Treatment Volume and Technique

Transcription

1 RADIATION THERAPY The standard of care for early lesions is surgical resection; however, selected patients with small central lesions may be considered for definitive radiation, particularly when the lesions are in close proximity to the urethra, clitoris, or anus. There are few published series of radiation alone used as definitive therapy for vulvar cancer. 103,104,105 The reported series include patients with recurrent disease postsurgery and patients who are not medically suitable for surgery or have declined it. In Ellis s 103 series of 65 patients treated with brachytherapy and or external beam, the crude 5-year survival rate was 23% (15 of 65). Twelve of these patients were free of disease. The local control rate was 40%, and 9 patients developed necrosis. Slevin and Pointon 105 reported on the results of 58 patients treated also with brachytherapy and/or external beam, depending on the extent of the disease. The crude 5-year survival rate was 26% (15 of 58). In this series the local control rate was also 40% (23 of 58). The survival was better in the newly diagnosed group, 39% (9 of 23), compared to 17% (6 of 35) for the group of patients treated for recurrence. Nine patients developed necrosis. These series reflect the difficulty of achieving appropriate curative doses for gross disease with radiation alone without the aid of radiosensitizing chemotherapy. Brachytherapy has been used for inoperable vulvar cancer and as a boost to the primary tumor and/or to the lymph nodes. The efficacy of this treatment is difficult to evaluate because of the variability of the clinical situation in which this type of treatment may be employed. A high rate of necrosis was reported in up to one-third of the patients. 103 A series from the Centre Alexis Vautrin Institute in France describes 34 patients, 21 with primary and 13 with recurrent disease, treated with brachytherapy only. 104 The median brachytherapy dose was 60 Gy, with a range of 53 to 88 Gy. In the group of 21 patients who underwent brachytherapy as primary treatment, 3 patients developed locoregional recurrence, for a 5-year local control rate of 80% and a disease-specific survival of 70%. In the group of 13 patients who were treated for recurrence, 8 developed local recurrence, with or without disease at other sites, for a local control rate of 19%. Of the entire

2 group of 34, 5 patients developed necrosis. This relatively low complication rate most likely reflects that extensive experience and high quality of the brachytherapy carried out in this institution. The authors of this study advocate brachytherapy for primary vulvar cancer if the patient refuses surgery or if surgery is contraindicated. Nonetheless, due to the significant risk of necrosis, use of brachytherapy should be limited to very selected cases and performed by experienced practitioners. In most instances radiation is used in combination with surgery and/or chemotherapy. The objective of radiation varies with the target: regions with lymphatic spread or the primary tumor in the perineum. For instance, in patients with advanced, unresectable nodes but less advanced primary tumor, complete control of the primary may be obtained with the combination of chemotherapy and radiation, obviating the need for surgery to the primary while making the nodes amenable to surgery. 7 4,106 Concurrent chemotherapy and radiation may also be used for definitive treatment. For patients with advanced primary tumors and limited nodal disease it is possible to render the primary resectable while sterilizing the lymph nodes. Radiation can also play a significant role for palliation of symptoms. Treatment Volume and Technique The radiation target volume usually encompasses the vulva, both groins and the lower pelvic nodes. Use of a midline block to spare the perineum and vagina should be avoided except for highly selected situations because this may increase the risk of local recurrence. 107 The following factors increase the risk of vulvoperineal recurrences: close or positive margins (<8 mm), primary tumor size >4 cm, lymphovascular space invasion, deep invasion (>9 mm), tumor thickness >1 cm, infiltrative growth pattern (or spray pattern), >25% keratin in the tumor, and high mitotic rate (>10 per 10 high-power fields). 51 All patients found to have more than one positive inguinal node should receive postoperative radiation to the inguinal and pelvic node areas because this improves overall survival. 47 The pelvis must be included in the field because patients with positive inguinal nodes have a 28% incidence of pelvic node involvement. When planning the treatment, careful attention should be given to the location and depth at which the dose is calculated for the inguinal area. The depth of the inguinal vessels can be highly variable, ranging from

3 2.0 to 18.5 cm.1 08 CT- or MR-based threedimensional planning is essential to establish the location, extent, and depth of the inguinal nodes because underdosing of the nodes may easily occur, predisposing to local recurrence. Figure 74.6 demonstrates the distribution of inguinal nodes and can be used as a guideline for the design of an inguinofemoral treatment field.1 09 At the time of simulation, markers should be placed on the primary, the lymph nodes, and scars from previous surgery to document the extent of the disease. Medium- or high-energy photon beams with anteroposterior/posteroanterior (AP/PA) fields with Figure74.6 the patient in the supine position and with the Topographic thighs straight or in the frog-leg position are distribution of inguinal recommended for the delivery of external beam. The lymph node metastases frog-leg position minimizes the bolus effect from skin folds. Documentation of the in patients primary tumor with photos, tattoos, or fiducial markers prior to therapy may be used for objective evaluation of response to the treatment and for subsequent design of reduced fields or for brachytherapy boost. The superior border of the pelvic field should extend to the middle of the sacroiliac joints to cover the external and internal iliac nodes. If a patient has internal or external iliac node involvement, the superior border should be extended to the L3/4 interspace to cover the common iliac nodes. The inferior border should cover the entire vulva and the most superficial, inferior inguinal nodes. Laterally, the pelvic field extends 2 cm laterally to the widest point of the pelvic inlet. Although there are no data regarding scar recurrences, it is common practice to include the inguinal node dissection scars in the radiation field. Depending on whether the inguinal/femoral lymph nodes and/or pelvic lymph nodes are to be included in the radiation volume, different field configurations may be used. To reduce the dose to the femoral heads while delivering an adequate dose to the inguinal nodes, various techniques are available. One approach is to use a wide AP field that includes the pelvic and inguinal areas, with a narrow posterior field covering only the pelvis and sparing the femoral heads. The photon fields are weighted equally, and the inguinal dose is

4 supplemented by separate anterior electron fields matched to the pelvic field (Fig ). Bolus material should be used to ensure adequate dose to the superficial portions of the groin. An alternative method consists of using a wide AP field and narrow PA field, with a partial transmission block placed in the central portion of the AP field. The desired dose at a specified depth is delivered to the inguinal nodes through the AP field. 110 The degree of central anterior beam attenuation is calculated so that the midpoint of the pelvis receives equal doses from the AP and PA beams. This technique eliminates the dosimetric problems of photon/electron field Figure74.7 Treatment borders demonstrating the wide anterior field (outer matching, as well as the potential for daily setup variation, border) but the and design the of a precise partial transmission block is difficult. Another method consists in using matched AP/PA fields to include the primary and the pelvic nodes and treating the groins through separate anterior electron fields. This approach has the advantage of relatively easy setup, but the main drawback is ensuring an adequate dose at the match line, particularly when the match line is over gross disease. An example of an anteroposterior radiation field encompassing the inguinal/femoral and pelvic lymph nodes is shown in Figure 74.8.

5 Figure74.8 A: Portal for elective irradiation of regional lymphatics in Moran et al described a modified segmental boost technique using multileaf collimators with a single isocenter technique and a wide AP field to cover the vulva, pelvis, and groins and a narrow PA field to cover the vulva and pelvis. The supplemental anterior photon groin fields are angled such that the central axis is coplanar with the divergence from the PA field. The medial blocking of the groin fields is designed to match the divergence from the PA field. This technique provides a more homogeneous dose distribution and is easier to reproduce on a daily basis.

6 IMRT is now often used to treat the pelvis and inguinal nodes.1 1 2,1 1 3 Beriwal et al reported 15 patients treated with IMRT using a median of seven fields. The clinical tumor volume (CTV) was defined as a 1- to 2-cm margin around bilateral external iliac, internal iliac, and inguinofemoral nodes, as well as a 1-cm margin around the entire vulvar region. Gross tumor was also expanded by 1 cm for the CTV. The planning treatment volume was defined as 1-cm margin beyond the CTV, and the prescription dose was 43 to 48 Gy for preoperative treatment and 50 Gy for postoperative treatment, delivered partly on a twice-daily schedule. This early experience yielded reasonable clinical response, with 13 of 15 patients having no evidence of disease at last follow-up. This technique also resulted in improved dose conformality and lower doses to Figure74.9 normal structures, including rectum, bladder, small Intensity-modulated bowel, and femoral heads. A second publication by radiation therapy for the same group expanded on the preoperative vulvar cancer. This experience with 18 patients treated with concurrent patient had a cisplatin and 5-fluorouracil (5-FU), resulting in a pathologic complete response (pcr) rate of 64% and a 2-year cause-specific survival of 75% However, it must be noted that careful quality assurance is required when using IMRT. Placement of thermoluminescent dosimetry chips in the inguinal and perineum areas is recommended to document the dose given to the skin and target areas (Fig ). Preoperative Radiation Therapy with Concurrent Chemotherapy As the treatment for vulvar cancer has evolved with the goal of decreasing the sequelae of radical surgery and to maximize functional outcome, multimodality therapies have become the standard of care, particularly for patients with advanced stages of the disease.7 4 After initial concurrent chemoradiation and healing of the reaction, the response to the therapy at the primary site and the lymph nodes is assessed. If there is complete clinical regression of the disease at

7 the site of the primary, one option is to perform biopsies of the primary site, foregoing resection if there is a pathologic complete response. 106 In general, it is recommended to carry out the inguinal node dissection whether or not there has been complete response of the lymph nodes because residual disease is often found in the lymph nodes. 7 4 It also should be noted that whereas recurrences at the primary site following surgery or chemoradiation are potentially salvageable, nodal recurrences are not. The preoperative radiation dose for the primary and the lymph nodes areas should be 45 to 55 Gy. 67,114 The most common chemotherapeutic agents used have been 5-FU, cisplatin, and mitomycin-c. Acute mucocutaneous toxicity from combined therapy is rather severe, and a preferably short treatment break during the course of the treatment is often required. 7 3,7 4,106,115 In a GOG trial for patients with advanced primary and/or nodal disease, the radiation treatment consisted of 170 cgy twice daily on days 1 to 4 and 170 cgy once a day on day 5 and days 8 to 12, for a dose of 2,380 cgy. 7 4,106 Cisplatin, 50 mg/m 2, was given on day 1, and 5- FU, 1,000 mg/m 2 by a 24-h infusion, daily on days 1 to 4. The combined cycle of chemotherapy and radiation was repeated after about a 2-week break, thus delivering a total radiation dose of 4,760 cgy. In the locally advanced cohort, the pcr rate was 34%, R0 resections were possible in 77% of the patients, and 55% were alive and without disease at last follow-up. In the group of patients with advanced nodal disease, the nodes became resectable in 83%, with a pcr rate of 40% in those who underwent surgery, with 43% of the patients being alive and disease free at last follow-up. 7 4 A follow-up GOG study was recently presented by Moore et al. 102 in which T3 or T4 tumors were treated with a total dose of 5,760 cgy (180 cgy/fraction) and weekly cisplatin (40 mg/m 2 ). In an interim report, 40 of 58 (69%) patients were able to complete the protocol per plan, 37 of 58 (64%) achieved a complete response, and 29 of 58 (50%) had a pcr on surgical biopsy. Due to these encouraging initial results, the GOG is moving forward with radiation combined with weekly cisplatin as a potential backbone for continuing study. UPDATE GOG 205 Final Outcomes by Josephine Kang, September 2013 Hide

8 Results for GOG 205 by Moore et al. were recently published and consistent with the interim report; of 58 evaluable patients, 37 (64%) achieved a complete clinical response. Of this group, 78% had a complete pathologic response. Toxicity was acceptable, and 40 patients (69%) were able to complete treatment. The combination of radiation therapy (without a treatment break) and concurrent cisplatin appears to result in high clinical and pathologic response rates. As a result, standard treatment for locally advanced vulvar cancer now includes neoadjuvant radiation with concurrent weekly cisplatin. Moore DH, Ali S, Koh WJ et al. Gynecol Oncol 2012; 124: PMID: Definitive Chemoradiation Therapy Definitive chemoradiation is used for patients with advanced tumors considered unresectable at presentation or for patients who are medically inoperable (Table 74.3 ). This may be used when the tumor does not become resectable in the midst of preoperative intent chemoradiation or as an upfront alternative to surgically based treatment. In these patients, chemotherapy should be continued throughout the entire course of radiation for the purpose of radiosensitization of the tumor in the treatment volume and possible eradication of subclinical disease outside of the radiation field. With appropriate field reductions, the radiation dose should be brought up to 60 to 70 Gy. The total dose to certain areas is dependent upon the location and extent or bulk of the disease, the response to the therapy, and the estimated tolerance of the area requiring the high radiation dose. Often, it is the tolerance of normal tissue that limits the dose to 65 Gy.

9 Table74.3 Studies of Concurrent Radiation and Combination Selected patients without clinically involved nodes and at very low risk of having nodal involvement may be treated to the vulvar area alone. The treatment may be delivered using electrons or low-energy photons. When the treatment is given with electrons only, a generous margin around the primary tumor should be used because the dose decreases toward the periphery of the field. Bolus material should be used also to avoid underdosing the surface of the tumor. There is little in the way of comparative prospective trials for chemotherapy selection with concurrent treatment; however, a recent retrospective series from Dana-Farber/Brigham and Women s Cancer Center and Massachusetts General Hospital does shed some light In this series of 44 women, 24 of whom were treated definitively without surgery, 16 received weekly platinum-based regimens and 28 received a 5-FU based regimen every 3 to 4 weeks. The 2-year overall survival (74% platinum, 70% 5-FU), disease-free survival (62% platinum, 56% 5FU), and locoregional recurrence (31% platinum, 33% 5-FU) were no different. The grade 3 or higher skin toxicity was higher with weekly platinum (62% platinum, 32% 5-FU), but the nonskin toxicity was higher with 5-FU (13% platinum, 46% 5FU). Given these data and a recent GOG report of weekly platinum in preoperative treatment, weekly platinum at 40 mg/m2 is a reasonable option for concurrent treatment.1 02 Postoperative Radiation Therapy Adjuvant postoperative radiation can be used when limited surgery has been performed for organ conservation or when the surgical specimen reveals adverse pathologic features and local recurrence is likely to occur Local recurrence is a major cause of failure in all patients irrespective of the stage Patients with

10 positive or close (<8 mm) margins, LVI, and depth of tumor invasion >5 mm should undergo postoperative radiation because these are factors increase the likelihood of local recurrence. 51 Patients with close margins may be considered for re-resection prior to radiation, particularly if the area in question is not in close proximity to the urethra, clitoris, or anus. Patients with more than one involved inguinal node, extracapsular extension, or gross residual nodal disease should receive adjuvant radiation to both groins and the pelvis. When the surgical margins are clear and there is no pathologic indication to treat the vulva, a midline block can be used to avoid the reaction and the sequelae of the treatment to the vulvar area, although this practice raises the probability of local recurrence. 107 Adjuvant radiation to the primary site may be delivered with either photons or en face electrons with bolus. When treating a large area of the vulva and groins, AP/PA photon fields as described before are appropriate. If the area of involvement is small, a direct electron field can be used, and the groins are treated with separate fields. When it is indicated to treat the primary tumor bed area for possible residual microscopic disease, a dose of 50 Gy is recommended. If there is extracapsular extension of tumor in the lymph nodes, the dose to the groins should be carried to 50 to 60 Gy. If there is gross residual disease postsurgery, the dose to the area should be brought to 65 to 70 Gy. UPDATE by Josephine Kang, September 2013 Margin Status And Risk of Recurrence Hide A retrospective review from Dana-Farber/Brigham and Women s Hospital documented a significant relationship between postoperative margins of 5 mm or less, with risk of local recurrence (P = 0.002). On multivariate analysis, the vulvar relapse hazard ratio for close (<1 cm) and positive margins was 3.03 (95% CI ) and 7.02 (95% CI ), respectively. It was also noted that a post-operative radiation dose of 56 Gy or higher was associated with significantly lower risk of recurrence, compared to those who received 50.4 Gy or less. Viswanathan AN, Pinto AP, Schultz D et al. Gynecol Oncol.2013;

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