Therapeutic strategies in primary malignancies of the vagina – a literature review

Nicolae Bacalbasa, 2 Dimitrie Racovita St., Bucharest E-mail: nicolae_bacalbasa@yahoo.ro ABSTRACT Primary vaginal cancers are very rare malignancies accounting for only 1 to 2% of all gynecologic malignancies. The most frequent histologic subtype is squamous cell carcinoma followed by adenocarcinoma. Due to its rarity, data concerning the natural history, prognostic factors, and treatment are rather poor; however an extension of the reported clinical experience for cervical and anal cancer has been proposed given the similarities in disease etiology and the desire for organ preservation. This is a literature review of the most appropriate therapeutic strategies used in vaginal cancer management.


INTRODUCTION
The overall reported incidence of vaginal cancer is 0.45 cases per 100 000 women with lower rates in white (0.42) compared with black (0.73) and Hispanic women (0.56) (1). The median age at diagnosis is 58. According to FIGO classifi cati on, tumors should be classifi ed as carcinoma of the vagina only when the primary place of growth is the vagina therefore being necessary the exclusion of cervical, vulvar or urethral origins (2).
When talking about the most common seen histopathological subtypes, squamous cell carcinoma (SCC) represents more than 90% of all primary tumors while adenocarcinomas account for approximately 5% (3). Other histological subtypes are very rare and include malignant melanomas, neuroendocrine carcinomas and papillary squamo-transiti onal cell carcinomas Abbreviati ons SCC = squamous cell carcinoma; VAIN = vaginal intraepithelial neoplasia; EBRT = external beam radiati on therapy; RT = radiotherapy (4). Müllerian adenosarcoma developing from vaginal endometriosis or endometrioid carcinoma have also been described in the literature but their incidence remains very low (5,6).
Due to the low incidence of the primary vaginal tumors there is a wide variety of therapeuti c modaliti es to which women can be subjected to. This review focuses on the most appropriate treatment opti ons for the primary vaginal cancer.

RISK AND PROGNOSTIC FACTORS
The peak incidence of SCC is reached during the sixth and seventh decades while less than 15% of pati ents are diagnosed below the age of 50 years, and <10% of these tumors occur in pati ents under the age of 40 years. SCC vaginal cancer frequently metastasizes to the lung and liver (4).
SCC of the vagina has been linked with the human papillomavirus infecti on, specifi cally with serotypes 16 and 18 which were identi fi ed in more than 50% of all pati ents. Due to the associati on with HPV infecti on, vaginal in situ and invasive SCC present similar risk factors to the cervical cancer. Vaginal intraepithelial neoplasia (VAIN) is a precursor to invasive cervical cancer and almost 2% of pati ents with VAIN will progress to invasive cancer (7).
Adenocarcinomas usually occur in younger pati ents, with ages ranging between 17 and 21 years; the sites of distant metastases are lung, supraclavicular and pelvic nodes (5). Clear cell adenocarcinomas usually occur in women below the age of 30 years who had been exposed to syntheti c estrogen-diethylsti lbestrol (8).
The prognosis of primary vaginal tumors seems to be strongly correlated with FIGO stage at the moment of diagnosis; it seems that the initi al FIGO stage signifi cantly impacts on the rate of survival also being correlated to the development of local recurrence or distant metastasis (9). Other incriminated prognosti c factors are the tumor size and locati on and pati ent's age, but their impact on the prognosis is sti ll a matt er of debate (10).
Several studies have reported that cancers developing in the proximal half of the vagina have a bett er survival and a decreased recurrence rate when compared to lesions involving the distal half or the enti re length of the vagina. Lesions of the posterior vaginal wall have a worse prognosis with a higher incidence of lymph node metastasis than cancers located in the anterior wall or the vaginal apex (11)(12)(13).
Another prognosti c factor is the lymph nodal status. The lymphati c fl ow from the upper third of the vagina drains primarily at the level of common, internal and external iliac lymph nodes while the lower part of the vagina drains into the inguino-femoral lymph nodes (14). The histologic type and grade are independent predictors of survival, a higher incidence of local recurrences being observed in women with ade nocarcinoma than those with SCC (11).

STAGING AND MANAGEMENT
According to FIGO staging of the lesion, various imagisti c studies have been proposed including chest radiography, cystoscopy, rectoscopy and intravenous urography; CT scanning, MR imaging and FDG-PET may also help to guide therapy (15).
The staging system for vaginal cancer is rather based on clinical criteria.
Stage I disease is limited to the vaginal wall, stage II disease involves the surrounding ti ssues with no extent to the pelvic wall, stage III tumor extends to the pelvic wall while stage IV tumors extend beyond the true pelvis or present local invasion of the bladder or rectal mucosa. The therapeuti c opti ons depend on FIGO stage of the tumor, lesion's locati on and histopathological subtype. Most data available in the literature concerning the surgical and radio-therapeuti c procedures refer to SCC of the vagina (16).

Stage I
The treatment approaches for stage I include RT with or without surgery. In stage I vaginal cancer, the rate of lymph node involvement ranges from 6 to 16% (17). Surgery in this stage refers to: wide local excision with disease with tumor free margins (for small lesions) or more extended resecti ons such as parti al vaginectomy, total simple vaginectomy and radical vaginectomy (removal of the involved vagina and paravaginal ti ssue to the pelvic sidewall) for larger lesions. Vulvovaginectomy and dissecti on of the inguinofemoral lymphati c nodes seems to be the most appropriate approach for cancers located in the lower third of the vagina followed by adjuvant RT if the margins are positi ve for tumor invasion aft er resecti on (17).
Reports from the Nati onal Cancer Database show that in women with FIGO stage I of the disease surgery alone has clinically and stati sti cally bett er results than RT with a 5-year relati ve survival rate of 56-90% for cases treated only with surgery; however these rates signifi cantly improve whether adjuvant radiati on therapy is associated (with a reported rate of 5 year overall survival of 79-100%). Studies have shown that this improvement has been parti cularly obtained in cases at risk to develop local recurrences (16,18).
RT alone with the use of intersti ti al (singleplan implant) and intracavitary therapy with a minimum dose of 75 Gy is an accepted method of treatment for stage I vaginal cancer with a cumulati ve 5-year survival rate between 33-100% (11,19). Pelvic failure rates following brachytherapy alone range from 14% to 33%. Anterior, posterior, or total exenterati on is performed less commonly for early-stage disease, as radiati on therapy is the preferred modality for organ preservati on (10,11).
External Beam Radiotherapy (EBRT) can be used for large, infi ltrati ve or poorly diff erenti ated tumors which are associated with a high risk of lymph node metastasis or loco-regional failure (20).

Stage II
The standard treatment of this stage consists in brachytherapy associated with EBRT, a therapeuti c strategy which has been associated with improved pelvic control and improved rates of survival (21,22). The predominant patt ern of failure following RT is locoregional, similar to the one encountered aft er surgery (22).
Intersti ti al brachytherapy has been proved to have bett er results in terms of disease free survival and local control when compared to intracavitary therapy (22). The choice between intracavitary or intersti ti al radiotherapy depends on the site and size of the tumor. Intracavitary radiati on therapy is used if the residual disease is no more than 3-5 mm from the vaginal surface. Pati ents with deeper lesions are treated with intersti ti al implants. Tumors of the middle third of the vagina are handled with intracavitary and intersti ti al brachytherapy. Intersti ti al radiati on therapy boosts are used for the tumors of the distal part of the vagina; in these cases pelvic and inguinal irradiati on might be taken in considerati on if lymph node metastases at these levels are expected (23,24).
There are few studies which examine the impact of RT combined with systemic cytotoxic agents such as 5-Fluoro-Uracil or Mitomycin-C on the local control and survival in pati ents with stage II vaginal cancer. Dalrymple et al conducted a study involving 14 cases diagnosed with stages I and II vaginal cancer and reported a 5-year overall survival of 93% aft er a protocol which included the associati on of RT (with doses of 63 Gy) and chemotherapeuti c regimens based on 5-Fluoro-Uracil (25).
Further investi gati on is required to determine if women with stage II disease can be cured with radical surgery. Total vaginectomy or an exenterati ve procedure is required in order to obtain negati ve surgical margins (14). Laparoscopic radical vaginectomy with the constructi on of a neovagina has been proposed as an organ-sparing surgical alternati ve (26).
Neoadjuvantchemotherapy (NACT) with cisplati n and paclitaxel followed by radical vaginectomy and pelvic lymphadenectomy might provide a parti al and respecti vely a complete response in 64% and respecti vely 27% of cases (27). In pati ents with an incomplete resecti on or positi ve lymph nodes, adjuvant RT might provide a 5-year survival rate of 40-69% (9,14,17).

Treatment of locally advanced disease (FIGO stages III-IV)
The associati on between EBRT and brachytherapy remains the treatment of choice for stage III vaginal cancer (22,28). EBRT administered for 6 weeks appears to improve survival (22) while brachytherapy is important for the local management of the disease (28). In selected cases another appropriate approach is pelvic exenterati on or a combinati on between irradiati on and exenterati on (9,18).
For stage IVA of the disease the most appropriate therapeuti c approach consists in a combinati on between intersti ti al, intracavitary RT and EBRT with reported 5 year survival rates of 0-62% (9,18,22,28). For women with stage IV A who are in good general conditi on a pelvic exenterati on with vaginal reconstructi on using a gracilis myocutaneous fl ap or rectus abdominis myocutaneous fl ap may be a treatment opti on with a 5-year survival rate of 0-50%; a similar approach might also be useful in cases necessitati ng palliati on in order to treat a locally advanced vaginal cancer associated with rectovaginal or vesicovaginal fi stula (16,29).
For stage IV B of the disease, palliati ve radiati on therapy with or without simultaneous chemotherapy remains the most appropriate therapeuti c opti on (11,18).
The cause-specifi c survival rates of the advanced-stage vaginal cancer range from 23-59% for stage III of the disease and from 0-25% for stage IV of the disease. Corresponding pelvic control rates are 62-71% and respecti vely 12-30% (30,31). However, almost 80% of pati ents report persistent or recurrent pelvic confi ned disease aft er EBRT or brachytherapy. When talking about distant metastases, their incidence reaches almost 25-30% among pati ents with locally advanced tumors (32).
A survival advantage for the use of NACT prior to radical surgery has not been found in randomized trials of pati ents with locally advanced vaginal cancer; however experience in this directi on proved to be limited (32,33).

Concurrent chemoradiotherapy
Although there are no prospecti ve trials for the use of concurrent RT in pati ents with vaginal cancer, insti tuti onal reports support the uti lity of chemoradiotherapy based on survival rates observed in trials of locally advanced cervival cancer (34). Series of pati ents with early-and late-stage of the disease had a local control rate of 92% and a 5-year progression-free survival rate of 75% with concurrent weekly administrati on of cisplati n (40 mg/m 2 ). A series of 26 pati ents with predominately locally advanced disease was treated with defi niti ve RT and 5-FU with or without mitomycin C or weekly singleagent cisplati n. A 5-year survival rate of 50% and a pelvic failure of 31% were reported (35).

Treatment considerations and follow-up
Treatment-related factors associated with poor survival in vaginal cancer are prolonged overall treatment ti me and low hemoglobin levels. RT should be completed within 8-9 weeks and transfusion should be performed in order to maintain hemo globin levels of > 10-11 g/dl. Prolongati on of the treatment ti me does not appear to have a signifi cant impact on pelvic tumor control (31). Some authors emphasized the potenti al advantage in terms of disease-free survival and local control using intersti ti al RT when compared to the use of intracavitary therapy (14,22).
The follow-up for vaginal cancer implies a clinical examinati on every 3 months for 2 years followed by less frequent intervals aft er 2 years. Based on the practi ce for locally advanced cervical cancer, considerati on of post-treatment PET/ CT surveillance is reasonable for pati ents with initi al bulky disease (36).

CONCLUSIONS
Vaginal cancer is a very rare disease which is frequently diagnosed when the disease has already involved the submucosal layer and someti mes the pelvic sidewall. Moreover, the prevalence of the disease in elderly pati ents makes the treatment more diffi cult. The management depends on the extent of disease, the presence of comorbiditi es, and the desire to maintain the ovarian and/or sexual functi on.
For cases diagnosed in FIGO stage I, the most appropriate treatment consists in radical surgery with or without adjuvant radiotherapy. The studies carried out on retrospecti ve series have shown equivalence or even the superiority of surgery compared to RT alone in FIFO stage I. In FIGO stage II the standard treatment remains the combinati on of brachytherapy and EBRT or radical surgery for selected pati ents. NACT followed by radical surgery is a valid alternati ve to the standard treatment in terms of survival.
Combinati on of EBRT and brachytherapy followed by resecti on is the most effi cient opti on in FIGO stages III-IV A. For women with FIGO stage IVB of the disease palliati ve RT may play an important role in alleviati ng the pain and bleeding associated with uncontrolled pelvic disease.
Further data are required for the use of concurrent chemo-radiotherapy as a treatment strategy.
However, it seems that the management strategies introduced in cervical cancer, such as NACT + RT will be applicable to primary vaginal cancer too; similar survival rates are expected, without aff ecti ng the quality of life.