While overall cancer-specific survival rates of 80-90% in early stage penile cancer have been reported with surgery alone. Higher stage disease (i.e., bilateral inguinal metastases, extranodal extension, pelvic nodal metastases) requires additional treatment in order to achieve a cure. The neoadjuvant paradigm aims to treat systemic disease prior to surgery as in other conditions, such as bladder cancer.17 Three contemporary series have shown that selected patients can benefit from induction chemotherapy. Corral et al.18 reported on the long-term follow-up of a prospective group of patients treated with bleomycin, methotrexate, and cisplatin. Objective responses were noted in 12 (57%) including 2/5 with distant metastases. Six patients in the group (28.5%) achieved disease-free status with either chemotherapy alone (n=2) or surgery (n = 3) or radiotherapy (n = 1) with a median survival of 27.8 months. This was significantly longer than that of those not achieving disease-free status (6.7 months, p = 0.004). Thus, this prospective study showed that a multidisciplinary approach to achieve a disease-free status could prolong survival.

Subsequently, Leijte et al. 1 9 from the Netherlands Cancer Institute reviewed their experience with neoadjuvant chemotherapy in patients with unresectable disease on presentation. The series included 20 patients treated with five different regimens including (1) single agent bleomycin; (2) bleomycin, vincristine, methotrexate; (3) cisplatin, 5-fluorouracil; (4) bleomycin, cisplatin, methotrexate; and (5) cisplatin, irinotecan. The objective responses were evaluable in 19 (one patient died due to bleomycin toxicity after 2 weeks) with 12 responses (63%, 2 complete, 10 partial). Among 12 responders only 9 subsequently underwent surgery, as two died of bleomycin-related complications while the third was deemed too unfit for surgery. Eight of nine responding patients undergoing surgery (two were pT0) were free of disease at their last assessment with a median follow-up of 20 months. This is in contrast to three nonresponders who underwent surgery for palliative intent. All three died within 4-8 months due to loco-regional recurrence. The findings from this study indicate that response to chemotherapy together with an aggressive surgical approach provides the optimal scenario for significant palliation or potential cure.

In a separate study, Bermejo et al.20 described the surgical considerations and complications among ten patients who had either a response or stable disease after combination chemotherapy followed by surgery. The regimens utilized included (1) bleomycin, methotrexate, cisplatin; (2) paclitaxel, ifosfamide, cisplatin (TIP), or paclitaxel, carboplatin. This cohort of patients exhibited bulky inguinal or pelvic metastases with the only exclusions being patients with fixed pelvic masses or complete encasement of the femoral vessels. Among five patients exhibiting an objective response, three were alive and disease-free at 48, 50, and 73 months. Two further patients died (one of disease at 30 months, another of unknown causes at 21 months). Among the five remaining patients with stable disease, three died from the disease within 7 months one patient treated with bleomycin died of "failure to thrive" at 8 months. However, another patient treated with paclitaxel and carboplatin achieving only stable disease was alive and disease-free at 84 months. These data appear to reinforce the concept that response to systemic chemotherapy prior to surgery enhances the chance for long-term survival among those undergoing surgical resection. Related to systemic therapy the authors reported that the TIP regimen was well tolerated and all three pT0 responses at surgery were among patients treated with TIP. This provided the rationale for the prospective phase II study of 30 patients (registered on the National Institute of Health website as NCT00512096). This cohort has completed therapy with the final results pending. Preliminary analysis of data of the first 20 patients describes an objective response rate of 55% and a pathologic complete response in 10% (two patients).2 1 In the United Kingdom, a multicenter nonrandomized trial has been opened examining the role of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy in patients with locally advanced or metastatic penile cancer. Primary outcome is to assess the efficacy of the regimen. The secondary outcomes are to assess the number of cases rendered operable following chemotherapy, to evaluate safety and tolerabil-ity of the regime and to report outcomes in terms of disease-free and overall survival. The inclusion criteria are histologically proven squamous cell carcinoma of the penis, and the following stages:

Ml disease, T any and N any

M0 with N3 disease

M0 with inoperable N2 disease

Any T4 disease.

Optional inclusion of N1 disease, depending on discussion by the multidisciplinary team. All cases are to receive three courses of chemotherapy, without a nontreat-ment arm. A total of 26 cases are to be recruited. Based on the activity of this regime, this phase II study may lead to larger studies.

16.5.2 Radiotherapy

The literature is particularly sparse in the area of radiotherapy as a treatment modality for advanced penile cancer. One of the largest series demonstrating a benefit of radiotherapy for lymph node metastases and/or distant metastases from penile cancer was published by Ravi and associates in 1994.22 Pertinent to the advanced disease presentation setting, 33 patients were treated with preoperative radiotherapy at 40 Gy over 4 weeks and subsequently underwent inguinal lymphadenectomy. Of note, after radiotherapy and surgery only 8% had evidence of extranodal extension (ENE) and 3% recurred within the groin. This is relevant as in a prior report within a contemporary time frame the incidence of ENE was 33% among patients treated with surgery alone and groin recurrence was noted in 19%. The difference for both ENE and local recurrence were both statistically lower (p=<0.01 and 0.03, respectively). The data are strongly suggestive but not definitive that preoperative radiotherapy for nodes >4 cm without skin fixation improved local control. The 5-year survival among the latter group was 70%.

In women with cancer of the vulva, a disease site that has a natural history and lymphatic drainage similar to that of the penis, Hyde et al.23 reported that debulking plus adjuvant radiotherapy was as effective as radical inguinal node dissection. Parthasarthy et al.2 4 noted that after primary inguinal node dissection, there was improved disease-free survival when they received adjuvant postoperative radiotherapy. Specific to bulky inguinal nodes at presentation the Gynecologic Oncology Study Group performed a phase II study to assess the efficacy of preoperative chemoradiation prior to inguinal lymphadenectomy among patients with bulky N2/ N3 inguinal nodes from vulvar squamous cancer.25 Forty-two patients received split course chemoradiation consisting of cisplatin (50 mg/m2) and 5-fluorouracil [5-FU] (1000 mg/m2) combined with 4760 cGy to the primary tumor and inguinal nodes. In a total of 38 patients, 37 were taken to surgery and had an inguinal node dissection and in 15 (40.5%) no tumor was found. Thirty-six of thirty-seven patients (97%) had no inguinal recurrence. However, only 12 patients (31%) remained alive without evidence of disease at 78 months follow-up as death due to other causes7 and distant metastases9 occurred. Thus preoperative chemoradiation in this prospective study improved resectability and local control among this cohort of patients with bulky inguinal metastases. Thus there is some evidence in advanced stage penile cancer that preoperative radiotherapy for bulky nonfixed nodes may improve resectability and decrease local recurrence. However, the morbidity of this approach requires further study. Based on the available data from other squamous malignancies, the use of chemoradiation should be further explored in multi-institutional trials.

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