1, 6 months)

appearance of cervical cancer in MRI appearance of parametrial tumor in MRI

· Cervix tumor usually low T1, high T2 (dark)​ [​1​]. o ● Cervix low T1, low (bright) T2. Parametrium high T1, high (dark) T2. o ● Uterine junctional zone: low (bright) T2 inner myometrium, if high (dark), think uterine invlmt. o ● Take home: Tumor low/high, cervix low/low, parametrium high/high. · Staging accuracy: 86%; superior than CT in detecting uterine body and parametrial involvement; uperior in detecting vaginal extension ● MRI is frequently used for the initial assessment of the cervical tumor and of extracervical tumor extension, often in lieu of an EUA ● MRI is contraindicatedin patients with pacemakers/ICDs, cochlear implants, metallic prostheses, metallic fragments from prior accidents, or large vascular clips ● On T2-weighted images, a cervical cancermay be seen as: ○ a mass of intermediate to high signal intensity, usually of greater intensity than the fibrocervical stroma ● On T1- weighted images, tumors are usually: ○ isointense with the normal cervix and may not be seen ○ but can increase in intensity with the administration of IV contrast ● These are indicative of more extensive tumors: ○ T1-weighted images ■ Abnormal, irregular cervical margins, prominent parametrial strands, exocentric parametrial enlargement, and loss of parametrial fat planes ○ T2- weighted images ■ high signal in the parametria or cardinal/uterosacral ligaments ○ may be identified as brighter regions on T2-weighted images when compared to the low signal intensity of the cervix and uterine ligaments

● The HPV genome ○ integrates into the host cell chromosomes in cervical epithelial cells ○ codes for SIX earlyand TWO late open reading frame proteins, of which three alter cellular proliferation

■ E5, E6, and E7

○ Two viral genes, are typically expressed in HPV-positive cervical cancer cells.

■ E6 ● inactivates the major tumor suppressor p53; ● this causes chromosomal instability, inhibits apoptosis, and activates telomerase ● P53 around 23% of all cervical cancer. ■ E7 ● affects the retinoblastoma protein (Rb) ● resulting in a loss of regulation of the cell's proliferation and immortalization

● Evidence continues to mount that INCREASING levels of plasma micronutrientsare associated with a DECREASING risk of cervical cancer ○ Increasing these were significantly inversely associated with cancer:

■ serum lycopene ■ α- and γ-tocopherol levels ■ higher intake of dark green and deep yellow vegetables and fruit ○ Women should be counseled to eat a well-balanced diet, particularly those at high risk for developing cervical cancer.

● The cervix ○ measures approximately 3 by 3 cmand is predominantly a fibrous organ. ○ divided into:

■ upper or supravaginal portion, above the ring containing the endocervical canal ■ vaginal portion, projecting in the vaginal vault. ● Central in the rounded vaginal region is the external os, bounded by the anterior and posterior lips of the cervix, extending inward to the internal os, the endocervical canal, and endometrial canal.

● Wang et al. ○ studied 1,010 patients with cervical cancer after radiotherapy between 1993 and 2000 ○ The HPV genotypes were determined by a gene chip that can detect 38 types of HPV ○ A total of 25 genotypes of HPV were detected in 992 specimens, of which 8 types that predominated were: ■ HPV types 16, 58, 18, 33, 52, 39, 31, and 45 ○ Two high-risk HPV specieswere identified: ○ Risk groups determined included the: ■ high-risk group, which consisted of: ■ medium-risk group included

■ α-7 (HPV types 18, 39, 45) ■ α-9 (HPV types 16, 31, 33, 52, 58) ● patients without HPV infection OR ● those infected with the α-7 species only ● patients coinfected with the α-7 and α-9 species

● Adjusting for population growth and aging, the global incidence rate for cervical cancer DECLINED by 1.2% from 2005-2015 ● The majority of cases are in:

○ Africa ■ because of the paucity of screening measures and the prevalence of immunodeficiency because of human immunodeficiency virus (HIV).

● The NRG/GOG combined data from randomized trials of chemoradiotherapy and created nomograms predicting progression-free survival, overall survival, and pelvic recurrence in locally advanced cervical cancer ● Multivariable analysis of 2,042 patients identified the following as significant measures for outcomes:

○ Histology ○ race/ethnicity ○ performance status ○ tumor size ○ stage ○ grade ○ pelvic node status treatment with cisplatin-based chemotherapy concurrently

● As tumors expand, the newly formed blood vessels may no longer reach the central portions of the tumor, and a hypoxic core develops ● These regulate the response to hypoxic stress:

○ Hypoxia-inducible factor (HIF-1α) ■ has been associated with poor DFS ○ HIF-2α ■ The HIF-2α/CD68 ratio was correlated with poor DFS

Epstein-Barr Virus, Transforming Growth Factor, β-Integrin, and Other Markers Pretreatment transforming growth factor-β1 (TGF-β1) levels

○ In 79 patients undergoing radiation therapy for carcinoma of the cervix, this were a significant prognostic factor for: ■ survival and local tumor control ○ There were WEAK significant correlationsof TGF-β1 levels with disease stage and the levels of circulating tumor markers (CA 125) ○ Hazelbag et al ■ also assessed TGF-β1 and plasminogen activator inhibitor (PAI-1) expression in 108 specimens of cervical carcinoma ■ noted that: ● TGF was NOT ASSOCIATED with WORSE prognosis ● whereas PAI-1 WAS ASSOCIATED

● A prospective study by the American College of Radiology Imaging Network ○ compared clinical examination, CT, and MRI

○ MRI was significantly better than clinical examination or CT for detecting UTERINE BODY INVOLVEMENT or MEASURING TUMOR SIZE ○ but NO METHOD WAS ACCURATE at evaluating the cervical stroma ○ MRI was significantly better at detecting the tumor and parametrial involvement ○ MRI also somewhat increased detection of involved lymph nodes ● The tumor is LESS LIKELY to be as visible on MRI for adenocarcinomacases, compared to squamous cell cancer

Role of ultrasound in cervical cancer

○ Ultrasonography, therefore, is not reliable in preoperative detection of lymph node metastases, but it has limited value in evaluating extrauterine tumor involvement. ● Ultrasound (US) ○ has a primary role in assisting with intracavitary brachytherapy applicator insertionand may detect uterine perforation, allowing for proper positioning, which is critical for adequate dosing and affects survival.

● The uterus is a hollow, thick-walled, pear-shaped, muscular organ located in the pelvis above the vagina, behind the bladder, and in front of the rectum (Fig. 73.1). (measurements?)

○ approximately 7 to 8 cm long ○ 5 to 7 cm wide ○ 2 to 3 cm thick

● The uterosacral ligaments ● The cardinal ligaments

○ are paired supports for the lower uterus ○ extending from the uterus to the sacrum and running along the rectouterine peritoneal fields ○ also called transverse cervical ligaments (Mackenrodt) ○ are thickened connective tissue and fascia arising at the upper lateral margins of the cervix and inserting into the fascial covering of the pelvic diaphragm.

Cell Cycle and Cellular Oncogenes in cervical cancer ● Gadd45

○ belongs to the class II family of DNA damage-inducible genes ○ its role in DNA repair has been proven in many experimental models ○ Santucci et al ■ in 14 patients with cervical cancer ■ found a correlation between the LACK OF gadd45 induction and a clinical response to irradiation (both local tumor control and DFS) when a dose ranging from 18 to 25 Gy was delivered to the pelvis

● Social factorsrelated to cervical cancer include those associated with HPV transmission, such as:

○ early age of first intercourse ○ a history of multiple sexual partners ○ a male partner with a history of multiple sexual partners ○ a large number of pregnancies ○ a history of sexually transmitted disease, including: ■ gonorrhea ■ chlamydia ■ herpes simplex virus II ■ HIV

Cell Cycle and Cellular Oncogenes in cervical cancer ● c-myc oncogene

○ is amplified from 3 to 30 times in approximately 20% of squamous cell carcinomas ○ is more frequent in high-stage compared with low-stage tumors. ○ has been associated with a worse clinical outcome

● The Cancer Genome Atlas (TCGA) identified three main subtypes: _________ ● HPV integration was observed in: ● Endometrial-like cervical cancer

○ keratin-low, keratin-high, and adenoma-rich. ○ all HPV-18 ○ 76% of HPV-16 related cases ○ was HPV-negative ○ occurred in 5% of cases ○ had high frequencies of KRAS, ARID1A, and PTEN mutations

Cell Cycle and Cellular Oncogenes in cervical cancer ● c-Ha-ras gene

○ loss of heterozygosity of the c-Ha-ras gene in squamous cell carcinomas was NOT ASSOCIATED with advanced-stage disease ○ mutations were associated with a POOR PROGNOSIS

● In an analysis of 322 patients in whom distant metastases developed, the most frequently observed metastatic sites in cervical cancer were the: ● Bone metastases ○ occurred in 16% ofpatients ○ most commonly to the_________ (Table 73.3)

○ lung (21%) ○ PALNs (11%) ○ abdominal cavity (8%) ○ supraclavicular lymph nodes (7%) ○ most commonly to the lumbar and thoracic spine (Table 73.3)

● Patients with cervical cancer may present complaining of: ● In cases with more advanced disease, these may occur:

○ metrorrhagia (intermenstrual bleeding) ○ menorrhagia (heavier menstrual flow) ○ postcoital bleeding ○ If chronic bleeding occurs, the patient may complain of fatigue or other symptoms related to anemia ○ bowel obstruction ○ renal failure ○ foul smelling serosanguinous or yellowish vaginal discharge ○ pelvic pain, flank and/or leg pain ○ rectal bleeding ○ obstipation ○ dysuria, hematuria ○ persistent edema of lower extremities because of lymphatic/venous blockade by pelvic sidewall disease ○ Pain in the pelvis or hypogastrium may be caused by tumor necrosis or associated pelvic inflammatory disease

● Conization must be performedin the following situations:

○ no gross lesion of the cervix is noted and an endocervical tumor is suspected ○ the entire lesion cannot be seen with the colposcope ○ diagnosis of microinvasive carcinoma is made on biopsy ○ discrepancies are found between the cytologic and the histologic appearances of the lesion the patient is not reliable for all necessary follow-up

● When obtaining the Pap smear, special attention should be directed to: ● The patient should be instructed not to cleanse with a douche before the examination ○ if indicated, specimens should be: ● If the cytologic smear shows atypia or mild dysplasia(class II): ○ it should be _____

○ not using a lubricating agent (warm water on the speculum will suffice) ○ to obtaining good "scrapings" from the cervix and vaginal posterior fornix (without blood) ○ to using a small brushto obtain an endocervical sample obtained to check for trichomonas repeated no sooner than 2 weeks after the initial testto allow representative cellular exfoliation to occur

● The uterus including the uterine cervix has a rich lymphatic network (Fig. 73.2) that drains principally into the: ● The major lymphatic drainage of the cervixruns in: ● The pelviclymphatics drain into the: ● Lymphatics from the FUNDUS

○ paracervicallymph nodes; -> goes to the external iliac(of which the obturator nodes are the innermost component) and the hypogastriclymph nodes ○ the cardinal ligamentsuperior to the ureter, and ○ in the uterosacral ligamentsto the rectal area ○ NO LYMPHATIC VESSELS RUN IN THE VESICOUTERINE SPACE, rather those from the upper vagina fuse with those from the bladder and extend laterally into the parametrium ○ common iliac and the para-aortic lymph nodes (PALNs) ○ pass laterally across the broad ligamentcontinuous with those of the ovary, ascending along the ovarianvessels into the PALNs ○ Some of the fundal lymphatics also drain into the common iliaclymph nodes

Tumor Factors in cervical cancer: Margin Status After Radical Hysterectomy ● In addition to the known HIGH-RISK FACTORS of: ● and the INTERMEDIATE-RISK factors of: ● small series have indicated the significance of:

○ positive margins ○ positive parametrial spread, and/or ○ positive lymph nodes ○ depth of stromal invasion ○ lymphovascular invasion ○ tumor size CLOSE MARGIN STATUS

● Whether regional differences in predisposition to developing cervical cancer exist is debated because it is impossible to adequately correct for unknown and known confounders, such as:

○ socioeconomic status, ○ access to health care ○ parity ○ smoking ○ presence of other infections ○ immune status ○ and other factors affecting host immunity such as nutritional status

● Squamous cell carcinoma of the uterine cervix usually originates at the:

○ squamous columnar junction (transformation zone) of the endocervical canal and portion of the cervix.

● Worldwide, cervical cancer remains:

○ the MOST COMMON gynecologic cancer ○ the fourth most common malignancy in women ○ with over 526,000 women globally developing this tumor as reported in 2015 ○ 239,000 dying of the disease every year.

● The wall of the uterus has three layers:

○ the outer serosal layer; ○ the middle myometrium ■ approximately 12 to 15 mm of muscle through which the main blood vesselsand nervesflow; and ○ the inner coat called the endometrium.

● The uterus is divided into

○ the uterine corpus- superiorly ■ most superior part of the corpus also known as the fundus ● located superior to the line joining the entrance of the fallopian tubes ■ middle portion of the corpus known as the body ● enclosed between layers of the broad ligament and is freely mobile. ○ uterine cervix- inferiorly ■ rests inferior to the LUS (isthmus) ■ The most inferior, slightly constricted, portion of the uterus is called the isthmus or lower uterine segment (LUS)

Cytokeratin Markers and the Epidermal Growth Factor Receptor Pathway in cervical cancer ● Altered expression of c-ercB-2(HER2) protein ● HER1, as well as coexpression of epidermal growth factor receptor and HER2 ● PTEN mutations ● Expression of cytokeratin 10 and 13 and involucrin ○ In 80 patients with carcinoma of the cervix, was found in 24%, 64%, and 53%, respectively ○ There was _________ in the EXPRESSION of cytokeratin or involucrin between patients with positive or negative lymph nodes ■ although in the lymph node-positive group, survival was HIGHER in patients ________ cytokeratin 13 expression (P = .02).

○ was shown to have prognostic significance in ADENOCARCINOMA but not in squamous cell carcinoma of the cervix ○ has been associated with POOR DFS. ○ have also been associated with POOR prognosis NO DIFFERENCE LACKING

Epstein-Barr Virus, Transforming Growth Factor, β-Integrin, and Other Markers ● Activity of Epstein-Barr virus antigen-specific killer T cells and shedding of Epstein-Barr virus

○ were evaluated in 55 patients with carcinoma of the cervix ○ Activity was DECREASED in patients with cervical carcinomacompared with control patients ○ it became increasingly LOWER as the clinical stage of the disease advanced, and activity after treatment was clearly related to patient survival ○ These data may indicate an imbalance in local immunity against viral infection and impairment of T-cell immunity in patients with advanced cervical carcinoma.

Patient-Related Factors in cervical cancer: Age

● According to some reports, age is not a prognostic factorin carcinoma of the cervix ● Other authors noted decreased survival in women younger than 35 or 40 years, who have a greater frequency of poorly differentiated tumors ● In contrast, two European studies showed improved outcome for younger patients

○ is a rare variant of adenocarcinoma of the cervix (<1%) ○ with an appearance similar to its counterparts in the salivary gland or the bronchial tree. ○ The tumor is composed of nests and nodules of small carcinoma cells with a few characteristic cribriform patterns ○ Immunohistochemical findings for type IV collagen and laminin reveal intercellular cylinders composed of basement membrane material in the solid area without a cribriform pattern ○ They are locally aggressive and prone to metastasize.

● Adenoid cystic carcinoma

○ is a rare form of cervical cancer that is difficult to diagnose ○ often highly malignant and refractory to treatment ○ is associated with Peutz-Jeghers syndrome and has an ominous natural history, with few reported cures.

● Adenoma malignum

○ is also relatively rare (2% to 5%) ○ consists of intermingled epithelial cell cores with squamous features and glandular structures ○ The squamous component is frequently nonkeratinizing. If the squamous component is benign metaplasia, the tumor is called:

● Adenosquamous carcinoma ○ Adenoacanthoma

General Medical Factors in cervical cancer: Anemia and Tumor Hypoxia

● Although stage, tumor volume, histologic type of the lesion, and vascular or lymphatic invasion are known to affect the prognosis of patients with cervical carcinoma, whether hemoglobin levels contribute to patient prognosis is CONTROVERSIAL ● Many radiation oncologists routinely administer red blood cell transfusions (RBCTs) to correct anemia before treatment with radiation therapy ● This may have a generally favorable effect on the patient's sense of well-being and energy level and an impact on tumor radiosensitivity ● Typically, patients receive transfusion to maintain hemoglobin levels >12 to 12.5 g/dL. ● Investigators have reported worse outcomesfor patients whose tumors have either a ○ median partial pressure of oxygen (PO2) level of <10 mm HgOR ■ measured using polarographic needle electrodes for direct tumor tissue oxygen measurements ○ a high percentage of PO2 measurements <5 mmHg ● Comparisons of intratumoral oxygen measurements before and after external beam radiation therapy have usually indicated A TREND toward IMPROVED oxygenation AFTER radiation therapy, but the significance of posttreatment measurements is UNCLEAR Hypoxic tumors are MORE LIKELY TO RECUR locoregionally than well-oxygenated tumors

○ an extremely uncommon tumor ○ is characterized by: ■ nests or cords of small basaloid cells ■ prominent peripheral palisading of cells in the tumor nests ■ no significant stromal reaction or capillary space invasion, and an infiltrating growth pattern ○ Some authors have suggested a slow growth pattern with limited local invasiveness and low probability of lymph node metastases. ○ Prognosis is EXCELLENT

● Basaloid carcinomaor adenoid basalcarcinoma

○ compared with their counterparts in the corpus, are more commonly CONFINED at presentation and may have a BETTER prognosis ○ Clement et al. ■ described the clinicopathologic features with mixed Müllerian tumors of the cervix in nine patients ■ Gross examination revealed polypoid or pedunculated masses that invaded the cervical wall in 50% of the hysterectomy specimens ■ On microscopic examination, five tumors contained basaloid carcinoma or squamous cell carcinoma and four contained adenocarcinoma. ■ In seven tumors, the sarcomatous component was homologous, usually resembling fibrosarcoma or endometrial stromal sarcoma, and two tumors contained heterologous sarcomatous elements.

● Cervical malignant mixed Müllerian tumors

○ involves a conical removal of a large portion of the ectocervix and endocervix ○ Cold knife cone biopsy specimens should always be obtained with a scalpel or other appropriate instrument ○ At least 50% of the endocervical canalshould be removed without compromising the internal sphincter ○ Curettage of the remaining endocervical canal should be carried out.

● Conization

● should be performed in: ○ all patients with symptoms consistent with presence of a fistulaof the urinary or lower gastrointestinal tract ○ patients with clinical stage IIB, III, or IVA disease who cannot undergo an MRI ○ patients with an MRI suspicious for bladder or bowel invasion

● Cystoscopy or rectosigmoidoscopyshould be performed in:

○ is the most common cell type of endocervical adenocarcinoma; ○ the cells resemble those of the endometrium, and the presence of intracytoplasmic MUCIN in some cells may be seen in a substantial proportion of tumors ○ The World Health Organization recommends that endometrioid or endocervical types of adenocarcinoma be graded according to their architecture, based on the degree of gland formation.

● Endometrioid carcinoma

Pap smear screen: when to start and frequency ○ Women who have had a hysterectomy for benign reasons and have no history of high-grade squamous intraepithelial lesion: ○ Women who have been treated for CIN2 or CIN3: ○ Those who have had a hysterectomy and a history of CIN2/CIN3:

● General screening​: ○ Screen ages 21-65y, earlier if sexually active. ○ In 20s, q3y Pap and no HPV if wnl​. If 3 consecutive negative tests: ○ In 30s​, ​q5y Pap/HPV​ [​USPTF '18],​ q3y Pap, or q5y HPV only. ○ At age 65 ■ women can stop having Pap smears as long as their routine screening was within the past 10 years, with normal results ■ may discontinue testing ■ need annual screening for at least 20 years ■ should continue to undergo screening with annual pelvic exams

○ (1% to 2%) ○ is considered a poorly differentiated adenosquamous tumor ○ it is rare and highly malignant ○ Survival is poor after surgery or irradiation ○ Ulbright and Gersell, ■ in five cases of glassy-cell carcinoma evaluated by light and electron microscopy, described both glandular and squamous differentiation ○ Littman et al. ■ reported only 4 of 13 patients, the majority with stage II disease, surviving 5 years (6 had extrapelvic failures) ○ Piura et al. ■ reported on five patients with cervical glassy-cell carcinoma, three with stage IB1 disease. ■ All three patients were alive without disease 4, 12, and 18 months after diagnosis.

● Glassy-cell carcinoma

General Medical Factors in cervical cancer: Other medical factors

● Jenkin and Stryker ○ observed a higher incidence of pelvic recurrencesand complicationsin patients with ARTERIAL HYPERTENSION (diastolic pressure of >110 mm Hg) ● Kapp and Lawrence ○ reported on 398 patients ○ Patients with TEMPERATURES of >101°F had a HIGHER INCIDENCE of: ■ distant metastases and a lower survival rate ● Campbell et al ○ In patients with cervical cancer screened for HIV and treated with RT ○ observed a 4.2% positive HIV rate. ■ These patients had more-advanced tumors ○ The duration of remission was shorter than in the HIV negative group ○ RT had no effect on the HIV titers ○ Women who are HIV positive or have acquired immunodeficiency syndrome associated with in situ or invasive carcinoma of the cervix are: ■ at a HIGHER RISK for tumor recurrence after treatment and death as a consequence of the malignant process ● Evidence continues to mount that INCREASING levels of plasma micronutrientsare associated with a DECREASING risk of cervical cancer ○ Increasing these were significantly inversely associated with cancer: ■ serum lycopene ■ α- and γ-tocopherol levels ■ higher intake of dark green and deep yellow vegetables and fruit ○ Women should be counseled to eat a well-balanced diet, particularly those at high risk for developing cervical cancer. ● The neutrophil-to-lymphocyte ratio has been shown to be prognostic ○ with an NLR > 2.95 associated with a worse OS (HR 1.65, P < .001) and EFS (HR 1.57, P < .001).

○ are frequently done in an office setting as an alternative to conization

● Laser conization and loop diathermy excision ○ loop excision is less expensive and more reliable than laser conization

○ is rare (about 4% of all tumors) ○ should be considered in the differential diagnosis ○ Metastases to the cervix from the breast, ovary, and kidney have been reported

● Metastasis of distant tumorsto the uterine cervix

Tumor Factors in cervical cancer: Histologic grade

● Most reports have shown NO SIGNIFICANT CORRELATION of survival or tumor behavior with the DEGREE OF DIFFERENTIATION of squamous cell carcinoma or adenocarcinoma of the cervix ● In the era of chemoradiation, Monk et al. ○ showed NO SIGNIFICANT IMPACT of histology or grade on survivalin postoperative cervical cancer patients with other high-risk features.

Biopsy of cervical cancer

● Multiple punch biopsiesof a grossly visible lesion should be adequate to confirm the diagnosis of invasive carcinoma ● Specimens should be obtained from any suspect area and from ALL FOUR quadrantsof the cervix and from any suspect areas in the vagina ● It is important to obtain tissue from the PERIPHERY of the lesion with some adjoining normal tissue; ○ biopsy specimens from central ulcerated or necrotic areasmay not be adequate for diagnosis ● Dilation and curettage IS NOT required if the biopsy confirms a diagnosis of invasive disease.

Patient-Related Factors in cervical cancer: Race/socioeconomic status

● Mundt et al. ○ examined factors affecting outcome in 316 African American and 94 white patients undergoing RT for cervical cancer ○ With a median follow-up of 72.4 months, African Americans had a trend toward POORER 8-year CSS rates (47.9% vs. 60.6%; P = .10) compared with white patients. ○ Factors correlating with poor outcome were more likely to be present in the African Americangroup: ■ lower hemoglobin (Hb) levels during RT (P = .001) ■ lower median income (P = .001) ■ less frequent intracavitary brachytherapy (P = .09), ● Multivariate analysis demonstrated that RACE WAS NOT an independent prognostic factorafter controlling for differences in patient, tumor, and treatment factors

Epidemiology of cervical cancer

● Over the last 80 years, the relative morbidity and mortality of locally advanced invasive cervical cancer has declinedin the United States and Europe because of effective screening and treatment of preinvasive lesions ● In the United States, 50%of women who develop cervical cancer have never been screened, and another 10%have not been screened within the previous 5 years ● However, in the last decade, incidence rates of invasive carcinoma have remained relatively constant due to population growthand aging ● The American Cancer Society estimates in 2018 that approximately 13,240 new cases of invasive carcinoma of the cervix arise in the United States and about 4,170 deaths will occur per year, in addition to >60,000 cases of carcinoma in situ.

○ is a universally accepted component in the evaluation and clinical staging of patients in order to provide a pain-free examination that allows a clearer estimation of parametrial or sidewall tumor extension ○ In countries in which magnetic resonance imaging (MRI) is available, this may be used to assist with assessing tumor extension beyond the lower cervix, and in many institutions, it has replaced the EUA

● Pelvic examination under anesthesia (EUA) - pelvic exam: 47% staging accuracy

Impact of Histology on Outcomes

● Several series have questioned whether adenocarcinoma has a worse prognosis than squamous cell carcinoma ● A Surveillance, Epidemiology, and End Results (SEER) analysis of women ○ with stage IB to IVB cervical cance ○ treated between 1988 and 2005 ○ stratified 24,562 women by squamous cell carcinoma (77%), adenocarcinoma, or adenosquamous histology ○ Patients with adenocarcinoma were younger and presented with early-stage disease (P < .0001) ○ For both early and advanced stage diseases, women with adenocarcinoma had ■ an INCREASED likelihood of dying from diseasecompared to those with squamous neoplasms (HR 1.39 and HR 1.21, respectively) ● Rose et.al. ○ a retrospective analysis of 1,671 patients accrued on prior prospective GOG trials with locally advanced cervical carcinoma treated with either radiation alone or chemoradiation ○ a total of 70 ADENOCARCINOMApatients treated with RADIATION ALONEhad a borderline POORER SURVIVAL DIFFERENCE(P = .0499) compared to 647 patients with squamous cell carcinoma ○ In patients treated with CONCURRENT CHEMO-RT, 112 adenocarcinoma patients had NO DIFFERENCEin overall survival (P = .47) compared to 842 patients with squamous cell carcinoma ○ The authors conclude that in the era of chemoradiation, NO DIFFERENCE IN OUTCOME existsbetween squamous cell and adenocarcinoma in this large retrospective analysis

○ according to some authors, arises from endocervical argyrophilic cells or their precursors, multipotential neuroendocrine cells; ■ however, some small cell tumors do not contain morphologic evidence of neuroendocrine origin. ○ Nuclear molding, absence of nucleoli, cell necrosis, and high mitotic activity are common ○ One-third to one-half stain POSITIVELY for neuroendocrine markers such as chromogranin, serotonin, synaptophysin, or somatostatin. ○ In the majority of patients, the cervical stroma is extensively infiltrated by single small, round cells. ○ Lymphatic and vascular invasion are significantly more common in small cell carcinomas (noted in 58% of patients with stage IB disease; 40% of these patients had lymph node metastases at the time of radical surgery) ○ HPV-18 has been detected in the majority of these tumors.

● Small cell carcinoma of the cervix

○ is composed of cores and nests of epithelial cells arranged randomly; ○ cells show central keratinization with pearls and sometimes necrosis ○ Nonkeratinizing tumors may be seen ○ Electron microscopy may show desmosomes and tonofilaments ○ are divided into three types: ■ large-cell keratinizing, nonkeratinizing ■ small cell carcinomas ○ They are subdivided according to the degree of differentiation into well, moderately, or poorly differentiated.

● Squamouscell (or epidermoid) carcinoma

Normal orientation of uterus?

● The uterus ○ is usually bent anteriorly(anteflexed) between the cervix and the uterine body. ● The entire uterine cervix structure ○ is normally bent anteriorly(anteverted) in the pelvis. ● The uterus may be posteriorly retroverted, ESPECIALLY IN older womenwho have a small uterus.

Tumor Factors in cervical cancer: Tumor volume

● There is a close correlation between: ○ depth of stromal invasion, tumor size, and incidence of parametrial and pelvicnode metastases and survival in patients with cervical cancer

○ is a variant of a very well-differentiated squamous cell carcinoma ○ characteristically has a tendency to RECUR LOCALLY but NOT TO metastasize ○ Mitotic activity is very low ○ It may be difficult to discriminate verrucous carcinoma from a giant condyloma with cytologic atypia or from a well- differentiated invasive squamous carcinoma. ○ Microscopically, verrucous carcinoma is exophytic, with an undulating, hyperkeratotic surface; the deep margin is composed of large, bulbous masses that invade along a wide front in a "pushing" fashion

● Verrucous carcinoma

apoptosis in cervical cancer ● Wootipoom et al. ○ in 174 patients with cervical cancer ○ noted Bax, Bcl-2, and p53 expression in 68.4%, 25.9%, and 77.6% of the cases, respectively ○ Bax expression was associated with ____________ ○ Bcl-2 expression was associated with __________

● Whether apoptotic markers might be of importance in cervical cancer is UNCLEAR, given heterogeneity in the data. ● Morphologic studies have been negative, but some studies evaluating apoptotic protein expression such as that of: ○ Bcl-2 and p63 show association with POOR DFS BETTER survival POOR survival

● Patients presenting with low-grade squamous intraepithelial lesions (LSIL) on cytology are further triaged based on age and HPV status ○ Women age 30 and older ■ with LSIL and positive HPV (+) LGSIL, (+) HPV __________ ■ those with LSIL and negative HPV testing (+) LGSIL, (-) HPV __________ ○ Women younger than age 30with LSIL ___________ ○ Guidelines for management of abnormal cervical cytology in women age 21 to 24 have been revised recently, based on the higher prevalence of HPV infection and low risk of cervical cancer in this population ○ For younger women, ASCUS or LSIL on cervical cytology: ___________

● are evaluated with colposcopy ● are recommended to follow up in 1 year with repeat cervical and HPV cotesting rather than colposcopy ■ are managed based on cytology alone ■ is managed with repeat cytology at 12 months

● Fyles et al ○ reported approximately ____ LOSS OF TUMOR CONTROL PER DAY of prolongation of treatment time beyond 30 days in 830 patients with cervical carcinoma treated with irradiation alone

1%

● Risk of progression to cancer​ for ASCUS / LGSIL / AGC-NOS / HGSIL of

< 1→ 5→ 17→ 22%.

● women with early-stage cervical cancer have an approximately ○ ___% risk of ovarian metastasis with squamous cell carcinomaand ○ ___% risk with adenocarcinoma ○ Therefore, women should be counseled on the potential risks of recurrence with ovarian preservation

1% 5%

Second Malignancy ● The risk for induction of secondary primary cancers by pelvic irradiation is low, and many potential confounders either are unknown or may not be fully accounted for, given the available information ● Using the population-based cancer registries of Denmark, Finland, Norway, Sweden, and the United States, Chaturvedi et al ○ found a significantly increased cancer risk in both SCC and AC survivors, with standardized incidence ratio of _____(95% CI = 1.29 to 1.34) and 1.29 (95% CI = 1.22 to 1.38), respectively ○ The risk of smoking-related lung cancer was higher in the ______ than in the _______ population, whereas second malignancies of the colon, soft tissue, melanoma, and non-Hodgkin lymphoma were HIGHER in the _____ population

1.31 SCC than AC AC than SCC

● Approximately ______ of patients with carcinoma of the uterine cervixhave extension into the LUS and the endometrial cavity

10% to 30%

Interstitial applicators: ● With image-based planning including either a CT or an MRI, the physician evaluates the placement of the needles and may choose either to not treat specific catheters or to lower the dose given through catheters close to normal-tissue structures ● An approximate ___% rate of bowel insertion and a long-term fistula rate of _______% have been reported in studies using CT for planning after insertion

11% 4% to 10%

ADENOCARCINOMA OF THE CERVIX ● Adenocarcinoma has been linked to HPV-_____, which has a HIGHER RATE of nodal and distant metastases than HPV-___

18 16

● Therefore, for POSTOPERATIVE PATIENTS, the vagina is contoured: ○ using a FULL-BLADDER CT scan fused to an empty-bladder CT scanto account for vaginal mobilitybecause of differences in bladder filling ■ This vaginal target volume has been referred to as an integrated target volume (ITV). ● The expansion of the CTV and/or ITV to the PTV is necessary, although given the movement of the uterus, the exact amount of margin is a matter of debate ○ Generous margins of approximately _____ cm are considered, particularly in the regions of the uterus and cervix or in the postoperative case around the ITV vagina. ● In order to cover the uterosacral ligaments, the rectum cannot be spared

2 to 3

● Although a high prevalence of HPV exists worldwide: ○ peaking at ages _______ years ○ ____% of exposed women develop persistent infectionthat results in dysplasia ○ whereas the MAJORITY of women clear the infection within ____ years ● Cervical cancer may develop: ○ _____ years after initial exposure to HPV

25 to 35 <15 2 10 to 20

● If para-aortic node metastases are enlarged or suspected to harbor disease, patients are treated with ○ ________ Gy to the para-aortic area plus a sequential 5- to 10-Gy boost to enlarged lymph nodes through reduced lateral or rotational portals. ○ If feasible, 3D planning with IMRT treatment is preferred to spare normal tissues: ■ superiorly covering above the level of the renal hilum or the highest extent of disease ■ inferiorly covering 2 cm below the lowest extent of disease (Fig. 73.14). ● The use of IMRT has allowed dose escalation to para-aortic nodes, particularly unresectable nodes ● The upper margin of the field ● The lowermargin is

45 to 50 ○ is at the T12-L1 interspace to reach the infrarenal hilum ○ at L5-S1

● Depending on the institution and brachytherapy dose administered, midline shielding with rectangular or specially designed blocks has been TRADITIONALLY used for a portion of the external beam dose delivered with the AP-PA ports ● Midline blocks may be individualized, based on the point A isodose line or a rectangular block of approximately 4-cm width ● In one series, overall survival and incidence of chronic complications were NOT RELATED to the type of shielding ● However, in the era of 3D brachytherapy planning, the use of a midline block has been questioned because ○ it may result in tumor underdosing while still contributing significant dose to the bladder, sigmoid, and rectum ● Several institutions reported placing a midline block after a full course of external beam treatment to the pelvis in order to boost the parametria or nodes for patients with persistent disease after approximately 45 to 50 Gy ● When parametrial tumor persists ○ __________ Gy may be delivered to the parametria, with reduced anteroposterior/posteroanterior portals ■ 8 by 12 cm for unilateral ■ 12 by 12 cm for bilateral parametrial coverage

50 to 60

● Girinsky et al. ○ in 386 patients with stage IIB or III carcinoma of the cervix, also observed that the 10- year local recurrence-free survival rate decreased when OTT exceeded _____days. ○ A ____% loss of pelvic tumor control per day was also observed in their regression analysis

52 days 1.1%

Gardasil 9 ​for ​ages 9-45 (male and female)​, covers against

6, 11, 16, 18, 31, 33, 45, 52, and 58. ○ >70% caused by 16/18, while 19% are attributable to 31, 33, 45, 52, 58. ○ 6/11 MCC of warts. 16 SqCC, more common. 18 AC, more aggressive. ○ 3 injections over 6 mo, or 2 injections over 12 mo if < 15y. ○ Reduces lesions by 30%.

● Lower body mass index (BMI) ○ is correlated with an increase in toxicity ○ A total of 404 patients with stage IB1 cervical cancer with positive lymph nodes or stage IB2 or higher were treated from 1998 to 2008 ○ A BMI of _____ was associated with a decreased overall survival (HR = 2.37, P < .01). ○ Grade 3 and 4 complications appeared to trend higher; overall, 17% versus 14%; specifically, for fistula, 11% versus 9% (P = .05), for bowel obstruction, 33% versus 4% (P < .01), and for lymphedema, 5.6% versus 1.2% (P = .02)

<18.5

○ ses from the cylindrical mucosa of the endocervix or the mucus-secreting endocervical glands ● is the most common subtype ● may form mucosal glands lined by high columnar cells and produce tubular folds oriented in many directions ● In another subtype, cells resemble those of the intestines; the epithelium tends to be pseudostratifiedand may contain goblet cells ● The third variant ● which is rareand usually mixed with the endocervical or intestinal patterns

Adenocarcinoma Mucinous intestinal (?) Signet-ring cell adenocarcinoma

● Stockleet al. ○ performed laparoscopic lateral ovarian transposition during staging lymphadenectomy in 11 patients with carcinoma of the cervix treated with ■ brachytherapy (11 cases), EBRT (9 cases), and chemotherapy (2 cases). ○ Ovarian preservation was achieved in 30% of the cases. ○ ______ was the MOST PREDICTIVE FACTOR for ovarian function preservation

Age

● Whether circumcision may be protective to women is _______ ○ because circumcision may be a surrogate for unknown factors related to HPV transmission

CONTROVERSIAL

● Chemical, hormonal, or other carcinogens MAY BE implicated in cervical cancer ○ An association between cervical carcinoma and ORAL CONTRACEPTIVE USE has been reported but is considered ________ ○ Prenatal exposure to diethylstilbestrol (DES) ■ linked to the development of _______ ■ although the overall incidence is small (0.14 to 1.4 per 1,000 DES-exposed women)

CONTROVERSIAL clear cell adenocarcinoma

● Perez et al. ○ quantitated the effect of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in 1,456 patients treated for cervical cancer with external beam irradiation plus two LDR intracavitary insertionsto deliver 70 to 90 Gy to point A ○ Median follow-up was 11 years ○ In stage IB, the frequency of grade 2 morbidity was 9%, and in grade 3, it was 5%; ○ in stages IIA, IIB, III, and IVA, the frequency of grade 2 morbidity was 10% to 12% and that of grade 3 was 10% ○ The MOST FREQUENT GRADE 2 urinary/rectal sequelae were ______________(0.7% to 3%) ○ The MOST COMMON GRADE 3 sequelae were:

CYSTITIS and PROCTITIS ■ vesicovaginal fistula (0.6% to 2% in patients with stage I to III tumors), ■ rectovaginal fistula (0.8% to 3%), ■ intestinal obstruction (0.8% to 4%)

Radiation proctitis (types, treatment)

Chronic radiation proctitis: tricks to prevent and treat [​Vanneste Int J Colorectal Dis '15] o ○ Three types: Inflammation predominant, Bleeding predominant, mixed. § Bleeding predominant most common form. § Likely to resolve with time. o ○ Bleeding predominant § First, optimize bowel fxn and stool consistency. § Start ​Vit A/E/C​ or ​Metronidazole​. § ● Vit A 10,000 IU,Vit E 400 IU TID,Vit C 500mg TID. § ○ May have cytoprotective effects by reducing oxidative stress. § ○ 90 day course! (E and C used for a year) § ● Metronidazole 400 mg TID. § ○ Effective due to immune modulator effects and selective toxicity to microorganisms that contribute to pathogenesis of CRP. § ○ 30 day course! § If bleeding effects QoL, ​Sucralfate enema​: 2g BID and consider holding OAC. § ● Aluminum salt that adheres to mucosal cells and stimulated PG production, producing cytoprotective effects. § ● 30 day course! 77% improvement of bleeding by two grades. § Discuss​APC​, ​formalin​, ​HBO​ (if accessible) if persistence of symptoms, but discuss iatrogenic problems. § APC considered tx of choice. Rectal ulcers after APC in 26%,with one series up to 52% o ○ Inflammation predominant § ■ Loperamide, fibers, stool bulking agents, corticosteroids. § ● Rectal betamethasone 5 mg BID vs. rectal hydrocortisone 90 mg BID with potential symptomatic improvement with the latter.

● If pap reveals ASCUS​: ​ ● If pap reveals LGSIL ​(CIN 1):​ ● If pap reveals HGSIL ​(CIN 2/3, CIS, ASCUS-H): ​

Colposcopy if HPV+​, otherwise repeat Pap​ 6-12​ ​mo​ ○ ASCUS resolves ~70% of the time, < 1% progress to invasive. Colposcopy if age 25-29 or HPV+​, otherwise repeat Pap​ 6 mo​. ○ LGSIL resolves ~50% of the time, 5% progress to invasive. Do colposcopy and LEEP/conization​ ○ HGSIL: > 20% progress to invasive, so go straight to colpo.

● Neoadjuvant chemotherapy plus surgery ___________ survival over surgery alone

DOES NOT IMPROVE ● In a meta-analysis of six trials ○ although there was an improvement in PFS with neoadjuvant chemotherapy(HR = 0.76, 95% CI = 0.62 to 0.94, P = .01) ○ this did not translate into an overall survival benefit

● Injury to the GI tract usually appears within the _________ after radiation therapy ○ whereas complications of the URINARY tract are seen more frequently ________after treatment

FIRST 2 years 3 to 5 years

Cell Cycle and Cellular Oncogenes in cervical cancer ● Oka et al. ○ studied 202 biopsy specimens obtained from 77 patients with squamous cell carcinoma of the cervix before and during RT for expression of p27 and p53 proteins. ○ A high p27 LI before radiation therapy was associated significantly with _________ ○ A high p53 LI before irradiation was associated with _________

GOOD disease-free and metastasis-free survival rates POOR overall survival.

SMALL CELL CARCINOMA OF THE CERVIX ● Small cell carcinoma of the cervix, like its counterparts in the lung and other anatomic locations ○ has a ______________rate and marked propensity for regional lymph node and distant metastases

HIGH PROLIFERATION

● Chemical, hormonal, or other carcinogens MAY BE implicated in cervical cancer ○ Cigarette smoking ■ may increasethe risk of cervical cancer ■ However, passive smoking may not be an independent factor in the absence of active smoking ■ A review of >50 studies considers smoking a cofactor for HPV infection and carcinogenesis, although one study does not confirm this. ○ Current smoking (relative risk [RR] = 1.55) and younger age at HPV exposure (RR = 1.75) ■ are considered risk factors among ______ women ○ Intrauterine device use ■ may ______ cervical cancer risk, potentially through an increase in cellular immunity triggered by the device.

HIV-POSITIVE DECREASE

● HPV-16 and HPV-18 are the MOST FREQUENT HPV subtypesworldwide ● Studies have reported a HIGHER RISK of lymph node and other distant metastases with HPV- compared to HPV-

HPV-18 compared to HPV-16.

● In a comparison of 20 patients with lumbosacral plexopathy after irradiation and 30 patients with plexus damage from pelvic malignancy, Thomas et al. ○ noted that _________ occurred early in radiation-induced plexopathy (pain occurred initially in 10% of patients, although ultimately it was present in 50%) ○ whereas _______ was most frequently associated with tumor plexopathy ○ Muscular weakness, numbness, and paresthesia are common in both groups. ○ Electromyography showed abnormal myokymic discharges in 57% of patients, whereas this finding was very unusual in tumor-induced plexopathy ○ CT is extremely helpful in the detection of pelvic masses or bone destruction caused by tumor ○ The authors also reported extensive retroperitoneal fibrosis of the lumbosacral plexus in two patients and femoral nerve fibrosis with plexopathy in one patient.

INDOLENT LEG WEAKNESS PAIN

Treatment of recurrent disease

If further RT or surgery is being planned, no more than 2-4c of combination chemo should be given to avoid unnecessary delay before definitive salvage.

CCRT Overview ○CCRT for IB2 to IVA based on the results of 6 trials: CCRT reduces risk of death ____%vs. RT alone. Early stage disease: Several RCTs evaluated the utility of CMT, some included IB2-IIA. Most w OS advantage, except NCIC. There is no RCT for CCRT in IB1 or below. ● Meta​ [​Chemo for Cervical Cancer Collaboration JCO '08​]: ​RT alone vs. CCRT​.CCRT = ____% improvement in 5y OS​ with HR 0.81.

Keys (GOG123), Rose, Bundy (GOG 120), Morris (GOG 9001), Whitney (GOG 85), Peters (SWOG 8797) 30-50% 6%

LACC​ [​Ramirez NEJM '18​]:

LACC​ [​Ramirez NEJM '18​]: Phase III noninferiority. ​Open vs. minimally invasive surgery​. ● 740 pts with IA1 + LVSI or IB1 (92%). 84% laparoscopic, 16% robotic assisted. ● 5y DFS 96→ 86%, 3y DFS 97→ 91%.(LRR also higher for MIS)Almost 4x recurrences or deaths7→ 27 pts, 6x deaths 3→ 19 pts. ● 3y OS 99→ 94%. ○ Risk of lymphedema after LND ~25%​ regardless of if robotic.

● PET scanning is increasingly used in the evaluation of patients with malignant neoplasia, including invasive cervical cancer, using 2-[18F]-fluoro-2-deoxy-Dglucose (FDG). ● Rose et al. ○ observed uptake in 91% of the primary tumors in 32 patients with locally advanced carcinoma of the cervix. ● Squamous cell carcinoma is ________ FDG avid than is adenocarcinoma. ● Compared with surgical staging, PET scanning had a sensitivity of ____% and a specificity of ___% in detecting para-aortic metastasis. ● Care must be taken in interpretation because physiologic FDG excretion into the urinary bladder may result in false-positive assessment of the primary tumor, and ureters may be contoured as lymph nodes

MORE OFTEN sensitivity of 75% and a specificity of 92%

●acts as an alkylating agentand inhibits DNA and RNA synthesis ● Activation is increased in hypoxic conditions, and thus, it acts as a HYPOXIC SENSITIZER ● Interstitial pneumonitisand pulmonary fibrosisare usually related to the dose of drug. ● Use of IV dexamethasone before administrationof the drug may prevent pulmonary toxicity.

Mitomycin C

● Several small phase II studies have been performedshowing ○ ________ to weekly paclitaxel over weekly cisplatin ○ _________ with concomitant cisplatin-paclitaxel ● Concurrent weekly carboplatin ALONE

NO ADVANTAGE too high toxicity ○ has been shown in many studies to be feasible including in the elderly; ○ it is also an alternative in patients that have an elevated creatinine

● Thomas ○ summarized the rationale and potential limitations of neoadjuvant chemotherapy in carcinoma of the cervix ○ Although response rates to the chemotherapy are between 30% and 85%, ___________

NONE OF THE STUDIES SHOWED AN ADVANTAGE for pelvic tumor control or survival

● Stereotactic body radiotherapy (SBRT) in cervical cancer ○ uses highly conformal treatments with large fraction sizes ○ in selected cases has been considered for a nodal boost of an isolated para-aortic node ○ although care must be taken to treat the entire paraaortic chain to 45 Gy with IMRT or 4 Field (4F) prior to considering an SBRT boost in order to ensure eradication of adjacent micrometastatic disease ○ SBRT should ________

NOT BE USED instead of brachytherapy, given the significant increase in normal-tissue doses with SBRT compared to brachytherapy

● Recombinant human erythropoietin is _________ as an alternative means of sustaining or raising hemoglobin levels during radiation therapy

NOT ROUTINELY recommended Thrombotic complications and the lack of any survival benefit mitigate the utility of this as a therapeutic intervention.

● Loncaster et al. ○ in a retrospective study of 100 patients ○ found that VEGF expressionin tumor biopsies in advanced carcinoma of the cervix was associated with a _____ ● Level of thymidine phosphorylase ○ which increases hypoxic conditions ○ similarly was associated with ______ ● Nitric oxide synthase and carbonic anhydrase (CA) ○ may be prognostic for a poor outcome ■ CA9 is related to ________ ■ CA12, in contrast, was related to _________ ● Microvessel count ○ is higher in patients with cervical neoplasiathan in control patients and higher in patients who experience posttreatment recurrences

POOR PROGNOSIS poor outcomes poor DFS metastasis-free survival

● has been used for en masse removal of the pelvic viscera for recurrent carcinoma of the cervix ● Modern radiation therapy with concurrent chemotherapyresults in high complete response rates and has maderesidual extensive diseasea RARE indication

Pelvic Exenteration ● Patients with adjacent organ invasion are given a course of radical concurrent chemoradiation, followed by interstitial brachytherapy ○ with exenteration reserved for SALVAGE

Brachytherapy Dose Specification

Point based planning ● Point A ​(where uterine artery and ureter cross): In plane of tandem, 2 cm superior and 2 cm lateral to external os. ● Point B ​(parametrium/obturator): 5 cm lat to midline. Receives ~25-33% of Point A dose. ● Point C ​(sidewall): 6 cm lat to midline. Receives 20% of Point A dose. ● Bladder point​: Posterior surface of Foley on lat and center of balloon on AP. Fill w 7cm3​ ​, pull down against the urethra. ○ Without 3D, a point located 1.5 cm above ICRU bladder may be more representative of bladder dose. ● Recto-vaginal point​: 5 mm dorsal of post vaginal wall at intersection between tandem and mid-source position, resembles rectum and upper vagina (previously thought upper vagina to tolerate 120 Gy, now we limit this point to < 65 Gy). ● Vaginal point​: Lateral edge of ovoid/ring on AP film and mid-ovoid/ring on lateral film (Vs) and 5mm deep (Vd). ○ Vd is the same as recto-vaginal point, while Vs is surface vaginal dose. ● Tandem loading: usually ​15-10-10​ mgRaeq to ensure dose to lower uterine segment. ○ Small ovoids typically 10-15 mg Raeq. ○ Mini ovoids with 5-7.5 mg Raeq because they lack internal shielding. ● ABS review​ [Brachy '17]: ​Point based planning inferior to 3D​. Literature review of HDR BT. Pts treated w CCRT and 3D HDR BT had improved pelvic control and DFS compared to pts treated w Point A specifications. ● French STIC study​ [​Charra-Brunaud RTO '12]​: Prospective. ​Point A vs. CT-based planning​. 3D-BT is feasible and safe, with improved OS and toxicity compared to point based planning. ○ 705 pts. Stage IB-IIIB. Group I: BT→ Surgery. Group II: CCRT/BT→ Surgery.Group III: CCRT/BT. ○ 2ylocalRFSforgroup1ofc3○ 92→ 100%, group 2 of 85→ 93%, and group 3 for 74→ 79%. ○ G3-4 toxicity for group 1 of 15→ 9%, group 2 of 13→ 9%, and group 3 of 23→ 3%.

● For LDR, insertion of the applicator may be done after all external beam finishes, with the caveat that one or two insertions may be required, approximately 1 week apart ● All treatments, including external beam treatment and brachytherapy, should finish 8 weeks from the initiation of radiation ● The optimal time-dose-fractionation scheme and the technique for remote control afterloading intracavitary brachytherapy for cervical cancer have yet to be established through systematic clinical trials ● For HDR or PDR brachytherapy, the applicator insertion and treatment may commence AFTER external beam treatment finishes, to ensure optimal geometry with normal tissues far from the applicator ● Alternatively, the physician may choose to insert the applicator for treatment as early as during the ______________ of external radiation if the tumor is small enough, to minimize total treatment time ● However, brachytherapy and external beam treatments are not given on the same day.

SECOND WEEK

True or False ● The 5-year survival rate for carcinoma of the cervical stump treated with irradiation is SIMILAR to that reported for patients with carcinoma of the intact uterus ● The anatomic sites of failure and the incidence of recurrences are SIMILAR to those of patients in whom the uterus is intact ● Distant metastases also follow the same distribution (SIMILAR).

TRUE

Brachytherapy Process: Preparation and Timing

Technique​:​ ​ABS I​ ​[Viswanathan BT '12] ○ First insertion 4-6 weeks after initiation of RT with completion of therapy by 8 weeks. Trying to give enough time for tumor response, but minimize contraction of upper vagina. Start treatments based on tumor response (often at) week 4 once per week, then two fractions the last week, however, other fractionation of twice weekly or all after beam possible. ○ In OR, anesthesia. ​Dorsal lithotomy​. ○ EUA​, bimanual noting residual nodularity, cervix size, and size of fornices. ○ Place ​foley​, balloon filled with 7cc 30% renograffin, empty bladder. ○ Sound uterus​. Select tandem (60 degree most common, or 30, 45 based on sounding). If the sound does not insert uterus easily, ultrasound may help guide and confirm correct placement. Dilate os. Suture in ​smit sleeve​, based on sounding. No need to dilate os if smit sleeve is in place. ○ Place flange on tandem,​ insert tandem​ with flange flush against os/sleeve. Tenaculum on cervix for countertraction. Perforation usu occurs in posterior cervix but may also occur at fundus. Be sure to ​inspect flexion of uterus​ (anteversion, retroflexion) to help prevent perforation. If perforation occurs, reposition the applicator before treatment and give TMP/SMZ. The less angled the tandem, the more likely there will be a higher dose to sigmoid above rectal packing. ○ Remove speculum.​ Select ovoids​ with largest/snug fit. ○ Lock all 3 into place, maximize ovoid separation, and tighten screw to fix geometry. ■ External fixation​ devices: Fixation to table, a perineal bar or a "brachy board" (base plate and clamp). ○ Place packing ​ant and post, impregnated with diluted KY contrast.■ Consider starting with packing posteriorly, as anterior rectum wall has lower tolerance. ○ Take fluoro, AP-lat to ​verify adequate implant​:■ Tandem bisects ovoids on AP and lateral​ and point away from sacrum, > 3 cm away from sacrum. ● Avoid tandem too close to sacrum, as could lead to increased sigmoid toxicity. ■ Ovoids overlap on lateral film ​and not be displaced from flange. ● Flange flush with cervix (< 1 cm from marker seeds).■ Tandem 1⁄2 to 1⁄3 of the distance between the symphysis and sacral promontory, no packing sup to ovoids. ● No superior packing so ovoids flush in high fornices. ■ Implant quality matters​ [​Viswanathan IJGC '12]​: ● MFU 2y. Reviewed BT records. Higher LR with unacceptable geometry:

CARCINOMA OF THE CERVIX AND PREGNANCY true or false ● Survival is the same REGARDLESS of the trimester of the pregnancy in which definitive treatment is instituted

True

TRUE or FALSE ● Studies of external beam treatment as an alternative boost instead of brachytherapy demonstrate significantly INFERIOR SURVIVAL rates compared to those that use brachytherapy

True

True or False ● With IMRT, there is a need for replanning because of rapid tumor regression and an increase in integral dose, with normal tissues throughout the pelvis receiving more radiation than with brachytherapy ● Given the large movement and the increased dose to the normal tissues resulting in an increase in normal-tissue toxicity, highly conformal (IMRT, IGRT, SBRT) methods for boosting the cervix are NOT ROUTINELY recommended

True

True or False in cervical cancer ● Mixed beam external radiation with neutrons and photons resulted in unacceptably high toxicity rates and is NOT RECOMMENDED ● Similarly, carbon ion therapy was reported but resulted in MAJOR INTESTINAL complications

True

True or False: ● Miller et al. ○ demonstrated that all small cell carcinomas of the cervix are aneuploid, compared with only 30% of large-cell nonkeratinizing squamous carcinomas ○ The incidence of lymphatic vascular space invasion is 80% to 90%, and that of lymph node metastases has been reported to be 40% to 67%

True

True or False: ● Rectal contrast and placement of a Foley catheter for bladder contrast are NOT CONSIDERED NECESSARY in the majority of cases that use CT simulation because the outer wall of these normal-tissue structures can be contoured without contrast on CT.

True

True or False: ● The CT contours of the cervix OVERESTIMATE the tumor contours compared to an MRI, ○ although the additional width contoured on a CT may not be of detriment to the patient because cervical cancer tends to spread laterally along the parametrial tissues

True

True or False: ● The choice of definitive irradiation or radical surgery for stage IB and IIA carcinoma of the cervix remains controversial ○ the preference for one procedure over another depends primarily on the impact on the patient's fertility and on the institution, the gynecologic oncologist or radiation oncologist involved, the general condition of the patient, and characteristics of the lesion ● An operation has been preferred by some in young women to preserve the ovaries, attempting to prevent premature menopause ● However, in some reports, ovarian function preservation has been observed in only 50% to 60% of surgically treated patients not receiving irradiation ● Postmenopausal patients may have a survival benefit with chemoradiation and avoid the operative risks ● When therapeutic results in invasive carcinoma of the cervix are evaluated, a direct comparison of surgically treated or irradiated patients is fraught with many uncertainties, including patient selection, reporting of surgical cases using staging determined by laparotomy findings, and different treatment techniques. ● In particular, in the modern era when concurrent chemoradiation is known to be superior to radiation alone, a direct comparison of chemoradiation versus surgery in early-stage cervical cancer is needed. ● Surgery provides an opportunity for a thorough pelvic and abdominal evaluation ● However, surgical staging has NOT BEEN SHOWN to improve overall patient survival

True

True or False: ● Unfortunately, as in radiation myelopathy, the neurologic deficit is IRREVERSIBLE, and no effective therapy other than supportive care has been found.

True

True or False: ● When the depth of penetration of the stroma by tumor is <3 mm, ○ the incidence of lymph node metastasis is 1% or less, and a lymph node dissection or pelvic external irradiation is not warranted

True

True or False: ● With 2D imaging, the ICRU 38report requires only reporting point estimatesfor the rectumand bladderbecause the sigmoid cannot easily be visualized ● However, the ICRU bladder point may UNDERESTIMATE maximum doses to the OAR, in particular for the bladder; it is LESS LIKELY that rectal doses will be incorrectly estimated. ● Numerous publications correlate the ICRU point dose and the probability of late complications for bladder and rectum.

True

True or False: ● Postsurgical complicationsare usually MORE AMENABLE to correction than are late complications after irradiation.

True

True or false ● Squamous cell carcinoma accounts for 80% of cervical cancers, adenocarcinoma for 15%,and adenosquamous carcinoma for 3% to 5% ● SEER data from 1972 to 2002 suggest that the incidence of cervical adenocarcinoma is rising, but based on SEER data, cause-specific mortality is NOT SIGNIFICANTLY DIFFERENT than that for SCC ● Despite a slower regression after irradiation, reflecting cellular kinetics and slow growth ○ NO DIFFERENCE in tumor control or survival has been observed in adenocarcinomas compared with squamous cell carcinomas although prognosis is related to clinical stage, volume of disease, and dose of irradiation

True

True or false in cervical cancer: ● Complication risk may be HIGH (Table 73.9), particularly when patients are treated with POSTRESECTION RT ● One study showed an 11.5% incidence of major primarily small-bowel complicationswith transperitonealcompared with 3.9%in the extraperitoneallymphadenectomy group (P = .03).303 ● **Transperitoneal lymphadenectomy SHOULD BE AVOIDED. ● Because of a HIGH RATE of complications, preirradiation laparotomy was DISCONTINUEDat the MD Anderson Cancer Center

True

True or false? ● NO DEFINITE conclusions can be drawn concerning the use of hyperbaric oxygen in carcinoma of the cervix ● It is possible that hyperbaric oxygen administered with fewer high-dose fractions may be more efficacious than when combined with conventional dose and fractionation schemes. ● The trials reported have not shown an increased incidence of distant metastasis, which has been observed in a clinical study and in some animal experiments

True

True or false? In cervical cancer, ● Exploratory laparotomy and nodal staging to evaluate the presence of metastases to the pelvic or para-aortic nodes ○ may provide diagnostic information ○ but has NOT HAD a demonstrated impact on survival (Table 73.8)

True

● The definition of microinvasive (stage IA) carcinoma of the cervix includes invasive carcinoma diagnosed only by microscopy ● Conization is MANDATORY for a more accurate diagnosis ● According to Kolstad ○ lesions <1 mm in depth can be treated with conization, provided all margins are tumor-free and continued careful follow-up is instituted ● ___________ may be a MORE RELIABLE criterion than depth of invasionto arrive at a definition of stage IA ● ___________ DOES NOT IMPACT stage

Tumor volume in the stroma Vascular space involvement

● Intra-arterial infusion of chemotherapeutic agents in cervical carcinoma was used for some years based on the distinct arterial supply to the tumor-bearing area Unfortunately, the responses have been __________, and the toxicity and complication rates have been significant

UNCOMMON AND SHORT

● Intra-arterial infusion of chemotherapeutic agents in cervical carcinoma was used for some years based on the distinct arterial supply to the tumor-bearing area ● Unfortunately, the responses have been _________, and the toxicity and complication rates have been ___________

UNCOMMON AND SHORT significant

MC major sequelae for St IB

Vaginal stenosis

· General treatment recommendations o Surgery for IA, IB1 and selected IIA1 § Less commonly, HDR alone (5.5 Gy x 4 fx). o ● IA1​: o ● IA2​: o ● IB1-IIA1 o ● IB2 or IIA1​: o ● IB3+:

Without LVSI, IA1 has extremely low LN mets. Less than 3 mm invasion has < 1% chance of nodal mets. § ○ Conization is curative​ unless LVSI or SM+. Prefer​ 3 mm​ margins without LVSI or SM+. § ○ If LVSI, TAH vs. radical trachelectomy​ (if ≤ 2 cm) ​+ PLND vs. RT alone ± pAO​. Higher chance of LN metastasis. Less than 5 mm invasion has ≤ 8% of LN metastasis. Double that if LVSI. § ○ For fertility preservation, add LND to conization or trachelectomy​. § ○ At least Type B/MRH ​(to ureters) ​+ PLND ± pAO sampling​→ risk stratified RT ± CT. § ○ Follow up after fertility preservation: Pap q3 mo pap x2y, then q6m x3y, then routine screening. (non-bulky)​: RH preferred due to wider margin of resection: paracorpos, upper vagina, nodes ± pAO. § At least Type C/RH ​(to side wall) +​ PLND ± pAO sampling​→ risk stratified RT ± CT. § Post-op WPRT​ [​Sedlis​]: For IB1-IIA1 (non-bulky).SeDLis criteria: ​S​ize ≥ 4 cm (bulky), ​D​epth middle/outer third, ​L​VI. § If two of three ​S​e​DLi​ s criteria met→ postop WPRT alone (no chemo). § EBRT 45/25 (boost R2 nodes 10-20 Gy) ± CDDP. § Post-op CCRT​ [​Peters​]: If positive margins, >4cm (IIA2), positive LNs, or parametrium (IIB). § EBRT 45 Gy + CDDP ± BT 6 Gy x 3 to vaginal surface (Peters paper didn't do brachy). § ○ Would add brachy for positive/close vaginal mucosal margins, can consider for surprise IIB or high risk histology. § Definitive RT​ (​80-85​ Gy to point A) ± concurrent chemo. § Generally speaking, favor RH + PLND for non-bulky, CCRT for bulky, as they'll get RT. § RT alone: Surgery preferred in younger pts to preserve ovarian fxn and prevent vaginal stenosis § Very small IB1 (< 1 cm) may rec ICBT alone in non-operable, bring Point A to 65-75 Gy. Either surgery or RT can be considered as equivalent outcomes. This is new IB2, or 2-4 cm. § ○ Get a PET scan to r/o extrapelvic disease. § ○ Bulky disease: Definitive CCRT (​≥ 85​ Gy to point A). CCRT​, though select/limited IIB may be candidates for RH/Type C. Around 80% of IB3/IA2 need PORT. ○ GOG 71 with no benefit of adjuvant hysterectomy after RT alone except in case of residual disease.

● The main areas of side effects because of radiation are

bowel, bladder, skin, and sexual function

● The spinal cord dose (T12 to L2-L3) should be kept to ○ <45 Gy ○ Done by:

interposing a 2-cm-wide 5-half-value-layer shield on the posterior portal (usually after 40-Gytumor dose) or using lateral ports and limiting the kidney dose to <18 Gy

Treatment for stage IA

o Surgery for IA, IB1 and selected IIA1 § Less commonly, HDR alone (5.5 Gy x 4 fx). o ● IA1​: Without LVSI, IA1 has extremely low LN mets. Less than 3 mm invasion has < 1% chance of nodal mets. § ○ Conization is curative​ unless LVSI or SM+. Prefer​ 3 mm​ margins without LVSI or SM+. § ○ If LVSI, TAH vs. radical trachelectomy​ (if ≤ 2 cm) ​+ PLND vs. RT alone ± pAO​. o ● IA2​: Higher chance of LN metastasis. Less than 5 mm invasion has ≤ 8% of LN metastasis. Double that if LVSI. § ○ For fertility preservation, add LND to conization or trachelectomy​. § ○ At least Type B/MRH ​(to ureters) ​+ PLND ± pAO sampling​→ risk stratified RT ± CT. § ○ Follow up after fertility preservation: Pap q3 mo pap x2y, then q6m x3y, then routine screening.

Treatment of Stage Ib to IIA

o ● IB1-IIA1 (non-bulky)​: RH preferred due to wider margin of resection: paracorpos, upper vagina, nodes ± pAO. § At least Type C/RH ​(to side wall) +​ PLND ± pAO sampling​→ risk stratified RT ± CT. · Post-op WPRT​ [​Sedlis​]: For IB1-IIA1 (non-bulky).SeDLis criteria: ​S​ize ≥ 4 cm (bulky), ​D​epth middle/outer third, ​L​VI. o If two of three ​S​e​DLi​ s criteria met→ postop WPRT alone (no chemo). o EBRT 45/25 (boost R2 nodes 10-20 Gy) ± CDDP. · Post-op CCRT​ [​Peters​]: If positive margins, >4cm (IIA2), positive LNs, or parametrium (IIB). o EBRT 45 Gy + CDDP ± BT 6 Gy x 3 to vaginal surface (Peters paper didn't do brachy). § ○ Would add brachy for positive/close vaginal mucosal margins, can consider for surprise IIB or high risk histology. § Definitive RT​ (​80-85​ Gy to point A) ± concurrent chemo. · Generally speaking, favor RH + PLND for non-bulky, CCRT for bulky, as they'll get RT. · RT alone: Surgery preferred in younger pts to preserve ovarian fxn and prevent vaginal stenosis · Very small IB1 (< 1 cm) may rec ICBT alone in non-operable, bring Point A to 65-75 Gy.

MC major sequelae for St IIB

proctitis/ cystitis

Rule of 15 and rule of 10 in cervical cancer

see ROR

Recommended brachytherapy doses

see RadOnc Copper

● Analysis of the LDR and HDR brachytherapy positions for 103 patients enrolled on RTOG trials 0116 and 0128 ○ found that patients withunacceptable symmetry of ovoids to the tandem had a ○ Patients with displacement of ovoids in relation to the cervical os had a significantly ___________(HR = 2.50; 95% CI = 1.05 to 5.93; P = .04) and a _________(HR = 2.28; 95% CI = 1.18 to 4.41; P = .01) ○ Inappropriate placement of packing resulted in a __________(HR = 2.06; 95% CI = 1.08Y3.92; P = .03).

significantly HIGHER risk of LRthan patients in the acceptable group INCREASED risk of LR; LOWER DFS rate LOWER DFS rate

● A four-arm comparison of cisplatin/paclitaxel versus cisplatin/vinorelbine, cisplatin/gemcitabine, or cisplatin/topotecan ○ found that the ________remained the BEST option for patients with stage IVB, recurrent or persistent cervical carcinoma

standard arm of CISPLATIN/PACLITAXEL

Roughly what percent reduction in mortality has been achieved with pap screening for cervical cancer?

~70%

Cost-Effectiveness of LDR Versus HDR Brachytherapy

· LDR vs. HDR no different​: No RCT compared HDR vs. LDR for cervical cancer subpopulations (NCIC data suggests no difference; meta-analysis suggests HDR less toxicity). o ○ LDR: Manual afterloading Cs-137. PDR: Remote afterloading Ir-192 ~4 kU (1 Ci) vs ~42 kU (10 Ci) as for HDR. o ○ Whereas LDR < 2 Gy/h (usu 0.4-0.8 Gy/h), HDR > 12 Gy/h.

Volume-based Brachytherapy target volumes

· ● GTV​B​ = ​GTV at time of BT​, GTV​D​ at diagnosis. · ● HR-CTV​B​ = GTV​B​ + cervix + presumed extracervical extension at time of BT​. o ○ Superior border of cervix ≥ 1 cm above uterine vessels or where uterus begins to enlarge. o ○ If CT alone, may use height ~3 cm for cervix with caveat that CT planned cases should tx entire length of tandem, as difficult to determine sup extent of dz [​Viswanathan IJROBP '14​]. · ● IR-CTV​B​ ​= HR-CTV​B​ + 5-15 mm and initial extent of disease.

● Coughlinand Richmondand Douple ○ suggested two mechanisms for radiation enhancement by cisplatin: ● It is important, however, that patients complete the full course of 45 Gy with, ideally

■ (a) in hypoxic or oxygenated cells, free radicals with altered binding of cisplatin to DNA are formed at the time of irradiation, and ■ (b) interaction inhibits repair of sublethal damage. ○ five to six weekly doses of cisplatin or ○ two doses of cisplatin and 5-FU every 3 weeks

● Huanget al ○ assessed 758 patients and found that 38 (5%) and 42 (6%) had isolated and nonisolated PALN recurrences after a median follow-up of 50 months (range, 2 to 159 months), respectively ○ The 3- and 5-year overall survival rate after PALN recurrence was 35% and 28%, respectively, with those with isolated recurrences faring better than those with a nonisolated recurrence (P < .001) ○ These wereindependent factors associated with PALN relapse on multivariate analysis: This group subsequently identified pretreatment CEA of _______ as an additional risk factor of PALN relapse after definitive concurrent chemoradiation therapy (CCRT) for SCC of the uterine cervix

■ An SCC-Ag level of >40 ng/mL (P < .001) ■ advanced parametrial involvement (score 4 to 6; P = .002) ■ the presence of pelvic lymphadenopathy (P = .007) ≥10 ng/mL

Cyclooxygenase-2 in cervical cancer

■ COX-2 stainingintensity was found to CORRELATE positively with tumor SIZE(P = .022). ○ found COX-2 expression MORE FREQUENTLY in the adenocarcinomagroup (57% vs. 24%; P = .007) ○ The 5-year survival rate was 83% for COX-2-negative and 57% for COX-2-positive patients, regardless of histologic subtype (P = .001) ○ also showed that expression of COX-2and coexpression of COX-2 and thymidine phosphorylasewere correlated with HIGH LOCOREGIONAL recurrence and LOWER SURVIVAL

● For MR-based contouring, the Groupe Europeen Curietherapy-European Society for Therapeutic Radiation Oncology (GEC-ESTRO) guidelines delineate volumes for MR ● The recommended volumes include the: ○ GTV, including all T2- bright areas of enhancement; ○ the HR-CTV, which is the: ○ intermediate-risk clinical target volume (IR-CTV):

■ entire cervix ■ any regions of high to intermediate signal intensity in the parametria ■ uterus, or vagina, and ■ any residual disease detected on clinical examination at the time of brachytherapy; ■ which subtracts out the OARs but includes the tumor extension at the time of diagnosis, adding 1 cm to the HR-CTV volume ■ The IR-CTV defines regions with potential microscopic seeding of tumor cells (Fig. 73.24)

● Parkin et al. ○ reported a 26% incidence of severe urinary symptoms (urgency, incontinence, and frequency) in patients treated with irradiation alonefor cervical carcinoma ○ They carried out urodynamic studies in 42 women and compared them with 28 women having urodynamic evaluations before and after treatment. ○ There was NO DIFFERENCE in the two groups: ○ However, these were significantly lower in the postirradiation groupthan in the pretreatment group: This same dysfunction may be noted in approximately 10% of the general female population, and the incidence increases in older women

■ mean maximum flow rate or ■ mean residual volume ■ mean volume of full bladder sensation ■ mean maximum cystometric capacity

● If high- or intermediate-risk features are present: ○ (i.e., presence of positive lymph nodesor positive margins) after a trachelectomy

■ radiation should be performed without requiring a completion hysterectomy ■ Leaving the uterus intact results in less small-bowel dose; ■ radiation or chemoradiation followed by image-based brachytherapy with an attenuated dose based on amount of residual disease in the uterus is feasible in order to minimize bladder and rectal dose

● In the RTOG postoperative clinical trial 0921 using IMRT (dose constraints for OARs)

■ the small/large bowel (30% of the entire bowel volume must not receive >40 Gy) ■ rectum/sigmoid (60% of the rectosigmoid volume must receive ≤40 Gy), ■ bladder (35% of the bladder volume must receive ≤45 Gy) ■ femoral head (15% of the femoral head volume must receive <35 Gy)

● Symonds et al., in a review of seven randomized trials, found NO EVIDENCE to support the use of hydroxyurea with RT in cervix cancer ● In larger randomized trial by the GOG reported by Stehmanet al.

○ 296 surgically staged patients with stage IIB to IVA disease and negative para-aortic nodes were randomized to: ■ irradiation pluseither hydroxyurea(139 patients) or misonidazole(157 patients). ○ Survival was NOT STATISTICALLY DIFFERENT between the regimens, with 33.8% deaths in the hydroxyurea group and 38.9% deaths in the misonidazole group (P = .25). ○ Failure limited to the pelvis occurred in 18% of patients in the hydroxyurea group and 23.6% in the misonidazole group

URGENT BLEEDING AND PALLIATIVE IRRADIATION ● Patients who present with a new diagnosis ○ may be treated with: ● A single LDR intracavitary insertion with tandem and colpostats for approximately _________ may be used for palliation ● If irradiation was delivered previously, lower intracavitary doses should be prescribed: ______________

○ 3 to 4 Gy for two or three fractions ○ followed by standard 1.8 Gy to approximately 39.6 Gy and then brachytherapy. ○ 6,000 mgh (55 Gy to point A) ○ 4,000 to 5,000 mgh

● In GOG 123 (Keys)

○ 369 women were enrolled ○ One hundred eighty-three women with bulky (≥4 cm) stage IB carcinomaof the cervix with negative pelvic and para-aortic nodes radiographically or surgicallydetermined were randomized to be treated with ■ pelvic EBRT and brachytherapy, followed by extrafascial hysterectomy, and ■ 186 received EBRT and brachytherapy with weekly cisplatin(40 mg/m2; total dose not to exceed 70 mg/week) followed by extrafascial hysterectomy ○ In an updated analysis with median follow-up of 101 months the 6-year PFSrate for women treated with ■ irradiation and cisplatinwas 71%, compared with ■ RT alone was 60%after adjusting for age and tumor size (P < .004) ○ The unadjusted 6-yearoverall survival rates were 78% and 64%,respectively (P < .015). GOG 123 ​[​Keys NEJM '99​, ​'07​]: ​RT alone vs. CCRT/CDDP→ Surgery ​in 3-6w. The addition of weekly cisplatin to preoperative radiation therapy for > 4 cm cervical cancer provides a LC and OS benefit. See [​GOG 71​] which suggested an OS benefit with preoperative RT alone for tumors > 4 cm prior to hysterectomy. -> Cons: Used relatively low dose of RT, protracted RT and no CCRT. ● ○ 370 pts. New IB3, old ​IB2​ (> 4 cm, new IB3). ○ 45 Gy EBRT→ 75 Gy Point A. ○ CDDP 40 q1w x6c→ Surgery at 3-6 weeks. ● ○ 3yOS74→83%,3yLR37→21%. ● ○ 5y PFS 60→ 71%, 5y OS 64→ 78%. ● ○ pCR 41→ 52%.

Postoperative External Beam Radiation Dose ● When metastatic pelvic lymph nodes are present, treatment has consisted of ● If gross residual diseaseis present, dose escalation to ● Patients with positive common iliac or para-aortic node metastases should receive ● If gross residual nodal disease is left, a nodal boostup to ● In patients for whom postoperative irradiationis indicated:

○ 45 Gy to the whole pelvisdelivered with a four-field technique with concurrent weekly cisplatin ○ 54 to 65 Gy, depending on small-bowel dose limits (e.g., D5cc < 55 Gy), may be considered with a sequential IMRT nodal boost ○ 45 Gy to the entire para-aortic region with the superior border covering the renal hilum, with consideration of a boost to the tumor bed ○ 65 Gy with IMRT is particularly suited to treat these patients ○ for deep stromal invasionin the cervix or close or positive surgical margins ○ an alternative is to deliver ■ 45-Gy pelvic external irradiation in combination with an intracavitary insertion (LDR, PDR, or HDR) and LDR equivalent dose of 65 Gy to the vaginal mucosa, using colpostats or a cylinder. ■ At some institutions, external irradiation alone (50 Gy to the midplane of the pelvis) with a four-field box technique has been used

● Although extremely RARE,lumbosacral plexopathyhas been occasionally reported in patients treated for pelvic tumors with doses of ● This syndrome was observed in 4 of 2,410 patients with cervical or endometrial carcinoma receiving

○ 60 to 67.5 Gy ○ 45 Gy to the PALNs (without spinal cord shielding) or ○ external pelvic irradiation (60 Gy to the parametria) and brachytherapy, with the lumbosacral plexus receiving total doses of ■ 70 to 79 Gy

● The goalsare to treat pointA to at least a total LDR equivalent of ● The pelvic sidewall dose recommendations are ● As with LDR BT, every attempt should be made to keep the bladder and rectal dosesto

○ 80 to 85 Gy for early-stage disease ○ 85 to 90 Gy for advanced-stage disease ○ 50 to 55 Gy for early lesions ○ 55 to 65 Gy for advanced ones ○ <100 Gy and 75 Gy LDR-equivalent doses, respectively

Brachytherapy in the Elderly ● Magné et al

○ Age DID NOT INFLUENCE the effectiveness of BT in elderly patients, and BT should be considered whenever possible, even in elderly patients presenting with a cervix cancer.

● With MR-planned brachytherapy, the most common dose-volume parameters reported for target structures of the entire cervix and any residual disease at the time of brachytherapy, the HR-CTV, are (based on the GEC-ESTRO recommendations):

○ D90 ■ defined as the dose received by at least 90% of the target volume ■ The cumulative D90 equals the sum of D90 values from the individual fractions plus the dose from a homogeneous 3D conformal external beam treatment ○ D100 ■ the minimum target dose, may be more sensitive to inaccuracies in contouring and dose calculation ○ V100 ■ assesses dose coverage of the whole target volume and is 100% when the entire target is covered by the prescribed dose ○ V150 and V200 ■ are often reported in interstitial brachytherapy

● For patients with para-aortic nodal involvement (borders)

○ Dose escalation to para-aortic nodes to approximately >45 Gy is not feasible with AP-PA fields, given potential bowel complications ○ The use of four fields, including AP-PA and two lateral fields, is implemented as an alternative to AP-PA alone as a way to reduce some of the dose to the anterior small bowel ○ Patients receive oral barium approximately 30 minutes before the simulation to ensure blockage of as much small bowel as feasible superiorly ○ The superiorborder covers the ■ renal hilum, often at the T12- L1 interspace ○ The inferiorborders cover the ■ obturator foramen, unless there is distal vaginal or inguinal node involvement. ● For the para-aortic portion of the field ○ the anterior border ■ rests 2 cm in front of the vertebral body or enlarged nodes as contoured ○ posteriorly, the border ■ bisects the midvertebral body

● A treatment planning report compared inversely planned EBRT with photons(IMRT/SBRT) and protons(IMPT) to 3D MRI-guided brachytherapy (Georg D, Kirisists et al)

○ EBRT was planned to deliver the highest possible doses to the PTV while respecting D2cc limits from brachytherapy, assuming the same fractionation ○ Volumes receiving 60 Gy(in equivalent dose in 2-Gy fractions) were approximately twice as large for IMRT compared with brachytherapy, and ○ the high central tumor dose was lower than that seen with brachytherapy ○ Both IMRT and protons were INFERIOR to 3D image-based brachytherapy.

Epstein-Barr Virus, Transforming Growth Factor, β-Integrin, and Other Markers ● β3 - integrin

○ Gruber et al. ■ in biopsies of 82 patients with cervical cancer ■ found that β3 - integrin was expressed in 50 (61%) and correlated it with HIGHER INCIDENCE of locoregional recurrencesand decreased survival.

● The ICRU in its Report 38defines brachytherapy dose rateas follows: ○ LDR? ○ medium dose rate (MDR) or PDR? ○ HDR? ● For LDR, the most commonly used isotope is _____ ● For PDRand HDR, it is _____

○ LDR, 0.4 to 2 Gy/hour; ○ medium dose rate (MDR) or PDR, 2 to 12 Gy/hour; ○ HDR, >12 Gy/hour ● For LDR, the most commonly used isotope is 144Cs ● For PDRand HDR, it is 206Ir.

● Genitourinary symptomssecondary to cystourethritis are ○ dysuria, frequency, and nocturia. ● The urine is usually clear, although there may be microscopic or even gross hematuria. ● These can can relieve symptoms:

○ Methenamine mandelate ○ antispasmodics such as phenazopyridine hydrochloride or ○ a smooth muscle antispasmodic such as flavoxate hydrochloride, hyoscyamine sulfate, oxybutynin chloride, or tolterodine tartrate

● ccasionally, a simple or total abdominal hysterectomy is performed and invasive carcinoma of the cervix is incidentally foundin the surgical specimen ● In general, extrafascial abdominal hysterectomy is NOT CURATIVEbecause the paravaginal or paracervical soft tissues and vaginal cuff are NOT REMOVED. ● Furthermore, it may be technically DIFFICULT to perform an adequate radical operation after previous simple hysterectomy ● If only MICROINVASIVEcarcinoma is found when a total or extrafascial hysterectomy with a WIDE cuff is performed ● If a less comprehensive resection was carried out ● In patients with FULLY INVASIVE tumor, therapy consists of

○ NO ADDITIONAL THERAPY is necessary for lesions with deeper stromal invasion; ■ at most, one or two vaginal intracavitary insertions to deliver a 65-Gy LDR mucosal dose (or 7 Gy × six fractions prescribed at the vaginal surface or 5 Gy at 0.5 cm × six fractions with HDR brachytherapy) to the vault are sufficient ○ it is critical that these patients receive radiation therapy immediatelywith or without concurrent chemotherapy ○ depending on the risk factors present pathologically when their postoperative status allows it ○ because the prognosis is worse if postoperative irradiation is not administered. ○ approximately 40 to 45 Gy to the whole pelvis with cylinder brachytherapy to the vaginal vault for an approximately 60-Gy mucosal dose ○ If there is gross tumor present in the vaginal vault or parametrium, the dose to the whole pelvis should be 45 Gy with concurrent weekly cisplatin chemotherapy, followed by an additional parametrial dose of 10 to 20 Gy ■ An intracavitary insertion should be performed ■ If there is gross residual tumor, an interstitial implant should be carried out to selectively increase the dose to this volume.

● What RT dose can cause ovarian failure? What about sterility?

○ Ovarian failure: 5-10 Gy ○ Sterility: 2-3 Gy

● Possible explanations for the discrepancy in resultsbetween the five US trials and the Canadian study were analyzed by Lehman and Thomas

○ Some theories include that a higher percentage of early-stage patients were accrued, who therefore had less of a difference in survival, given that the baseline survival rate for both arms was quite high; ○ and that treatment time was short for both arms, again minimizing the difference in improving survival in the chemotherapy arm ○ This was the smallest of the randomized chemoradiation trials, and although the HR was reduced, given the factors equalizing the two arms, a larger number of patients would have possibly shown a significant difference.

● Snijders-Keilholzet al.

○ The MOST IMPORTANT prognostic factor for survival and DFSwas ■ pelvic lymph node positivity

Hormonal Receptors in cervical cancer

○ The estrogen receptor status DID NOT CORRELATE with the local tumor control, disease-free survival, or CSS ○ The DISEASE FREE SURVIVAL RATE of PgR-positive patients was SIGNIFICANTLY HIGHER than that of PgR-negative patients(P = .044) ■ but PgR status was NOT STATISTICALLY SIGNIFICANT in relation to 5-year CSS or local tumor control.

CARCINOMA OF THE CERVICAL STUMP ● A supracervical hysterectomy, which removes the uterus and leaves the cervix behind, may be performed for BENIGN conditions of the uterus ● The use of subtotal hysterectomy has declined, given the persistent risk of cervical cancer arising in the remnant tissue and the difficulty of managing cancer of the cervical stump. It is important todivide carcinoma of the cervical stumpinto:

○ True ■ when the first symptom occurs 3 or more years after subtotal hysterectomy ■ significantly BETTER prognosis ○ Coincidental ■ when the symptoms are noticed before the third postoperative year ■ carcinoma was probably present when the hysterectomy was performed

● In 2007, after a consensus conference in Japan, a new classification system was released based only on the lateral extent of the resection. ■ with minimum resection of the paracervix medial to the ureter ■ minimal vaginal resection <1 cm ■ WITHOUT removal of the paracolpos (comprises the lower part of the Mackenrodts ligament covering the lower part of cervix and upper vagina)

○ Type A: Extrafascial hysterectomy

● In 2007, after a consensus conference in Japan, a new classification system was released based only on the lateral extent of the resection. ■ with PARTIAL resection of the vesicouterine and uterosacral ligaments ■ unroofing of the ureter ■ transection of the parametrial tissue at the ureter, and ■ removal of at least 1 cm of the vagina ■ This type is divided into:

○ Type B: Modified radical hysterectomy ● B1 ○ without removal of paracervical lymph nodes ● B2 ○ with removal of lateral paracervical nodes

● In 2007, after a consensus conference in Japan, a new classification system was released based only on the lateral extent of the resection. ■ variant in which the ENTIRE uterosacral and vesicouterine ligaments are removed ■ 1.5 to 2 cm of the vagina with paracolpos is excised, and neuronal preservation is critical

○ Type C: Classic radical hysterectomy

● In 2007, after a consensus conference in Japan, a new classification system was released based only on the lateral extent of the resection. ■ Includes the complete radical hysterectomy ■ resects tissues to the pelvis sidewall, including the hypogastric (internal iliac) vessels, and exposes the sciatic nerve (type 1).

○ Type D: complete radical hysterectomy Type D2 also removes the fascial and lateral muscles, called the laterally extended endopelvic resection.

● For the rectum, dose-volume constraints selected as a conservative starting point that have not yet been validated for 3D treatment planning include ● No dose constraint for external beam planning for the bladder could be identified, although the limits for prostate cancer may be adopted for gynecologic IMRT, including a dose constraint of:

○ V50 < 50% ○ V60 < 35% ○ V65 < 25% ○ V70 < 20%, ○ V75 < 15%. ○ no more than 15% of the volume to receive a dose >80 Gy ○ no more than 25% of the volume to receive a dose >75 Gy ○ no more than 35% of the volume to receive a dose >70 Gy, or ○ no more than 50% of the volume to receive a dose >65 Gy

● In the RTOG postoperative clinical trial 0921 using IMRT (dose prescriptions)

○ a PTV of 7 mm around the nodal contours is recommended, and the dose is prescribed to cover 97% of the vaginal PTV and nodal PTV ○ A volume of 0.03 cc within any PTV should not receive >110% of the prescribed dose ○ No more than 0.03 cc of any PTV will receive <93% of its prescribed dose Any contiguous volume of 0.03 cc or larger of the tissue outside the vaginal/nodal PTVs must not receive >110

● Based on the American Brachytherapy Society guidelines, vaginal cuff boost should be considered in patients with:

○ a less-than-radical hysterectomy ○ close or positive margins ○ large or deeply invasive tumors ○ parametrial or vaginal involvement ○ extensive lymphovascular invasion

● Early invasive carcinoma of the cervix (stage IA2)is usually treated with ● Inoperablepatients may be treated with

○ a total abdominal or modified radical hysterectomy or ○ in some cases with simple conization or radical trachelectomy ○ intracavitary radioactive sources ALONE with 6,500 to 8,000 mgh, 60 to 75 Gy to point A, in two LDR insertions, respectively, or ○ with the equivalent dose using HDR brachytherapy, approximately 10 fractions of 5 Gy per fraction

● Consideration of postoperative vaginal intracavitary brachytherapy after external beam therapyis recommended for patients with: ● If parametrial margins were close or positive, defined by either surgical clips or in the region of the surgical tumor bed

○ carcinoma at the vaginal margin of resection ○ an external beam dose of at least 54 Gy for close margins and higher for positive margins is recommended

● A 2005 update of a meta-analysis (by Green et al) of concomitant chemotherapy and radiation therapy found 24 trialsand concluded that

○ chemoradiation improves overall survival and PFS, whether or not cisplatin was used, with absolute benefits of 10% and 13%, respectively

● The French STIC trial

○ collected data from 20 centers prospectively and stratified to 2D versus 3D(mainly with CT) brachytherapy ○ A total of 705 patients were treated with one of three arms: ■ (a) brachytherapy followed by surgery (stage IB1, 165 patients); ■ (b) EBRT plus chemotherapy, BT, then surgery (305 patients); or ■ (c) EBRT plus chemotherapy and then BT (235 patients). ○ For the 235 patients treated with concurrent chemoradiation and then brachytherapy, ■ 2-year overall survivalwas 74% for 3D versus 65% for 2D (P = .27) ■ DFSwas 60% versus 55% (P = .09) ■ local regional relapse-free survival was 70% versus 61%(P = .001), and ■ local-only relapse-free survivalwas 79% versus 74% (P = .003) ■ Toxicity was reduced overall from 23% with 2D to 2.6% with 3D (P = .002); ● urinary from9% in 2D to 1% with 3D (P = .02) ● gastrointestinal from 9% to 0% (P = 0.17), and gynecologic from 15% to 1% (P = .01).

● RTOG 88-05

○ conducted a phase II trial of hyperfractionation(1.2 Gy to the whole pelvis twice daily at 4- to 6-hour intervals, 5 days/week) withbrachytherapy ○ in 81 patients with locally advanced carcinoma of the cervix ○ Total dose to the whole pelvis was 24 to 48 Gy, followed by one or two LDR intracavitary applications to deliver 85 Gy at point A and 65 Gy to the lateral pelvic nodes ○ Grigsby et al. updated the results and noted that external irradiation was completed in 71 cases (88%) ○ The cumulative rate of grade 3 and 4 late effects for patients with ■ stage IB2 or IIB tumors ● at 5-years was 7% ● at 8 years was 10% ■ with stage III or IVA disease ● at 5 years was 12% ○ The absolute survival was 48% at 8 years, and DFS was 33% ○ Comparison with historical control patients treated on other RTOG studies showed EQUIVALENT rates of ■ pelvic tumor control, survival, and grade 3 and 4 toxicities at 3, 5, and 8 years, respectively.

● Hareyamaet al

○ conducted a randomized study in 132 patients with stage II or IIIB cervical carcinoma treated with LDR or HDR BT and identical pelvic EBRT ○ The conversion factor from LDR to HDR was 0.588 ○ The 5-year DSSwith HDR for stages II and IIIB was 69% and 51%, respectively, and with LDR it was 87% and 60%, respectively ○ Pelvic tumor control for stage II and III was 89% and 73% with HDRand 100% and 70% with LDR, respectively ○ grade 3 or greater morbidity was 10% and 13%, respectively (differences were not statistically significant).

● The RTOG (9001) (Morris/Eifel)

○ conducted a randomized study of 389 patients with stage IB to IIA of >5 cm, proven positive pelvic lymph nodes, or stage IIB to IVA carcinoma of the cervix ○ in which patients were treated with either ■ pelvic and para-aortic irradiation (best arm of RTOG Protocol 79-20; Rotman: recall that EFRT vs WPRT provided OS benefit of around 10%)) or ■ pelvic irradiation and three cycles of concomitant chemotherapy with cisplatin (75 mg/m2) and 4-day infusion of 5-FU (1,000 mg/m2 per day) ○ Results were updated by Eifel et al. with a median follow-up of 6.6 years for 228 survivors ○ the 8-year overall survival rate for women on the: ■ irradiation and cisplatin/5-FU armwas 67%versus ■ irradiation-onlyarm was 41%(P < .0001) ○ DFS rates were 66% and 36%, respectively Therewere no significant differences in late complicationsin the treatment groups RTOG 9001 ​[Morris/​Eifel JCO '04​]:​ ​EFRT​/B vs. CCWPRT/B​.The addition of concurrent chemo decreased LRF by 50%.The addition of concurrent chemo improved OS, LR, and DM, especially for stage I-II disease.OS benefit diminishes with advancing stage, but benefit for CCRT for IIIB was finally prospectively validated in 2018 [​Tata​] ○ 389 pts. IIB-IVA, IB3-IIA2 ≥ 5 cm, or PLN+ (no pAO, 10% common iliac). EFRT/B to 85 Gy vs. CCWPRT/B w Cis q3wk + 5-FU. EFRT pAO to​ L1/L2​ while WPRT to L4/5 w inf to mid-pubis or 4 cm below lowest extent of disease. Superior pAO field now set higher at T12/L1 (level of renal hilum) Brachy in both arms. Point A→ 85 Gy over 58 days, 16% major deviations. ○ Equivalent pAO failure (4 vs 7%), Equivalent long term toxicity but acute toxicity 1→ 11%. ■ Role of ppx EFRT is unclear due to ​significant acute/late toxicity ​with CCRT. ○ 8y OS 41→67%, 8y DFS 46→61%, 8y LRF 36→18%, 8y DM 35→20%. 5yOS 52→72%, 5y DFS 43→67%. ○ Best OS advantage for stage I and II disease with CCRT... NS for III and IV! [​Eifel​]

● Based on the general principles guidelines for cervical cancer brachytherapy published by the American Brachytherapy Society and the ICRU report, the point A definition was updated in 2012 To determinepoint A

○ connect a line through the center of each ovoid or the lateral most dwell position in the ring; extend this line superiorly along the radius of the ovoids (or ring), and then move an additional 2 cm superior along the tandem ○ From this point, extend out 2 cm on each side laterally on a line perpendicular to the tandem (Fig. 73.22) ○ For tandem and cylinders, begin at the flange or cervical marking seed and move 2 cm superiorly along the tandem and then 2 cm laterally

● Patients with any two of thesehave an intermediate riskof failure and are candidates for postoperative radiation: ● Whether to add concurrent chemotherapy to postoperative radiation in the intermediate-risk group is being tested in an accruing randomized trial; many institutions routinely implement chemoRT for intermediate-risk patients

○ deep stromal invasion ○ vascular/lymphatic permeation ○ large tumor size

● Acutegastrointestinal side effects of pelvic irradiationinclude: ○ diarrhea, abdominal cramping, rectal discomfort, and occasionally rectal bleeding, which may be caused by transient enteroproctitis ● Patients with hemorrhoids may experience discomfort earlier than other patients ● Diarrheaand abdominal crampingcan be controlled with the oral administration of ● Proctitis and rectal discomfort can be alleviated by

○ diphenoxylate hydrochloride, with loperamide ○ atropine sulfate ○ opium preparations ○ small enemas with Hydrocortisone and ○ anti-inflammatory suppositories containing bismuth, benzyl benzoate, zinc oxide, or Peruvian balsam

● Management of acute radiation vaginitis includes ● Superficial ulceration of the vagina responds to ________, which stimulate epithelial regeneration within 3 months after irradiation ● Use of vaginal dilators several times daily, started during the course of treatment, prevents vaginal stenosis ● Psychoeducational interventionand motivation improve the compliance in use of dilators More severe necrosis may require debridement on a weekly basis until healing takes place

○ douching every day or at least three times weekly with a 1:5 mixture of hydrogen peroxide and water ○ Douching should be continued on a weekly basis until the mucositis has resolved or for 2 or 3 months as necessary topical (intravaginal) estrogen creams

Genitourinary Toxicity ● Ureteral stricture at 20 years was observed in 2.5% of 1,784 patients with stage IB carcinoma of the cervix treated with irradiation (274 followed for up to 20 years or longer) ● The MOST COMMON presenting symptoms were

○ flank pain ○ urinary tract infection

● After completion of GOG 85, the group opened GOG 120(Rose)

○ for the same patient population ○ was a three-arm randomized trial comparing ■ irradiation plus hydroxyurea ■ irradiation plus weekly cisplatin ■ irradiation plus hydroxyurea, cisplatin, and 5-FU ○ In 526 evaluable patients with a median follow-up for survivors of 106 months, the 5- and 10-year survival ratesfor women ■ in both the weekly cisplatin and irradiation arm and the irradiation, 5-FU, and cisplatin armwere 60% and 53%, respectively, VS ■ in the hydroxyureaand irradiation arm were 40%and 34% (P ≤ .01) ○ Overall survival was also significantly better in the two patient groups receiving cisplatin ○ Hematologic toxicity was greaterin the group treated with the three drugscompared with cisplatin or hydroxyurea alone ● GOG 120​ [​Rose NEJM '99​, ​JCO '07]​: 3 arm CCRT: ​WPRT/B + (HU vs. CDDP/5FU/HU vs. CDDP)​. This trial established CDDP-alone as the preferred concurrent chemotherapy.Cisplatin-based chemo with OS advantage, particularly for Stage IIB and III.Cisplatin thought to be radiosensitizer by preventing sublethal damage repair ○ 526 pts. IIB-IVA with no pAO LNs. ■ LDR to 81 Gy Point A dose. ○ 2y PFS 47→ 64→ 67%. 3y OS 47→ 65→ 65%.■ Stage IIB and III: 10y LR 34→ 21%, 10y PFS 26→ 43→ 46%, 10y OS 34→ 53→ 53%. ○ Equivalent G3/4 toxicity, although CDDP alone demonstrated less toxicity.

● The use of PET scanning to determine residual disease allows selection of patients who may be appropriate candidates for a hysterectomy after completion of external beam treatment ● Therefore, patients should receive definitive doses of chemoradiation, with hysterectomy reserved for salvage in patients with either:

○ gross residual disease or ○ PET-positive disease that is biopsy proven at 3 months after completion of radiation.

IRRADIATION AND HYPERTHERMIA ● A Cochrane database review

○ identified six randomized, controlled trials published between 1987 and 2009 ○ comparing RT versus combined hyperthermia and RT ○ The results show 74% of patients had stage IIIB cervical cancer. ○ A SIGNIFICANTLY HIGHER complete response rate(RR = 0.56, 95% CI = 0.39 to 0.79) and LOWER local recurrence rate (HR = 0.48, 95% CI = 0.37 to 0.63) and IMPROVED overall survival(HR = 0.67, 95% CI = 0.45 to 0.99) with NO DIFFERENCE in acute or late grade 3 to 4 toxicity were seen for patients treated with combined therapy ○ Catheter-based US devices provide a method to deliver heat with HDR brachytherapy, but clinical results are not yet available

CARCINOMA OF THE CERVIX AND PREGNANCY ● For carcinoma in situ

○ if the pregnancy is allowed to reach full term, confirmation of the diagnosis by colposcopy and conservative management with monthly Pap smears constitutes the best approach ○ Conization has frequently been performed. Punch biopsies can be obtained, but the diagnostic accuracy is less reliable ○ As many as 50% of the patients have residual carcinoma in situ after delivery.

● The GOG conducted randomized Protocol 85(Whitney)

○ in which patients with carcinoma of the cervix ■ a clinical stage of IIB to IVA, and negative para-aortic nodeswere treated with external pelvic irradiation (51 Gy) combined with 30 Gy to point A with LDR brachytherapy ○ One hundred twenty- seven patientsreceived 5-FU(IV infusion, 1 g/m2 for 4 days) and cisplatin(50 mg/m2 IV) on days 1, 29, and 30 to 33 ○ 191 patients received hydroxyurea(80 mg/kg orally twice weekly) ○ With a median follow-up for survivors of 8.7 years, the 5- year survival rate in the cisplatin/5-FU arm was 60%,compared with 47% for women in the hydroxyurea arm ● GOG 85​ [​Whitney​ JCO '99]: ​RT+HU vs. RT+CDDP/5FU​.OS and PFS improved with CDDP/5FU over HU. There is also less acute toxicity with CDDP/5FU. ○ ○ 368 pts. IIB-IVA with negative cytologic washings and PLN. ■ IIB 40.8/24 WPRT→ 40 Gy Point A, and if necessary, 55 Gy Point B. ■ III-IVA 51/30 WPRT→ 30 Gy Point A, 60 Gy Point B. No implant received 61.2 Gy. ○ ○ 3y OS 43→ 55%. 3y PFS 47→ 57%. ○ ○ G3+ 24→ 4%, Late complications ~16%.

Clinical Outcomes of Brachytherapy -Randomized Studies Comparing HDR to LDR Using Plain X-Ray Dosimetry ● Fourrandomized trials (Table 73.16) and a meta-analysis summarizing the results of these have been published comparing HDR and LDR brachytherapy for carcinoma of the cervix ● A meta-analysis

○ including these four trials ○ reported a pooled RR for HDR versus LDR of 0.95 (95% CI = 0.79 to 1.15), 0.93 (95% CI = 0.84 to 1.04), and 0.79 (95% CI = 0.52 to 1.20) for 3-, 5-, and 10-year overall survival rates and 0.95 (95% CI = 0.84 to 1.07) and 1.02 (CI = 0.88 to 1.19) for 5- and 10-year DSS rates ○ For local control rates, the RR was 0.95 (95% CI = 0.86 to 1.05) and 0.95 (95% CI = 0.87 to 1.05) at 3 and 5 years, respectively ○ For bladder, rectosigmoid, and small-bowel complications, the RR was 1.33 (95% CI = 0.53 to 3.34), 1.00 (95% CI = 0.52 to 1.91), and 3.37 (95% CI = 1.06 to 10.72), respectively, indicating NO SIGNIFICANT DIFFERENCES EXCEPT for increased SMALL BOWEL complications withHDR(P = .04) ○ Of note, none of the randomized studies used 3D imaging to optimize away from normal tissues.

Template-Based Interstitial Brachytherapy ● Interstitial implantswith 240Ra, 144Cs needles, or 206Ir afterloading plastic catheters to limited tumor volumes are helpful in specific clinical situations. ● Indications include:

○ large residual bulky cervical tumors after external beam treatment ○ residual tumor with sidewall invasion ○ vaginal extension presence of a fistula and/or adjacent organ invasion, or a prior supracervical hysterectomy (Fig. 73.26)

-Surgical Techniques in cervical cancer --Simple Conization ● In patients with these, simple conization with lymphadenectomy has been reported

○ minimal invasion ○ no parametrial involvement ○ small tumor size

Intraoperative Irradiation ● Abe and Shibamoto

○ noted that central recurrences, particularly in nonirradiated patients, and resection of the gross recurrent tumor in irradiated patients improve the benefit from IORT. ○ Significant toxicity included peripheral nerve injury and ureteral stenosis (with doses >15 to 20 Gy).

● In GOG Protocol 165

○ patients with stage IIB to IVA cervical cancers received either ■ radiation therapy and concurrent weekly cisplatin(40 mg/m2) or ■ radiation therapy and a protracted venous infusion (PVI) of 5-FU ■ Lanciano et al. reported that the study was prematurely closed after an interim analysis showed a failure rate 35% higher and would not result in improved DFS with PVI 5- FU/RT compared with weekly cisplatin ● GOG 165 ​[​Lanciano JCO '05​]: ​CCRT/B w CDDP vs. 5-FU​. Concurrent 5-FU with 35% higher distant failure than CDDP. ○ 316 pts. IIB, IIIB and IVA. ■ WPRT 45 Gy + PMB + ICBT with CDDP 40 q1w vs. protracted venous infusion 5-FU x6c. ○ Study closed prematurely when planned interim analysis demonstrated 35% higher DM with 5-FU.

● Antiangiogenic tyrosine kinase inhibitors

○ pazopaniband lapatinib ○ were tested in 230 patients with stage IVB persistent/recurrent cervical carcinoma. ○ An improvement in progression-freeand overall survivalwas seen with PAZOPANIB. ○ A trial of PD-1 positive cervical cancer treated with immunotherapy is ongoing.

● Patients who have undergone radical hysterectomywith no preoperative radiation therapyare considered for postoperative chemoradiation therapy if they have high-risk prognostic factors, which include:

○ positive pelvic lymph nodes ○ negative nodes who have microscopic positive margins of resection or ○ parametrial involvement

● Patelet al

○ published a randomized trial of 482 patients with invasive squamous cell carcinoma of the cervix. ○ The overall local tumor control rate with LDR brachytherapywas 79.7%, compared with 75.8% with HDR ○ The 5-year survival rates were ■ 73% with LDR and 78% with HDR in stage I ■ 62% and 64%, respectively, in stage II ■ 50% and 43% in stage III ○ The only statistically significant difference was the incidence of OVERALL RECTAL COMPLICATIONS, which was 19.9% for LDR, compared with 6.4% for HDR ○ However, the incidences of more severe grade 3 and 4 complications were NOT significantly different (2.5% and 0.4%, respectively) ○ Bladder morbidity was similar in both groups.

● Landoni et al. (Early stage)

○ published results of a prospective, randomized trial of radiation therapy versus surgery ○ 469 women with stage IB and IIAcervical carcinoma ○ were referred for treatment and 343 were randomized ■ 172 to surgery and 171 to radiation therapy ○ Postoperative irradiation was delivered after surgery for women with ■ surgical stage pT2b or greater ■ <3 mm of cervical stromal invasion and cut-through margins, or ■ positive pelvic nodes ○ Scheduled treatment was delivered to 169 and 158 women, respectively ○ 62 of 114 women with cervical diameters of <4 cm and 46 of 55 women with >4 cm received radiation therapy ○ After a median follow-up of 87 months (range, 57 to 120 months), 5-year overall survival and DFS rateswere NEARLY IDENTICAL in the surgery and radiation therapy groups(83% and 74%, respectively); ○ recurrent disease developed in 86 women: ■ 42 (25%) in the surgery group ■ 44 (26%) in the radiation therapy group (Fig. 73.18) ○ Forty-eight patients (28%) in the surgery group had severe morbidity, compared with 19 (12%) in the radiation therapy group(P = .0004; Table 73.11) ○ The combination of surgery and radiation therapy had the WORST morbidity, especially urologic complications. Italian​ [​Landoni​ Lancet '97,​ ​JGO '17​]: ​RT vs. RH ± RT​. Surgery and RT have similar efficacyfor IB-IIA. Basis for doing WPRT + brachy OR surgery in IB1/IIA1. There appears to be a trend to OS benefit with RT over surgery for tumors > 4 cmat long term follow up. Morbidity worse with surgerylikely due to CMT. This trial is prior to the era of concurrent chemotherapy. · ○ 343 pts. IB-IIA. Adjuvant RT if parametrial, ≤ 3 mm of uninvolved cervical stroma, SM+, LN+. § Definitive RT: 47 Gy (40-53 Gy)→ LDR to 76 Gy (70-90 Gy) to Point A. § Adjuvant RT (64%): 50.4 Gy. pAO to 45 Gy. · ○ 5y OS ~83%, 5y DFS ~77%, 5y LR ~25%. · ○ 20y OS ~75%. · ○ OS trend with RT for size ≥ 4 cm, with significant benefit at size ≥ 5 cm. · ○ G2/3 higher in surgery arm 12→ 28% although likely due to side effects from CMT. Caveat: No chemo! · Although RT may be better tolerated, surgery may improve outcomes for adenocarcinoma. Toxicity with combined treatment is worse than RT alone. ■ PORT delivered in 64% of surgery arm, including 83% tumors > 4 cm

Pelvic Exenteration which is not done as a palliative procedure, consists of a: ● Proof of this is mandatory: that there is: ● Absolute contraindicationsto the procedure: ● Relative contraindication ● Patients with these rarely benefit from this procedure and should be excluded on a clinical basis:

○ radical hysterectomy ○ pelvic lymph node dissection ○ removal of the bladder (anterior exenteration) ○ removal of the rectosigmoid colon (posterior exenteration), or ○ both (total exenteration) ■ The ileum or sigmoid has been the usual means of achieving urinary diversion ■ Because some patients have a pelvic recurrence after radiation therapy, the bowel is used for the urinary conduit. ○ no fixation to the pelvic wall and ○ no extension of disease beyond the pelvis ○ Metastases outside the pelvis, including those in PALNs or any viscera ○ Bilateral ureteral obstruction secondary to tumor ○ sacroiliac or hip pain or leg edema

SMALL CELL CARCINOMA OF THE CERVIX ● Patients have EXTREMELY POOR OUTCOMES, with the only reported survivors having had triple-modality therapy of small tumors treated by __________ ● Prophylactic cranial irradiation is ____________because cervix cancer will most commonly spread first to LUNG and then to brain. ● Patients with small cell carcinoma of the cervix are treated with the same irradiation techniques as outlined for other histologic varieties of cervical carcinoma in combination with multiagent chemotherapy, including:

○ radical hysterectomy, concurrent chemoRT, and adjuvant chemotherapy. NOT INDICATED ○ external beam radiation to 45 Gy, followed by nodal boost if PET-positive nodes are identified, followed by brachytherapy ○ The most frequently prescribed drugs are cisplatin and etoposide (VP-16) every 3 weeks

● Lertsanguansinchaiet al

○ randomized 237 patients with cervical cancer to be treated with LDR (109 patients) or HDR (112 patients) brachytherapy and EBRT ○ Median follow-up was 40 and 37 months, respectively ○ Three-year pelvic tumor control was 89% and 86.4%, respectively, and relapse-free survival was 69% in both groups ○ Grade 3 or 4 morbidity was noted in 2.8% of LDR and 7.1% of HDR patients (P = .23).

● Song et al.

○ reported a 20-year experience in stage IB to IIA cervical cancer patients with intermediate-risk factors (two or more of deep stromal invasion, lymphovascular invasion, and large tumor size) who received postoperative RT or chemoradiation. ○ Chemoradiation SIGNIFICANTLY decreased pelvic recurrence and distant metastases ○ There was no difference in acute or chronic grade 3 and 4 gastrointestinal side effects.

● Morice et al (GYNECO 02 Study)

○ reported a randomized trial of 61 patients treated with ■ adjuvant hysterectomy versus none after EBRT with concurrent weekly cisplatin and vaginal brachytherapy (15 Gy to intermediate-risk CTV) for stage IB2 or II cervical cancer ○ Hysterectomy INCREASED THE NUMBER OF DEATHS, with an 11% NON SIGNIFICANT survival advantage in the no-hysterectomy arm(86% vs. 97%) ○ As a result of this trial, routine adjuvant hysterectomy is NO LONGER PRACTICEDfor patients who have no residual disease at 6 weeks after chemoradiation.

Pearcey et al

○ reported on a Canadianrandomized study ○ in which 127 patients with stage IB to IIA of >5 cmor IIB carcinoma of the cervixwere randomized to be treated with ■ cisplatin (40 mg/m2 weekly) and RT, and ■ 126 patients were treated with RT alone(50.4 Gy to the pelvis combined with brachytherapy) ○ With a median follow-up of 65 months, the 5-year survival rates were 59% and 56%, respectively(P = .43) ○ There was a somewhat greater incidence of significant late morbidity in the RT-alone group(12% vs. 6%; P = .08) NCIC ​[Pearcey JCO '02]​:​ ​WPRT/B ± CDDP q1w​. The only trial without an OS benefit for CCRT over RT. Power may have been low to detect an OS benefit. Results may be explained by statistical variation, presence of anemia in CCRT arm or absence of pAO LN surgical staging. Also, the NCIC trial achieved a shorter average tx duration which might have rendered RT more effective.This was also only definitive trial with IB patients. ● ○ 250 pts. IA, IIA > 5 cm or IIB-IVA. Non-surgical staging of nodes. ○ WPRT45Gy+LDR35x1orHDR8Gyx3±CDDPq1w40x6c. ● ○ Equivalent 5y PFS and 5y OS ~60%.

Sedlis, Rotman et al; GOG 92; Early Stage

○ showed improved recurrence-free survivalwith postoperative pelvic irradiation(46 to 50.4 Gy in 23 to 28 fractions) after radicalsurgery in the presence of positive pelvic nodesor node-negative high-risk factorsin women with stage IB cervicalcancer treated by radical hysterectomy and pelvic lymphadenectomy ○ There were 277 eligible patients with at least twoof the following risk factors: ■ greater than one-third stromal invasion ■ capillary lymphatic space involvement ■ large clinical tumor diameter ○ 137 patients were randomized to pelvic radiation therapy and 140 to no further treatment ○ The results were updated by Rotman et al.; ○ 24 (17%) patients in the irradiation group and 43 (30.7%) in the no-further-treatment group had cancer recurrences ○ In the radiation therapy group, 27 patients died of cancer ○ in the no-further-treatment group 40 died from cancer ○ There was a STATISTICALLY SIGNIFICANT reduction in RISK OF RECURRENCE in the irradiation group, with recurrence-free rates at 2 years of 88% versus 79% for the irradiation and no-further-treatment groups, respectively ○ Overall survival difference DID NOT REACH statistical difference(P = .074; Fig. 73.19) ○ Severe or life-threatening (GOG grade 3 or 4) adverse effects occurred in 9 patients (6.6%) in the radiation therapy group and 3 (2.1%) in the observation group ○ A meta-analysis of trials including stage IB1 to IIA cervical cancer found that women who received postoperative radiation had a significantly lower risk of disease progression at 5 years (RR = 0.6, 95% CI = 0.4 to 0.9) ○ The risk of serious adverse events was NOT SIGNIFICANTLY HIGHER if women received radiotherapy rather than no further treatment, possibly because the rate of adverse events was low ● GOG 92​ [​Sedlis ​Gyn Onc '99​, ​IJROBP '06​]: ​→ RH/PLND ± 46-50.4 Gy WPRT ​(fields slightly smaller, no pAO or BT). Adjuvant RT improved PFS and LR in intermediate risk stage IB cervical cancer. ● Give RT to 2+ ​S​e​DL​is criteria (​S​ize ≥ 4 cm (bulky), ​D​epth middle/outer third, ​L​VI) for LRC/PFS benefit. ○ 277 stage IB pts. +LVI, middle 1⁄3 and 2 cm or greater. ○ 5y RFS 79→ 88%​, 5y LR 28→ 15%. ■ 78% of recurrences were local only (vagina and pelvis). ○ 10y LR 21→ 14%, 10y DR 9→ 3%, 10y PFS HR 0.58, 10y LR for ± AC or adenosquamous histo of 44→ 9%. ■ Results show RT may be even more valuable for AC (no LR w AC in RT arm). ○ 10y OS ~71→ 80% (p=0.07). ○ G3+ toxicity 6.6→ 2.1% ○ S-D-L

● Irradiation may be useful for the treatment of cervical carcinoma in situ, particularly in patients with

○ strong medical contraindications to surgery or ○ when there is extension of the lesion to the vaginal wall or ○ multifocal carcinoma in situ in both the cervix and the vagina

● Based on an overview of published data, in order to minimize severe acute toxicity if delineating the contours of bowel loops themselves ● Alternatively, if the entire volume of peritoneal space in which the small bowel can move is delineated

○ the absolute volume of small bowel receiving ≥15 Gy should be held to <120 cc when possible ○ the volume receiving >45 Gy should be <195 cc when possible

● The levels of lymph node dissection in cervical cancer include

○ the internal and external iliac (level 1) ○ common iliac and presacral (level 2) ○ aortic intramesenteric (level 3) ○ aortic infrarenal (level 4)

CARCINOMA OF THE CERVIX AND PREGNANCY ● In patients with invasive carcinoma

○ the lesion is usually clinically apparent ○ Multiple punch biopsies are adequate to confirm the diagnosis ○ Management is individualized based on tumor size and stage, patient age, and desires of the patient (or couple) regarding the pregnancy ○ The majority of patients with cervical cancer diagnosed during pregnancy (~75%) have stage I tumors

a 2008 meta-analysis of the 13 trials that compared chemoradiotherapy to radiation found that

○ there was a 6% improvement in 5-year survival with concurrent chemoradiation(HR 0.81, P < .001) ○ The effect was attributed to a reduction in both local and distant recurrence. ○ Chemoradiation increased acute hematologic and gastrointestinal toxicity, but no confirmation was made about a difference in late toxicity

-Surgical Techniques in cervical cancer ● Selection criteria for a trachelectomy include:

○ those patients requesting fertility-sparing surgery ○ age <40 years ○ stage IA1, IA2, or IB1 with no nodal involvement detected on MRI or PET scan ○ squamous cell or adenocarcinoma with a lesion <2 cm ○ no lymphovascular invasion on initial biopsy; and ○ no upper endocervical involvement

● Of note, NO randomized study has compared chemoRT to radical hysterectomy, although chemoRT has a significant survival advantage over RT alone for patients with stage IB to IIA cervical cancer ● In a meta-analysislooking at the value of adjuvant cisplatin-based chemotherapy after radical hysterectomy, radiation therapy, or both for patients with stage IA2, IB1, or IIA cervical cancer

○ three randomized clinical trials were evaluated ○ Two of the three trials showed a significant benefit compared to adjuvant chemotherapy concurrent with radiation, with a reduced risk of death(HR = 0.56, 95% CI = 0.36 to 0.87) ○ No benefit was seen when chemotherapy was given prior to radiotherapy.

CARCINOMA OF THE CERVIX AND PREGNANCY ● Women with tumors diagnosed early in pregnancy are often recommended to abort the fetus ● Because there is a greater need to institute therapy as soon as possible, the accepted method of treatment in patients in the first 6 months of pregnancy is _________ ● An abortifacient may be administered before initiating radiation to ensure fetal demiseand delivery of the placenta prior to initiation of treatment ● If the woman refuses abortion: ● When patients are diagnosed in midpregnancy (second trimester), ● Occasionally in late pregnancy (final trimester) ○ if tumors are small and an MRI confirms no lymph node involvement

○ to carry out definitive surgery or radiation therapy, as indicated by the stage of the disease, with resultant loss of the fetus ○ serial MRI scans at 2- to 3-month intervals to ensure no growth or spread to lymph nodes is recommended ○ consideration to keeping the pregnancy and treating with chemotherapy is given ■ definitive therapy is postponed until after imminent delivery ○ some gynecologic oncologists prefer a postpartum cesarean section, combined with a radical hysterectomy and lymphadenectomy followed by radiation for high-risk features when present ○ However, some authors report that vaginal delivery has no detrimental effect on the prognosis

● RTOG 0417

○ treated patients with once-weekly cisplatin (40 mg/m2) chemotherapy and standard pelvic radiotherapy and brachytherapy ○ Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles ○ A total of 49 patients were evaluable. ○ The median follow-up was 12.4 months (range, 4.6 to 31.4 months) ○ There were no treatment-related serious adverseevents ○ There were 15 (31%) protocol-specified, treatment-related adverse eventswithin 90 daysof treatment start ■ the most common were HEMATOLOGIC(12 of 15; 80%) ● Eighteen (37%) occurred during treatment or follow-up at any time. ○ An update with 3.8 years follow-up (range 0.8 to 6 years) showed a 3-year OS 81.3%, DFS 68.7%, and LRF 23.2%, with 26.5% grade 3 adverse events (mainly hematologic) and 10.2% grade 4 events

● Other surgical complications include:

○ ureterovaginal fistula (the incidence of which has decreased to <3%) ○ hemorrhage ○ infection ○ bowel obstruction stricture and fibrosis

● The MOST FREQUENT sequela after radical hysterectomy is:

○ urinary dysfunction as a result of partial denervation of the detrusor muscle ● Patients may have various degrees of ○ loss of bladder sensation ○ inability to initiate voiding ○ residual urine retention incontinence

● Radical hysterectomy alone may cause long-term side effects such as:

○ urinary retention requiring chronic suprapubic catheter placement ○ sciatic nerve injury ○ postoperative seroma or hematoma formation ○ pelvic pain ○ lifelong edema ■ when lymphadenectomy is performed

● Since the early 1900s, radiation has been used in the curative management of cervical cancer, with a combination of external beam and brachytherapy resulting in the highest survival rates. ● Over the ensuing 100 years, treatment planning techniques have evolved, as has the equipment used for treatment. ● Several methods have been developed to aid with conformality and normal issue sparing. ● External irradiation is used to treat the whole pelvis. Structures treated include the:

○ uterus and cervix or, in the postoperative cases, the tumor bed ○ the vagina ○ the parametrial tissue ○ the pelvic lymph nodes, including the internal, external, and common iliac nodes ○ In selected cases, the PALNs may be treated

● Southwest Oncology Group 8797(Peters)/ GOG 109/ INT 107

○ was a study for women with FIGO stage IA2, IB, or IIA carcinomaof the cervix with metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical marginsat the time of primary radical hysterectomy with total pelvic lymphadenectomy ○ Patients had confirmed negative PALNs; if the PALNs were not sampled, the patients had confirmed negative common iliac lymph nodes ○ One hundred twenty-seven patients were randomized to treatment with ■ pelvic EBRT with 5- FU infusion and cisplatin, and ○ 116 were treated with ■ irradiation alone ○ The 3- year survivalfor women on the ■ adjuvant cisplatin/5-FU and RT armwas 87%,compared with ■ pelvic irradiation arm was 77% ○ The difference was statistically significant ○ An updated analysis with 5.2-year median follow-up reported 5-year overall survivalof 80% versus 66%, favoring postoperative chemoradiationin high-risk patients GOG 109 ​/ SWOG 8797 [​P​eters​ JCO '00]:​ ​Surgery→ ± CCRT​.Adjuvant CCRT with CDDP improves OS and PFS. There is a 10% OS advantage for the "3 P's". Deliver post-operative CCRT for IB with ​P​LN+ (85%), ​P​arametria (33%), or ​P​ositive margins (5%). ○ 243 pts. IB (only 5% IA2, IIA). WPRT (45-50 Gy, no VBT, pAO if common iliacs +). WPRT 49.3/29 (1.7 Gy) with 45 Gy to pAO if common iliacs positive. CDDP 70 and 5-FU 1g/m2​ ​q3w x4c (2 concurrent, 2 adjuvant). ○ 4y PFS 63→ 80%, 4y OS 71→ 81% esp w/ bad histology (adeno). Subset​: 20% 5y OS benefit with CCRT for tumors > 2 cm or 2+ nodes, no benefit for < 2 cm or 1 node. ASTRO: This corresponds to an absolute benefit inoverall survival of 12%and in progression-free survival of 16%.7 There is an increase in acute grade 4 toxicities with the addition of chemotherapy (17% chemoradiation versus 4% RT), largely hematologic in nature.7The benefit of chemoradiation compared to RT alone is similar to the benefit observed for locally advanced patients with cervical cancer who undergo definitive chemoradiation compared 254 to RT alone.11

● 2017 Update on the Querleu-Morrow Classification of Radical Hysterectomy​[​ASO '17] Great table on Q-M classification located in Table 4 [​1​], risk groups guide degree of surgery:

○ ● Type A​: parametrium halfway to cervix and ureter. Minimal ventral/dorsal parametrium. ○ ● Type B1​:​ ​Parametrium ​to ureters​. Partial excision of vesicouterine and rectouterine/uterosacral ligaments. ■ ○ Consider for LR: < 2 cm, no LVSI, inner third stromal invasion. ○ ● Type B2​: B1 + paracervical LNs. ■ ○ Consider for IR: ≥2cm, no LVSI or <2cm w LVSI. ○ ● Type C1​: Parametrium ​to iliac vessels​, caudal preserved. Total vesicouterine and rectouterine. Most common Hys for cervical cancer. ■ ○ Consider for HR: ≥ 2 cm with LVSI. ○ ● Type C2​: C1+ caudal parametrium at iliac vessels. Bladder and hypogastric nerves sacrificed. ○ ● Type D​: Parametrium​ to sidewall​.

IRRADIATION AND HYPERTHERMIA

● Because of technical limitationsin the delivery of adequate heat to large parts of the body such as the pelvis, the use of hyperthermia in the treatment of carcinoma of the uterine cervix has been RARE

OUTBACK Trial

● CCRT→ Adjuvant chemotherapySuggestion from meta of 19% absolute improvement w CCRT and adjuvant chemo over RT alone.Conflicting evidence points towards possibly higher likelihood of DM for non-squamous (adenocarcinoma and adenosquam) histologies, suggesting a role for chemo. ○ OUTBACK Trial​B9E-MC-JHQS​ ​[Duenas-Gonzales JCO '11]​: ​WPRT/B/Cis→ ± Gem/Cis​*.Concurrent cis/gem with adjuvant Cis/gem improved PFS compared to standard definitive RT, but toxicity was increased. Was it the addition of gem, sequential therapy, or both that led to dec DM?OS favoring more chemo but more toxicity, unclear if due to gem or additional cisplatin. 515 pts. IIB-IVA. KPS ≥ 70. *Adjuvant Gem/Cis arm also got Gem concurrently with CCRT. CDDP 40mg/m2 q1w vs. CDDP 40/gem 125 q1w→ Cis 50 d1/gem 1g d1,8 q3w x2c. ● CCRT and BT to total point a dose of 85 Gy. ● CDDP 40 and gem 125 while on RT, CDDP 50 and gem 1k adjuvantly. ● EBRT 50.4→ VBT 30-35 Gy in 96h. 3y PFS 65→ 74%, 3y OS 69→ 80%. G3-4 toxicity 43→ 87% with two deaths related to treatment in gem/cis arm. Hospitalizations 11→ 30%. ○ GOG 0724/RTOG 0724​ [​Protocol​, ​NCT00980954​]: RH→ ​CCRT ± adjuvant CTX​.This trial investigates the use of adjuvant chemo in high risk, early stage cervical cancer. Primary endpoint DFS. IA2, IB, IIA→ RH with Peters Postop criteria. Strat by VBT, 3D/IMRT, and WPRT dose (45 vs. 50.4 Gy). ● WPRT/B/CDDP ± Carbo AUC5 with paclitaxel 155mg/m2 x4c ● Superior: L4/5 Sup unless PLN+ (L1/L2) or pAO+ (T11/12). ● Lateral: Ant 2 cm to VB and/or 1 cm ant to pAO. Post 1-1.5 cm into VB and/or 1 cm post to pAO. ● Bowel: V40 < 30%​. Same as [​TIME-C​] and [​RTOG 04-18​]. ● Bladder: V45 < 35%​. Same as [​TIME-C​] and [R​ TOG 04-18​]. ● Rectum: V45 < 60%. Compare to V30 ≤ 60% in [RTOG 04-18], or V40 ≤ 80% in [​TIME-C​]. CDDP 40 q1w w RT→ Carboplatin AUC 5 and palitaxel 135. Also allowed to enroll on [​TIME-C​].

Treatment of Metastatic disease

● Carboplatin/paclitaxel and cisplatin/paclitaxel preferred. ● Cisplatin/Paclitaxel + Bevacizumab improves overall survival [NEJM '14]. ○ Add bevacizumab if good performance status and risk of significant GI/GU toxicity has been carefully assessed. ● For SCV node only as DM, consider CCRT with curative intent ± adjuvant chemo. ● Around HALF of isolated pelvic or pAO failures will still be alive at 3y after treatment with SBRT [​2019 data​]! ● Stage IVB cervical cancer​ [​Perkins Gyn Onc '19​]: Retro. ​Chemo ± WPRT​. ○ 126 pts. 2005-2015. Nearly 3/4 SqCC. Median age 53y.■ Details concerning the sequence of chemo and RT, and the dose and type of RT were unable to be collected. ○ MS 18→ 42 mo

True of staging in cervical cancer

● 4.1.1 |Microinvasive disease Diagnosis of Stage IA1 and IA2 is made on microscopic examination of a LEEP (loop electrosurgical excision procedure) or cone biopsy specimen, which includes the entire lesion. It can also be made on a trachelectomy or hysterectomy specimen. The depth of invasion should not be greater than 3 mm or 5 mm, respectively, from the base of the epithelium, either squamous or glandular, from which it origi- nates. The horizontal dimension is no longer considered in the 2018 revision as it is subject to many artefactual errors. Note must be made of lymphovascular space involvement, which does not alter the stage, but may affect the treatment plan. Extension to the uterine corpus is also disregarded for staging purposes as it does not in itself alter either the prognosis or management. The margins should be reported to be negative for disease. If the margins of the cone biopsy are positive for invasive cancer, the patient is allocated to Stage IB1.18 Clinically visible lesions, and those with larger dimensions, are allocated to Stage IB, subdivided in the latest staging as IB1, IB2, and IB3 based on the maximum diameter of the lesion. ● 4.1.2 |Invasive disease ● In the case of visible lesions, a punch biopsy may generally suffice, but if not satisfactory a small loop biopsy or cone may be required. Clinical assessment is the first step in allocation of staging. ● Imaging evaluation may now be used in addition to clinical exam- ination where resources permit. The revised staging permits the use of any of the imaging modalities according to available resources, i.e. ultrasound, CT, MRI, positron emission tomography (PET), to provide information on tumor size, nodal status, and local or systemic spread. The accuracy of various methods depends on the skill of the operator. MRI is the best method of radiologic assessment of primary tumors greater than 10 mm.19-23 However, ultrasound has also been shown to have good diagnostic accuracy in expert hands.24 The modality used in assigning staging should be noted for future evaluation. Imaging has the advantage of the ability to identify additional prognostic factors, which can guide the choice of treatment modality. The goal is to identify the most appropriate method and to avoid dual therapy with surgery and radiation as this has the potential to greatly augment morbidity. ● For detection of nodal metastasis greater than 10 mm, PET-CT is more accurate than CT and MRI, with false-negative results in 4%-15% of cases.20,25-28 In areas with a high prevalence of tuberculosis and inflammation, especially HIV-endemic areas, large lymph nodes are not necessarily metastatic. The clinician may make the decision on imaging or, when possible, can use fine needle aspiration or biopsy to establish or exclude metastases.27,29,30 This is especially true in advanced stages, where surgical assessment of para-aortic lymph nodes may be used to tailor treatment according to extent of disease.31-33 They can be accessed by minimally invasive surgery or laparotomy. Surgical exclu- sion of para-aortic lymph node involvement has been reported to have a better prognosis than radiographic exclusion alone.34 ● A review of 22 articles that assessed the safety and impact of pre- treatment para-aortic lymph node surgical staging (PALNS) found that 18% (range, 8%-42%) of patients with Stage IB-IVA cervical cancer had para-aortic lymph node metastases.35 The mean complication rate of PALNS was 9% (range 4%-24%), with lymphocyst formation being the most common. In another study, up to 35% of clinically assessed Stage IIB and 20% of Stage III tumors were reported to have posi- tive para-aortic nodes.36 In the revised staging, all these cases will be assigned to Stage IIIC as lymph node involvement confers a worse prognosis.37 If only pelvic nodes are positive, it is Stage IIIC1; if para- aortic nodes are also involved it is Stage IIIC2. A further notation must be added to indicate whether this allocation is based on only imaging assessment (r) or whether pathological confirmation is available (p). In due course, the data can be analyzed and reported accordingly. ● FIGO no longer mandates any biochemical investigations or inves- tigative procedures; however, in patients with frank invasive carci- noma, a chest X-ray, and assessment of hydronephrosis (with renal ultrasound, intravenous pyelography, CT, or MRI) should be done. The bladder and rectum are evaluated by cystoscopy and sigmoidoscopy only if the patient is clinically symptomatic. Cystoscopy is also recom- mended in cases of a barrel-shaped endocervical growth and in cases where the growth has extended to the anterior vaginal wall. Suspected bladder or rectal involvement should be confirmed by biopsy and his- tologic evidence. Bullous edema alone does not warrant a case to be allocated to Stage IV. ● 4.2 |Pathologic staging ● In case a surgical specimen is available or where image-guided fine- needle aspiration cytology has been done, the pathologic report is an important source for accurate assessment of the extent of disease. As in the case of imaging, the pathologic methods should also be recorded for future evaluation. The stage is to be allocated after all imaging and pathology reports are available. It cannot be altered later, for example at recurrence. The 2018 FIGO staging includes involvement of nodes and thus enables both the selection and evaluation of therapy, as well as estimation of the prognosis and calculation of end results. ● The FIGO and TNM classifications have been virtually identical in describing the anatomical extent of disease. The TNM nomencla- ture has hitherto been used for the purpose of documenting nodal and metastatic disease status.38 The revised FIGO classification is now more closely aligned with the TNM classification in this respect as well. ● In some cases, hysterectomy is performed in the presence of unsuspected invasive cervical carcinoma that is diagnosed later on histopathology. Such cases cannot be clinically staged or included in therapeutic statistics for obvious reasons, but reporting them sepa- rately is desirable. -see notes

Three-Dimensional Conformal Treatment Planning (RadOnc Review)

● ESGO-ESTRO-ESP guidelines for the management of patients with cervical cancer​ [​June '18]​. ● Consider ovarian transpositionin women < 45y before pelvic RT. ● Complete RT in 56 days! ​[​1​]​ ​Prolonged RT = worse outcomes. Extending beyond 6-8 weeks results in ~0.5-1% decrease in LC and CSS for each extra day of overall treatment time. Based on RT alone data. ● Hypofx not advantageousb/c cervical CA relatively fast-growing. ● CT simulation: IV and small bowel contrast, anal marker, gyn marker (vaginal contrast or marker, gold seeds if intact cervix), mark inferior extent of vaginal disease. Full bladder, empty rectum. · ● 3D Field borders/Technique o ○ AP/PA​: ​L4-L5​, ​3 cm inf to dz ​or ​2 cm below obturator canal​, whichever is lower. ​1.5-2 cm​ lat to bony pelvis. § If common iliacs, extend to L3/L4 (bifurcation of aorta) as MDACC retro suggested most regional recurrences just above L4/L5. If pAO are positive, treat 3 cm above or to the top of the next vertebral body. o ○ Lat​: ​0.5 cm post​ ​to ant border of S2/S3​ junction (or entire sacrum), ​anterior to pubic symphysis​. § For non-bulky, you can tighten the field to L5/S1, and half sacrum. o ○ MBB: For IIB, IIIB or LN+, consider parametrial boost of 5.4-9 Gy (to 54 Gy) depending on response. § Reduces dose to bladder and rectum, but may underdose sacrum. § Block out middle 4 cm (Corresponds to matching point A) § ● If concerned about toxicity, may widen to 5 cm or put at 50% IDL. § ● Blocks narrower than 5 cm may include ureters. § ● Can go narrower if concerned about tumor. § With 3D, prescribe to the middle of unblocked field - point A gets 50%, point B gets 100%. § Ideally, it is customized based on the implant. § ● Sup: Bottom of SI § ● Inf/Lat: Same as pelvic field. o ○ EFRT: include 2 cm margin around uninvolved nodes § High common iliacs stop at L1. Usually EFRT stops at T10 § pAO: up to T12/L1. Lateral encompass tips of transverse processes. § ● If matching a PA field to pelvic fields, HBB each, or use IMRT. o ○ 4-field box technique. 23 MV for nearly everyone (deep) o ○ Weigh AP/PA beams 2:1 over laterals (converge closer together = better dose distribution). · ● IMRT Technique o ○ Contouring guidelines for IMRT​: ​[RTOG Atlas],​ ​[Lim IJROBP '11]​. § Do both full/empty bladder for cervix ITVgeneration. o ○ GTV ​+ intermediate/high signal on T2 MRI - "grey zone". o ○ CTV ​= GTV + entire cervix + uterus + parametria and ovaries, entire mesorectum if uterosacral involvement. § Borders: § ● Ant: posterior wall of bladder or external iliac vessel. § ● Post: uterosacral ligaments and mesorectal fascia. § ● Lat: Medial edge of internal edge of internal obturator. § ● Sup: Top of fallopian/broad ligament, which may also form ant boundary of parametrial tissue. § ● Inf: Urogenital diaphragm. § Caveats: § ● If distal third of vagina (stage IIIA), then flash to introitus and cover inguinal nodes. § ● If posterior vaginal wall or uterosacral involvement, then include mesorectum. § CTV1: GTV/Cervix/Uterus. ​Add 1.5 cm for PTV1. § CTV2: Parametria and sup vagina (3 cm below disease). ​Add 1 cm for PTV2. § ● Vagina​: Upper 1⁄2 if minimal/no vaginal extension, upper 2⁄3 if upper involved, entire if extensive. § ● Vaginal CTV: Vagina and paravaginal tissues. Utilize full/empty bladder scan. The inf limit of the vaginal ITV is approximately the level of the upper third of the symphysis pubis. Identify vaginal marker and add an additional 0.5-2 cm superiorly. Inf extend to 3 cm below vaginal marker or 1 cm above bottom of obturator foramen (whichever is lower). § CTV3: Common/II/EI and presacrals + 7 mm. ​Add 7mm for PTV3. § ● Contour presacrals up to S2/S3 (1-2 cm of tissue ant to S1-3), start external iliac above FH. § ● Contour commons up to 7 mm inf to L4/L5 interspace (aortic bifurcation) to account for PTV. § ● Consider EFRT if common iliacs are involved: L2 top of field (renal veins) or 4 cm above node. § ○ Most ​pAO nodes​ are to the left or right of the pAO, only 4% to the right of the IVC. Around 2⁄3 of these are in the low pAO, as compared to >2⁄3 above IMA for endometrial. § ● Gross nodal disease receives ​60​-70 Gy. o ○ ITV​:​ ​Includes CTV (cervix, uterus, parametria, uterosacral ligaments, proximal vagina, paracolpium) + ~1 cm. o ○ PTV margins for primary: 1.5-2 cm​; 7mm for nodal [​Khan IJROBP '12​] o ○ IMRT post-op guidelines​ (TIME C): 45-50.4 Gy. § Post-op targets: Vaginal cuff, upper vagina (3 cm), parametria, and pelvic LN. ○ o Intrafraction motion ​(ASTRO refresher 2018): § Pooled review of cervical motion: 18-63mm A/P, 18-36mm S/I. ​Therefore, 1.5-2 cm PTV recommended. § Pooled review of uterine motion: 20-48mm A/P, 32-45mm S/I. § Ask for daily IGRT for day 1-3, then weekly. Ensure cervix and uterus are within PTV. o ○ Nodal boosts: § 55/25 SIB to gross disease is reasonable (EQD2 57.2 Gy), but should consider 3-5 sequential boost after this to ensure EQD2 ≥ 60 Gy. Nodal control is quite good above 60 Gy EQD2. § Cover one echelon of lymph nodes above gross nodal disease. · ● Special considerations​: o ○ Treat initially to 45-50.4 Gy to shrink tumor. § Cervix shrinks 62% during tx, median change in 20 days, ​Beadle et al. § For < 20% shrinkage during treatment, significantly lower LC and DSS [​1​]. o ○ Goal 80 Gy EQD2 (e.g. 5.5 Gy x 5) for < 4 cm residual, 85Gy EQD2 (e.g. 6 Gy x 5) for larger tumors. o ○ Aim for 60-66 Gy if not resectable, 60 Gy to unresected nodes. ○ AP/PA for thin pts or uterosacral ligament. Consider MBB to avoid excess dose next to implant at 40 Gy.

--Types of Hysterectomy ○ includes complete dissection of the ureter from the vesicouterine ligament, ○ sacrifice of the superior vesicle artery, and ○ removal of the upper three-fourths of the vagina ○ Because of the high rate of fistula and significant morbidity, it is RARELY used.

● Extended radical hysterectomy (class IV) ○ ERH more paracervical/paravaginal tissue, remove superior vesicular artery, part of ureter/bladder.

○ a nucleoside analogue ○ showed a 4.5% partial response and 36% stable disease in 22 patients ○ In combination with cisplatin, it was evaluated in 32 women with previously treated cervix cancer (initial dose 800 mg/m2 on days 1 and 8, then every 28 days); there were 7 (22%) partial responses and 12 stable disease responses ○ A phase II trial of docetaxel and gemcitabine showed an overall response rate of 21% ○ With a median survival of 7 months, 39% were alive at 1 year. Docetaxel combined with carboplatin has been shown to have a 25% response rate.

● Gemcitabine

○ are camptothecin derivativeswhose cytotoxic mechanism is believed to target topoisomerase I ○ An international phase II trial reported a similar 21% response rate in patients predominantly with prior irradiation (1 complete and 8 partial responses among 42 patients)

● Irinotecanand topotecan

TREATMENT OF RECURRENT CARCINOMA OF THE CERVIX Para-aortic Lymph Node Recurrences

● Isolated recurrences in the para-aortic nodes after pelvic irradiation have been described in about 3% of patients, and some may be salvaged with aggressive therapy ● The advent of IMRTmakes treatment easier, with less morbidity

--Types of Hysterectomy ○ the cervix and upper vagina are removed, including paracervical tissues ○ the ureters are dissected in the paracervical tunnelto their point of entry into the bladder ○ Because the ureters are unsheathed and retracted laterally, parametrial and paracervical tissue can be safely removed medial to the ureter ○ This operation is performed with a lymphadenectomy ○ This is the MOST COMMON surgical approach selected for stage IA2 cervical cancer

● Modified radical extended hysterectomy (classII) ○ Type II​: ​MRH​. Half parametrium (uterosacral/cardinal ligs ​medial to ureter ​border) + ​1-2 cm​ of vag. ■ Consider for stage IA1 w LVSI or IA2 (< 8% w lymph nodes, double if LVSI).

○ a natural product found initially in the bark of the western yew tree, produces depolymerization and irreversible bundling of tubulinin the cell ○ It has been shown to have a radiosensitizing effect and may also be considered for patients with metastatic disease

● Paclitaxel

Treatment for cervical cancer: Carcinoma In Situ

● Patients with persistent high-grade carcinoma in situare usually treated with ○ a total abdominal hysterectomy with or without a small portion of the upper vagina removed ● The decision to remove the ovaries depends on the age of the patient and status of the ovaries ● Occasionally, when the patient wishes to have more children, carcinoma in situ may be treated CONSERVATIVELY with ○ a therapeutic conization ○ laser therapy, or ○ cryotherapy ● This approach should be judiciously selected when the extent of tumor allows it and the patient is reliable for continued follow-up ● Conization microscopic margins are CRITICAL in decision-making regarding a conservative approach or proceeding with a hysterectomy ● A therapeutic hysterectomycan be performed 6 WEEKS after the conization

TREATMENT OF RECURRENT CARCINOMA OF THE CERVIX -After Previous Surgery

● Radiation may salvage approximately 50% of patients with localized pelvic recurrences after surgery alone ● A combination of whole-pelvis external irradiation (45 to 50 Gy) with concurrent chemotherapy followed by interstitial brachytherapy is recommended ● If the tumor lies outside of an accessible region for brachytherapy, dose escalationwith conformal or IMRT techniquesmay be attempted, depending on the location of the tumor and the need to protect the bowel, with at least 65 to 70 Gy necessary for adequate control.

--Types of Hysterectomy ○ consists of a wider resection of the parametrial tissues to the pelvic wall ○ with dissection of the uretersand mobilization of the bladder, as well as of the rectumto allow for more extensive removal of tissues ○ This approach was described by Meigs in 1944 ○ In addition, a vaginal cuff of at least 2 to 3 cmis always included in the procedure, as well as the uterosacral ligaments ○ A bilateral pelvic lymphadenectomy is usually carried out ○ This operation is often referred to as the Wertheim or Meigs procedure

● Radical abdominal hysterectomy (class III) with bilateral pelvic lymphadenectomy ○ Type III​: ​RH​. Takes parametrium/cardinal ligament to​ pelvic sidewall ​w uterine artery ligated at internal iliac artery, uterosacral ligaments resected at attachment to sacrum, PLND. ​Upper 1⁄3 to 1⁄2 ​of vagina. ■ ○ Perform for 2-4 cm or non-bulky parametrial invmt. ■ ○ Most common Hys for cervical cancer.

-Surgical Techniques in cervical cancer ● Described in the 1960s ● entails removal of the cervix entirely ● Radical ________ ○ also removes the parametrial tissue ● As a means of fertility preservation in early-stage cervical cancer patients, trachelectomy should be combined with: ○ preoperative PET imaging - to confirm no nodal involvement ○ MRI - to confirm no endocervical canal extension of tumor into the uterus ● A laparoscopic lymphadenectomy ○ should accompany the trachelectomy to confirm no nodal involvement ● A non-absorbable cerclage is placed around the uterine isthmus ● Radical abdominal trachelectomy also may result in successful fertility preservation

● Radical trachelectomy § The radical vaginal trachelectomy with laparoscopic lymphadenectomy procedure (with or without SLN mapping) offers a fertility-sparing option for carefully selected individuals with stage IA2 or stage IB1 lesions (less than 2-cm diameter). The cervix, upper vagina, and supporting ligaments are removed as with a type B radical hysterectomy, but the uterine corpus is preserved. In the more than 300 subsequent pregnancies currently reported, there is a 10% likelihood of second trimester loss, but 72% of patients carry their gestation to 37 weeks or more.6 The abdominal radical trachelectomy is a reasonable fertility-sparing strategy. It provides larger resection of parametria than the vaginal approach, is suitable for select stage IB1-IB2 cases, and has been utilized in lesions between 2-4 cm in diameter. The operation mimics a type C radical hysterectomy.

TREATMENT OF RECURRENT CARCINOMA OF THE CERVIX -After Definitive Irradiation

● Reirradiationof previously irradiated patients must be undertaken with extreme caution ● It is very important to analyze the techniques used in the initial treatment(beam energy, volume, doses delivered with external or intracavitary irradiation) ● In addition, the period of time between the two treatments must be taken into consideration because it is postulated that some repair of the initial damage may take place in the interval. ● In general, external irradiation for recurrent tumor is given to limited volumes(40 to 45 Gy, 1.8-Gy tumor dose per fraction, preferentially using lateral portals) Occasionally,intracavitary or interstitial irradiationcan be used to treat relatively circumscribed recurrences. ● Selected patients with limited pelvic recurrences not fixed to the pelvic wall and without evidence of extrapelvic metastases can be potentially salvaged by radical hysterectomy or pelvic exenteration

Randomized Studies Comparing HDR to LDR Using Plain X-Ray Dosimetry ● Four randomized trials (Table 73.16) and a meta-analysis summarizing the results of these have been published comparing HDR and LDR brachytherapy for carcinoma of the cervix

● Teshima et al. ● Patelet al ● Hareyamaet al ● Lertsanguansinchaiet al

Plain X-Ray Simulation borders in cervical cancer

● The superior border is set at the L4-L5 interspace ○ in order to cover the common iliac lymph nodes ● the lateral borders 1.5 to 2 cm from the pelvic brim ● the inferior border covers at least the obturator foramen (Fig. 73.10). ○ More commonly in patients with large tumors, the inferior border extends to the ischial tuberosities ○ When there is vaginal involvement, the entire length of this organ should be treated down to the introitus ○ It is very important to identify the distal extension of the tumor at the time of simulation by placing a radiopaque clip or bead on the vaginal wall or inserting a small fiducial marker in the vagina ○ When the tumor involves the distal half of the vagina, the portals should be modified to cover the inguinal lymph nodes because of the increased probability of metastases (see Fig. 73.2). ● For the lateral field borders, in both postoperative and intact cervix settings ○ the posterior border ■ must be set in such a way that the entire sacrum is covered because the uterosacral ligaments are at high risk for harboring microscopic extension ■ The uterosacral ligaments insert onto the sacrum, and therefore, the posterior block should ensure coverage of the entire sacrum ○ The anterior border on the lateral field ■ should be set at a vertical line anterior to the pubic symphysis, because the external iliac lymph nodes must be covered.

Three-Dimensional Conformal Treatment Planning (borders)

● The superiorborder ○ is set based on the CT-visualized bifurcation of the common iliac nodes into the external and internal iliac nodes, which may lie as high as the L3-L4 interspace ○ If patients have positive pelvic nodes based on PET imaging, the superior border may be shifted to either ■ the superior border of the common iliac nodes or ■ the superior aspect of the renal hilum to treat the para-aortic nodes ○ In postoperative cases in which the patient has had an extensive surgical staging, the superior border may be ■ reduced to the L5-S1 interspace ● The inferiorborder ○ Similar to plain x-ray simulation, in patients with vaginal involvement ○ is extended to cover 2 cm below the lowest extent of disease, which may lie in the vulvar tissue, and in such cases, the inguinal lymph nodes are treated, resulting in a wider AP field. ● On the lateralfields, the anterior border ○ covers the front of the pubic symphysis ● For the lateralborders in postoperative and intact cervix cases, posterior coverage of the entire sacral hollow is imperative

--Types of Hysterectomy ○ consists of removal of the cervix and adjacent tissues, as well as a small cuff of the upper vagina in a plane outside the pubocervical fascia ○ There is minimal disturbance of the ureters and the trigone of the bladder ○ This may be the SURGICALTREATMENT OF CHOICE for stage IA1 cervical cancer

● Total (extrafascial) abdominal hysterectomy (class I) ○ Type I​: ​TAH ​(extrafascial). Uterus, cervix and small rim of vag cuff (outside pubocervical fascia). ■ Consider for stage IA1 without LVSI, inner third stromal invasion (< 1% w lymph nodes).

○ have been used to treat young patients with microinvasive carcinoma to preserve fertility ○ The overall incidence of central recurrence is approximately 5%.

● Vaginal trachelectomy (removal of the cervix) and laparoscopic lymphadenectomy

○ is a semisynthetic derivative of vinblastine ○ In a phase II trial in patients with prior irradiation, a 28% response rate was observed ○ Other trials used the drug as neoadjuvant chemotherapy; in 42 patients, 2 complete and 17 partial responses (45%) were observed

● Vinorelbine