Vaginal Cancer

Episode Notes

1. Epidemiology

1. Very rare - <1% of gynecologic cancers worldwide

2. Majority (~80%) metastatic from vulva, cervix, endometrium, etc

1. Can only be diagnosed if there is no other primary and does not touch the cervix or vulva

3. ~80% SCCs

1. Majority are HPV-dependent

1. Precursor lesions vaginal LSIL/HSIL

2. HPV 16 most common culprit

2. HPV-independent

1. More common in postmenopausal

2. P53 positive, p16 negative on staining

4. Peak incidence in 6th-7th decade of life

5. Other histologies

1. Primary vaginal melanoma second most common

2. Adenocarcinoma 

3. Sarcoma: sarcoma botyroides

4. Clear cell cancers of vagina

1. Idiopathic or from DES exposure

2. DES: diethylstilbestrol: historic synthetic estrogen given between 1940s-70s to prevent miscarriage, premature labor, and related complications of pregnancy

3. Vaginal adenosis can be precursor, but not always

2. Presentation

1. Symptomatology mimics cervical cancer

2. Posterior wall of upper ⅓ of vagina most common site

3. Prognosis

1. 5 yr OS

1. Stage I: 70-95%

2. Stage II: 35-70%

4. Workup

1. Thorough pelvic exam with biopsy

1. Consider EUA, cysto, and/or procto

2. Exclude prior h/o cervical or vulvar carcinomas in last 5 years

1. 5 year cutoff is arbitrary; cervical or vulvar cancers can come back after that time point but it’s rare… so look at both treatment algorithms to determine best plan of care

3. Pelvic MRI w/ and w/o IV contrast and vaginal gel for evaluation of local disease

4. Consider PET CT vs CT C/A/P

5. Labs: CBC, CMP, HPV testing, consideration of HIV testing

5. Staging

1. FIGO stage I: confined to vagina

1. T1a: <2 cm tumor diameter

2. T1b: >2 cm tumor diameter

2. FIGO stage II: invades paravaginal tissues but does not extend to side wall

3. FIGO stage III: extends to pelvic sidewall and/or causes hydronephrosis or a nonfunctioning kidney, or involves nodal disease (pelvic or inguinal nodes)

4. FIGO stage IVA: invades bladder or rectal mucosa but does not extend beyond the true pelvis

5. FIGO stage IVB: distant metastases

6. Pelvic vs Inguinal Nodes?

1. Classical teaching is that lesions of the upper ⅔ of the vagina drain to the pelvic nodes and lower ⅓ goes to inguinal nodes

2. Frumovitz et al. 2008

1. small series of 14 patients with vaginal cancer in 2008 which demonstrated that, on pretreatment lymphoscintigraphy, 3 of 5 patients with lower vaginal lesions had sentinel lymph nodes in the pelvis, and 2 of 4 patients with upper vaginal lesions had sentinel lymph nodes in the inguinal nodes. So for these patients, either nodal bed could be implicated.

7. Treatment Overall

1. No randomized trials!

2. Radiation therapy listed as preferred on NCCN, even for stage I lesions

1. Treatment time no greater than 8 weeks

2. Total 45-50 Gy if using IMRT; nodal boost can be considered

3. If brachytherapy is being added, the dose should be 70-80 Gy total, with lower doses (70-75) in the lower vagina

8. Stage 1 Treatment Options

1. Radiation: intracavitary brachytherapy alone (often a vaginal cylinder) is preferred if the lesions are < 2 cm (T1a) and the thickness of the lesion is <= 5 mm.  If the lesion does not meet this criteria, there is no standard recommendation, but most proceed with EBRT + brachytherapy

2. Surgery: only recommended if complete resection w/ completely negative margins is expected (usually correlating with a tumor <2 cm and maybe up to 3 cm)

1. For microscopic lesions of the upper vagina: consider an upper vaginectomy with or without a hysterectomy

2. Macroscopic lesions <2 cm: radical hysterectomy may be appropriate

3. No data about how to assess lymph nodes in primary vaginal cancer

3. Adjuvant Treatment after surgery?

1. Negative margins → observe

2. Positive or close margins → adjuvant RT or chemoRT and/or brachytherapy

9. Stage II-IVA Treatment

1. ChemoRT + brachytherapy

2. Consider ovarian transposition for premenopausal patients

10. Literature Informing Above

1. Brachytherapy Recommendation

1. Frank et al. 2005

1. 193 pts w/ primary SCC of the vagina treated between 1970-2000

2. EBRT + brachytherapy vs EBRT alone

3. Stage and tumor size > 4 cm were the only factors significantly associated with survival on multivariate analysis. 

4. Type of radiation (brachy or EBRT alone or in combination) was not significant for disease control rate, but again, recognize the heterogeneity in which the radiation was given over the span of time.

2. Orton et al. 2016

1. SEER database study of 2,517 patients

2. EBRT alone vs brachytherapy (alone or in combo with EBRT)

3. OS: 3.6 years w/ EBRT alone vs 6.1 years w/ brachy alone or in combo

4. Brachytherapy had a lower hazard for death compared to EBRT alone in all stage subgroups, and the benefit persisted in both squamous cell and adenocarcinoma.  Tumors > 5 cm had the greatest benefit from brachytherapy.

3. Takeaway: larger lesions and higher stages worse oncologically, improved OS with brachytherapy w/ or w/o EBRT; brachy is a part of all treatment recommendations, and for select small lesions, can be given w/o additional EBRT

2. Chemoradiation Recommendation

1. Miyamoto et al. 2013

1. 50 w/ RT alone, 20 w/ chemoRT

2. 3 year OS 56% for RT alone and 79% for chemoRT

3. ChemoRT w/ HR 0.31 for disease free survival

4. Other significant predictors for disease free survival and overall survival included radiation dose, FIGO stage, tumor size, and year of diagnosis.

2. Rajagopalan 2014

1. NCDB data

2. 8,222 with primary vaginal cancer treated 1998-2011

3. 47.8% received chemoRT

4. Median OS 52.6 mo w/ chemoRT vs 41.2 mo w/ RT alone

5. Significant benefit to median OS in stage I patients (83.5 mo vs 109 mo) which is why chemoRT is listed in NCCN guidelines as an option for stage I

6. Even stronger difference for later stage disease, nearly doubling OS

7. Factors independently prognostic on multivariate analysis from most to least impact on survival included: lower stage, use of brachytherapy, use of chemoRT, lower comorbidities, higher facility volume, and younger age.

3. Takeaway: chemoRT leads to superior oncologic outcomes in vaginal cancer compared to radiation alone, even in earlier stage disease.

3. Modern Radiation Studies

1. RetroEMBRAVE 2021

1. Provided support for the use of image guided adaptive brachytherapy in vaginal cancer

2. Retrospective, observational, multicenter study conducted in Europe. 

3. 64% of the 148 patients received chemoRT and 3 received brachytherapy alone. Median max tumor diameter at diagnosis was 4 cm.  

4. On multivariate analysis, only nodal disease was negatively associated with disease free survival, with a hazard ratio of 2.24.

5. In patients with larger tumors (T2-4), local control was significantly improved with higher doses of radiation at the time of brachytherapy. Importantly, higher doses of radiation did not seem to lead to higher severe late toxicity - an achievement of volumetric image guided brachytherapy compared to traditional 2D radiotherapy.

11. Surveillance

1. Seen every 3-6 months x 2 years, then every 6-12 months x 3-5 years, then annually

2. Imaging 3-4 months after finishing therapy to assess response

3. Concerned about Recurrence? → Biopsy!

12. Recurrence

1. Without prior radiation

1. chemoradiation +/- brachytherapy or EBRT +/- brachytherapy should be given.  If a patient has received prior intracavitary brachytherapy only, then EBRT +/- systemic therapy +/- interstitial brachytherapy can be given.  Surgery in select patients can also be considered.

2. With prior radiation

1. Options are based on location of recurrence 

1. If central recurrence, consider pelvic exenteration.  There is a category 3 recommendation to add intraoperative radiotherapy.  

2. If noncentral, systemic therapy OR resection +/- IORT (category 3) is recommended, or reirradiation, or best supportive care.

13. Stage IVB or Metastatic or Recurrent Treatment

1. Systemic therapy

2. Choice of agent depends on biomarker testing

3. First-line mirrors cervical cancer: cisplatin + paclitaxel +/- bevacizumab with the addition of pembrolizumab for PD-L1 positive tumors

4. Note that in the NCCN guidelines: pembrolizumab in the up front setting is recommended based on PD-L1 status, while in the second line/recurrent setting, it’s recommended for TMBH, MSIH, MMRd, or PD-L1 positive tumors

References

1. Frumovitz M, Gayed IW, Jhingran A, et al. Lymphatic mapping and sentinel lymph node detection in women with vaginal cancer. Gynecol Oncol. 2008;108(3):478-481. doi:10.1016/J.YGYNO.2007.12.001

2. Frank SJ, Jhingran A, Levenback C, Eifel PJ. Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys. 2005;62(1):138-147. doi:10.1016/j.ijrobp.2004.09.032

3. Rajagopalan MS, Xu KM, Lin JF, Sukumvanich P, Krivak TC, Beriwal S. Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: A National Cancer Data Base (NCDB) study. Gynecol Oncol. 2014;135(3):495-502. doi:10.1016/j.ygyno.2014.09.018

4. Miyamoto DT, Viswanathan AN. Concurrent Chemoradiation for Vaginal Cancer. PLoS One. 2013;8(6). doi:10.1371/journal.pone.0065048

5. Orton A, Boothe D, Williams N, et al. Brachytherapy improves survival in primary vaginal cancer. Gynecol Oncol. 2016;141(3):501-506. doi:10.1016/j.ygyno.2016.03.011

6. Westerveld H, Schmid MP, Nout RA, et al. Image-guided adaptive brachytherapy (Igabt) for primary vaginal cancer: Results of the international multicenter retroembrave cohort study. Cancers (Basel). 2021;13(6). doi:10.3390/cancers13061459

7.Naumann RW, Hollebecque A, Meyer T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739