SUMMARY OF LITERATURE REVIEW
Definition of Locoregionally Advanced Vulvar Cancer (LRAVC)
Vulvar cancer is a rare disease, with an estimated incidence of 4490 new cases and 950 deaths in the United States in 2012.1 Vulvar cancer predominantly involves older women, with 68 years as the median age of diagnosis. Over the past 25 years the incidence has slightly increased.2
Vulvar cancer prognosis is intricately related to the extent of the primary and most importantly lymph node involvement, as reflected in the recently revised 2009 staging system of the International Federation of Gynecology and Obstetrics (FIGO) staging.3,4
Although a formal definition of LRAVC does not exist, it has been addressed in the context of several clinical trials as vulvar disease without distant metastasis that is beyond surgical resection with standard radical vulvectomy, irrespective of groin lymph node involvement. Included in this category are patients with FIGO clinical stage III or IVA carcinoma of the vulva, tumor extension to the adjacent genitourinary system and anorectum, or fixation to bones. Approximately 30% of vulvar patients present with stage III-IV disease or lymph node involvement.2 In the revised FIGO staging, stage II disease includes tumor of any size with extension to adjacent perineal structures (one third lower urethra, one third lower vagina, anus, with negative nodes).4 These patients should also be included in this category as they are generally beyond curative resection with radical vulvectomy alone, and definitive curative surgery would be associated with significant morbidity. Management of LRAVC requires considerable pretreatment assessment and planning to determine the best course of therapy for individual patients.
Initial Workup and Evaluation of LRAVC
The staging workup for patients with LRAVC before neoadjuvant therapy or surgical resection is not standardized. The extent of the primary tumor can generally be assessed clinically, although imaging may aid in determining the extent of involvement or invasion into surrounding normal organs. Although inguinal-femoral lymph node involvement is a significant determinant of prognosis, clinical palpation is unreliable for determining the presence of groin lymph node metastasis,5 and imaging may assist with this assessment. In addition, for LRAVC, imaging can help identify inguinal lymph node depth and the presence of distant metastatic disease, both of which can impact treatment planning.
Potential imaging modalities for LRAVC include ultrasound, computed tomography (CT), positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI). Ultrasound along with fine-needle aspiration has shown a high level of sensitivity and specificity for identifying involved inguinal lymph nodes for vulvar cancer.6,7 Although CT can be used to assess depth of groin lymph nodes, some studies suggest that other imaging modalities, if available, are more useful. Given the rarity of vulvar cancer, many of the diagnostic and treatment approaches are extrapolated from cervical and anal cancer. The clinical value of fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT in cervical cancer for primary staging and surveillance has been extensively evaluated.8–11 A more limited number of studies have also evaluated the utility of FDG-PET for anal cancer.12,13
Scant studies have been reported concerning the management of vulvar cancer using FDG-PET. Cohn et al14 in a prospective study, evaluated the role of FDG-PET in staging disease with respect to groin nodal metastasis, before nodal dissection. These investigators registered 67% sensitivity, 95% specificity, 86% positive predictive value (PPV), and 86% negative predictive value (NPV) for detecting nodal metastasis, while for detection of extranodal disease, FDG-PET demonstrated high specificity and accuracy. Significantly, PET was better at detecting extranodal metastases than groin metastases in this small study of vulvar cancer patients.
For LRAVC, MRI can determine the degree of involvement of normal organs and assist in identifying lymph node metastasis. The sensitivity and specificity of MRI for detecting abnormal lymph nodes in vulvar cancer critically depend on the size threshold used for distinguishing normal and abnormal lymph nodes. For a group of 22 vulvar patients, using ≥10 mm in the short axis as the threshold for superficial inguinal nodes, MRI has a 40% sensitivity and 97% specificity for detecting nodal metastasis.15 In evaluating 39 vulvar cancer patients who had undergone MRI and inguinofemoral lymphadenectomy, MRI had a sensitivity of 86% (64% to 97%), specificity of 82% (70% to 91%), PPV of 64% (44% to 81%), and NPV of 94% (83% to 99%). Clinical examination had a specificity of 94% (84% to 99%), PPV of 70% (35% to 93%), and NPV of 80% (67% to 89%).16 On the basis of these small studies, MRI may be useful for assessing inguinal-femoral lymph node involvement, but given the significant implications of groin lymph node involvement, imaging is not a substitute for pathologic assessment.
Role of Sentinel Lymph Node (SLN) Biopsy
It is important to emphasize that the clinical investigations in SLN biopsy procedures have involved study populations primarily with early-stage disease. There are no data regarding SLN procedures for patients with locally advanced vulvar cancers who have a higher risk of lymph node metastasis and specifically bulky nodal disease.
It has been well recognized that the presence of lymph node metastasis is the most important prognostic factor in vulvar carcinoma.17,18 As no imaging technique can exclude the presence of lymph node metastasis with a sufficiently high NPV,19,20 surgical evaluation with inguinal-femoral groin lymph node lymphadenectomy is the standard method to assess for the presence of groin lymph node metastasis. The SLN procedure is emerging as a means to adequately assess for groin lymph node metastasis and minimize the risk for surgical complications. The Gynecologic Oncology Group (GOG) has reported the results of a phase II multi-institutional study of SLN biopsy. Eligibility was limited to women with vulvar squamous cell carcinoma, ≥1 mm invasion, primary tumor size 2 to 6 cm, and clinically negative groin lymph nodes. All women underwent intraoperative lymphatic mapping and SLN biopsy followed by inguinal-femoral lymphadenectomy. The sensitivity was 91.7% and the false-negative predictive value (1−NPV) was 3.7%.21
In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS)-V trial, patients with T1-T2 (primary < 4 cm) squamous cell carcinoma of the vulva underwent SLN detection. For patients with a negative SLN as determined by pathologic ultrastaging, inguinal-femoral lymphadenectomy was omitted. Among 259 patients with median follow-up of 35 months, there were 6 groin recurrences (2.3%; 95% confidence interval, 0.6%-5%), and the 3-year survival rate was 97% (95% confidence interval, 91%-99%).22 Patients with metastatic disease in the SLN(s), either by routine examination or by pathologic ultrastaging, underwent inguinal-femoral lymphadenectomy. In investigating the relationship of SLN metastasis size and risk of non-SLN metastasis and disease-specific survival, it was found that no size cutoff seemed to exist below which chances of non-SLN metastases were close to 0, and it was concluded that all patients with SLN metastases should have additional groin treatment. The prognosis for patients with SLN metastasis > 2 mm was poor, and novel treatment regimens should be explored for these patients.23
A second observational study (GROINSS-V II) has been initiated whereby groin lymphadenectomy is omitted and patients with positive SLNs will proceed with postoperative chemoradiation therapy. Eligibility criteria are those of the first GROINSS-V study plus pretreatment CT/MRI is required to exclude the presence of bulky groin lymph nodes. The study has reached approximately 30% of planned accrual and is expected to close in 2014.
Rationale for Neoadjuvant Therapy in the Management of LRAVC
In women presenting with LRAVC, surgical treatment options range from radical vulvectomy and bilateral inguinofemoral lymphadenectomy with or without partial resection of the urethra, vagina, or anus to pelvic exenteration. This can be followed by adjuvant radiotherapy (RT) or chemoradiotherapy depending on the residual disease or risk of recurrence. Plastic reconstruction procedures are considered following excision of large vulvar tumors. When the disease involves the anus, rectum, rectovaginal septum, proximal urethra, or bladder, in order to obtain adequate surgical margin, some form of pelvic exenteration is the only surgical option. Such radical surgery is often undesirable or inappropriate, as this treatment results in a 10% operative mortality and high complication rates, and may require a permanent colostomy and/or urinary diversion, with the subsequent severe implications in terms of significant physical and psychological morbidity. In addition, patients presenting with fixed or ulcerated groin nodes are often not amenable to surgery. Given the morbidity associated with upfront surgery in LRAVC, the use of neoadjuvant chemotherapy and radiation emerged.
Neoadjuvant RT Alone
Boronow and colleagues24,25 first reported on the efficacy of neoadjuvant RT followed by surgical resection as an alternative approach to pelvic exenteration in patients with LRAVC. In this series of 48 patients, including primary and recurrent disease, 77% of patients received preoperative RT or brachytherapy with or without external beam radiation therapy (EBRT) followed by radical vulvectomy. No residual disease was identified in 42.5% of surgical specimens. Exenteration was performed in only 5% of the cases. The 5-year survival rates were 75.6% for the primary cases, 62.6% for the recurrent cases, and an overall 72% for all 48 cases treated.
In a subsequent publication, Hacker et al26 published similar findings in 8 patients treated with moderate doses of preoperative RT. In 87.5% of them satisfactory shrinkage of tumor occurred, thus allowing conservative surgical excision. In 50% of the cases there was no viable tumor in the surgical specimen, and 62.5% of patients were without evidence of recurrent cancer. Although the data are limited, it seems that moderate doses of preoperative radiation alone (45 to 54 Gy EBRT ±24 Gy brachytherapy) allows downsizing of the tumor in 70% to 85% of patients, obviating the need for pelvic exenteration and resulting in significantly less morbidity without apparently compromising survival.
Neoadjuvant Chemotherapy Alone
Neoadjuvant chemotherapy alone has also been investigated as a potential means of downstaging advanced vulvar cancer to allow for a less extensive surgery. One of the initial reports of using neoadjuvant chemotherapy for advanced vulvar cancer was a case report out of Tokyo where a woman with stage IV (T3N3+M1B) vulvar cancer was treated with 3 cycles of bleomycin, vincristine, mitomycin C, and cisplatin. She showed a clinically complete response and was able to undergo a radical vulvectomy with bilateral inguinal and pelvic lymphadenectomy which showed a partial pathologic response.27
Different chemotherapy regimens have been used to avoid primary pelvic exenteration with varying degrees of success (Appendix 1). In countries where radiation therapy is not available, neoadjuvant chemotherapy could be considered as a potential neoadjuvant option.
Neoadjuvant Chemotherapy and Radiation
The addition of chemotherapy concurrent with RT for treating vulvar carcinoma was heavily influenced by advances in the treatment of squamous cell carcinoma of the anal canal, which showed improved local control and colostomy-free survival with concurrent chemotherapy, specifically 5-FU plus mitomycin C.28–32
There have been a number of retrospective reports published in the literature that demonstrated the feasibility and potential therapeutic benefit of concurrent chemoradiation in patients with vulvar cancer.33–43 Despite the fact that these studies included different patient populations, LRAVC and patients with recurrent disease, various chemotherapy regimens, and radiation fractionation schemes, most of them reported high response rates and impressive local control (Appendix 1). A recent survey from the Gynecologic Cancer Intergroup (GCIG) study on patterns of care for RT and chemotherapy in vulvar cancer confirms that there is a difference in the indications for treatment, treatment fields, and use of chemotherapy among various members of the GCIG, even though the doses of radiation were similar among the members.44
The GOG completed a phase II trial to determine the feasibility of using preoperative chemoradiotherapy to treat T3 or T4 primary tumors that were unresectable or to avert the need for more radical surgery (GOG 101).45 A total of 73 evaluable patients with unresectable T3/T4 primary vulvar tumors with either N0/N1 groin nodes (50 patients) or N2/N3 groin nodes (23 patients) were included in this analysis. The treatment schema consisted of a split course of chemoradiation therapy delivered with anterior-posterior/posterior-anterior (AP/PA) fields to a total dose of 4760 cGy using a split course followed by surgical excision of the residual primary tumor plus bilateral inguinal-femoral lymph node dissection. For patients with clinical N2/N3 groin nodes, the radiation field included inguinal-femoral lymph nodes and lower pelvic nodes, in addition to the primary vulvar tumor. During each split course of radiation, 5-FU 1000 mg/m2/day was given as a continuous infusion over the first 4 days, and cisplatin 50 mg/m2 was given as a single brief infusion on the first day. During the 4 days of chemotherapy administration, the radiation was administered in 2 daily fractions of 170 cGy given at least 6 hours apart. For the remainder of each half of the split course, radiation was given as a single daily fraction of 170 cGy, thus bringing the total dose per course to 2380 cGy. Courses were separated by one and 1/2 to two and 1/2 weeks as determined by the severity of the acute vulvoperineal skin reaction.
This concurrent chemoradiation regimen yielded encouraging results, with an overall response rate of 33/71 (46.5%). Only 2/71 patients (2.8%) had residual unresectable disease, and among the 50 patients initially requiring exenterative surgery, only 1 patient required exenterative surgery and 2 patients required colostomy to resect residual disease. At a median follow-up of 50 months, 24 women (32.9%) developed recurrent vulvar cancer and 40 patients (54.9%) were alive and without evidence for recurrent disease. Toxicity was acceptable, with acute cutaneous reactions to chemoradiotherapy and surgical wound complications being the most common adverse effects. This trial demonstrated that preoperative chemoradiotherapy is feasible in patients with LRAVC and may reduce the need for more radical surgery, including pelvic exenteration.45
GOG 101 also included 46 women with unresectable N2/N3 groin lymph nodes who underwent preoperative chemoradiation. Among patients who completed chemoradiation and were considered for surgery, the nodes became resectable in 38/40 patients (95%). One of these patients underwent radical vulvectomy without groin lymphadenectomy. The lymph node specimens were histologically negative in 15/37 patients (41%). Only 1 patient experienced a groin failure. Overall, 20 patients were alive and without evidence of recurrent cancer, and 5 patients expired without evidence of recurrence.46
In an attempt to further improve complete clinical/pathologic response rates, and ultimately improve local control, the GOG conducted a prospective phase II trial (GOG 205), using a combination of weekly cisplatin with daily fractionated RT to a total dose of 57.6 Gy. This dose was a 20% increase over that used in GOG 101, and the previously used planned break was been eliminated, as there was evidence that prolongation of overall treatment time may be counterproductive and should be avoided whenever possible.47 The primary objective of the study was to assess the efficacy and toxicity of the combination in achieving a complete clinical and pathologic response at the primary site. Among 58 evaluable patients, there were 40 (69%) who completed study treatment; 37 patients (64%) achieved a complete clinical response. Of them, 34 underwent biopsy and 29 (78%) had a complete pathologic response (50% of the entire series). The authors concluded that this combination of radiation therapy plus weekly cisplatin successfully yielded high, complete clinical and pathologic response rates with acceptable toxicity.48
Neoadjuvant Chemotherapy and Radiation Versus Definitive Chemoradiation
Shylasree et al49 published a systematic review of the role of definitive chemoradiotherapy in LRAVC. The review included 2 retrospective studies40,50 and 1 randomized controlled trial.51 The authors concluded that there was no significant difference in overall survival or treatment-related adverse events when primary chemoradiation or neoadjuvant chemoradiation were compared with primary surgery. In addition, none of these studies include data on quality of life49 (Tables 1 and 2).
Radiation Therapy Techniques in LRAVC
The target volumes for advanced vulvar cancers include the vulva and generally the bilateral external iliac, internal iliac, and inguinofemoral nodal areas, depending on nodal stage and involvement. Patients are set up supine and often in a frog-leg position to minimize skin folds. With 2-dimensional and 3-dimensional planning, vulvar cancer treatment has used an AP/PA field setup. Often, a wide AP and narrow PA field are used, with electrons supplementing the dose to the inguinal region (provided that the nodal depth is within electron range) to limit the dose to the femoral heads.35,39 The use of CT or MRI planning helps ensure adequate dosing of the target volumes, in particular for the inguinal lymph node regions.52 GOG 205 recommended a superior field border of the sacroiliac joints, an inferior border 2 cm below the primary vulvar tumor, and a lateral border to include groin nodes medial to the anterior superior iliac crest bilaterally.48 Patterns of care study from 12 cooperative groups of GCIG reported that the majority of groups use a superior pelvic field border of L4/L5 and that 16 of 18 groups use CT planning.44
Intensity-modulated Radiation Therapy (IMRT)
Beriwal et al53 evaluated using IMRT along with chemotherapy for preoperative treatment of 18 stage II-IVa vulvar cancer patients and found that the technique was well tolerated, with no patients experiencing grade 3 acute or late toxicity. Fourteen patients underwent surgery, 9 patients had a pathologic complete response, and 5 patients had partial responses. In a small dosimetric study, IMRT was shown to be a feasible way to allow for dose escalation while adequately sparing organs at risk.54 The Radiation Therapy Oncology Group is creating an IMRT contouring atlas for vulvar cancer.
The next GOG phase II study (GOG 0279) is building on the success of GOG 0205 neoadjuvant chemoradiation therapy approach by improving the radiation technique approach using IMRT, increasing the radiation dose, and adding gemcitabine to cisplatin in achieving complete pathologic response in the treatment of LRAVC.
Some small institutional studies have suggested that interstitial brachytherapy might be useful for delivering a boost to bulky primary vulvar tumors, for treating recurrences, or for palliation.55,56 The use of interstitial brachytherapy has not been assessed in a randomized controlled study.
Preoperative radiation dose has ranged from 30 Gy in 10 fractions of 3 Gy, 40 Gy in 20 fractions of 2 Gy, 47.6 Gy in 1.7 Gy fractions, and split course to 57.6 Gy in 1.8 Gy fractions in the recent GOG 205.35,45,46,48,57 The GCIG patterns of care study found that neoadjuvant radiation is generally used for unresectable disease or FIGO stage III or above, with most treating the vulva to a dose of 48.2±5 Gy, and that an average neoadjuvant inguinal dose was 49.9±5.5 Gy.44 Increasing dose for neoadjuvant chemoradiotherapy studies has shown improved overall and pathologic complete response rates, and perhaps future studies will help identify subpopulations of patients who can forgo surgery and be treated with concurrent chemotherapy and radiation alone (Table 3).
Although no established standard exists, the majority of the panel supports performing a physical examination every 3 to 6 months for the first 5 years and then annually. Any suspected recurrent or persistent disease should be biopsied. Extrapolating from cervical and anal cancer, PET/CT may be useful for assessing response and monitoring for new distant disease.
- LRAVC can have a variety of presentations, but generally would have significant morbidity if managed with upfront exenterative surgery.
- Whole-body FDG-PET/CT is a useful imaging modality for initial work-up and for assessing response to chemoradiotherapy.
- Standard treatment for LRAVC includes neoadjuvant chemoradiotherapy with weekly concurrent cisplatin, as in GOG 205.
- Radiation should involve CT planning, with treatment volumes including the vulva and the bilateral inguinal and pelvic lymph nodes, preferably with 3D or IMRT.
- In assessing response to neoadjuvant chemoradiotherapy, besides imaging, examination under anesthesia with directed biopsies can be helpful for determining if the patient requires surgery.
- Radiation can also be a useful palliative treatment option for patients with painful vulvar cancer and unable to tolerate more aggressive treatment.
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