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Surgical amputation of the primary tumor remains the oncologic gold standard for rapid definitive treatment of the penile primary tumor; local recurrence rates range from 0% to 8% (45). Amputation is often necessary for bulky stage T2-T4 tumors, but it has been shown to decrease sexual quality of life (50). It is generally accepted that patients with penile primary tumors exhibiting favorable histologic features (stages Tis, Ta, T1; grades 1 and 2 tumors) are at a lower risk for metastases. These patients are also best suited for organ-sparing or glans-sparing procedures, with the goal of preserving glans sensation where possible or at least to maximize penile shaft length. Such approaches include topical treatments (fluorouracil or imiquimod cream for Tis only), radiotherapy, Mohs surgery, limited excision strategies (eg, circumcision), and laser ablation (51,52,53,54,55).
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Partial or total penectomy should be considered in patients exhibiting adverse features that defy adequate control by organ preservation strategies. These include tumors of size 4 cm or more, grade 3 lesions, and those invading deeply into the glans, urethra, or corpora cavernosa.
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Therapeutic Lymph Node Dissection
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The biology of penile cancer is such that it exhibits a prolonged locoregional phase before distant dissemination. Lymphadenectomy alone can be curative and should be incorporated into the treatment planning for most patients. However, due to the morbidity of traditional lymphadenectomy, especially among those patients with clinically negative groins, contemporary controversial issues include the following: (1) the selection of patients for lymphadenectomy versus careful observation; (2) the types of procedures to correctly stage the inguinal region with low morbidity; and (3) multimodality strategies (eg, neoadjuvant chemotherapy, see further in the chapter) to improve survival among patients with bulky inguinal metastases.
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The presence and the extent of metastasis to the inguinal region are the most important prognostic factors for survival in patients with squamous cell carcinoma of the penis. The survival rates for therapeutic lymph node dissection in patients with established regional lymph node metastases are variable, averaging about 60% (range, 0%-86%) (35,46,48). This variability in survival rates is directly attributable to the extent of nodal metastasis. Patients with pN1 or pN2 with a minimal number of lymph nodes involved have an average 5-year survival of 77%, compared with only 25% when a greater degree of nodal involvement is present. In one study (56), the 5-year survival of patients with extranodal involvement was only 6% (1 of 17 patients). The combined results of several small series suggest an average 5-year survival of 15% when pelvic lymph nodes are present.
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Taken together, these data suggest that the pathologic criteria that predict long-term survival (ie, 80% 5-year survival rate) after attempted curative surgical resection of inguinal metastases are (1) minimal nodal disease (up to two involved nodes in most series); (2) unilateral involvement; (3) no evidence of extranodal extension of cancer; and (4) absence of pelvic nodal metastases.
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Chemotherapy for Stage IIIB/IV Penile Carcinoma
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The first candidate drugs for the chemotherapeutic treatment of stage IIIB/IV penile carcinoma included cisplatin, vincristine, methotrexate, fluorouracil, mitomycin, and bleomycin (37,57). In a multicenter study conducted by the Southwest Oncology Group (SWOG) (58), 26 patients with metastatic penile cancer received single-agent cisplatin at a dosage of 50 mg/m2 on days 1 and 8 of each 28-day cycle. Only four patients (15%) experienced responses that persisted for 1 to 3 months.
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The combination of bleomycin, methotrexate, and cisplatin (BMP) was studied in phase II clinical trials. In a single-institution study conducted at MD Anderson Cancer Center (59), 30 patients with squamous cell carcinoma of the urinary tract, including 21 men with metastatic penile carcinoma, received bleomycin at a dosage of 50 mg/m2 on days 2 to 6, cisplatin at 20 mg/m2 on days 2 to 6, and methotrexate at 200 mg/m2 with leucovorin rescue on days 1, 15, and 22 of each 28-day cycle. There were 12 responses (55%) in the group with penile carcinoma, and the median duration of response was 4.7 months for the entire study. A second phase II study was conducted by the SWOG (60), in which patients received bleomycin at a dosage of 10 U/m2 on days 1 and 8, methotrexate at 25 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1 of each 21-day cycle. Among 40 evaluable patients, there were 5 complete and 8 partial responses for an overall response rate of 32.5%, which narrowly exceeded the predetermined target rate of 30%. The median response duration was 16 weeks, and the estimated median survival time was 28 weeks. The toxicity of the regimen was considerable, however, with five treatment-related deaths due to bleomycin lung toxicity, other pulmonary causes, and infection. The BMP regimen and bleomycin in particular are no longer recommended for the treatment of penile cancer because of the unacceptable toxicity.
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Other cisplatin-based drug combinations demonstrated response rates of 8% to 50% (Table 38-4) (61,62,63,64,65). A regimen would be of interest if it has an overall response rate greater than 30% with acceptable toxicity. The study of irinotecan/cisplatin conducted by the European Organization for Research and Treatment of Cancer (61) was a prospective study with 26 evaluable patients, but was interpreted as having a negative result by the authors because the response rate had an 80% confidence interval of 18.8% to 45.1%, extending well below 30%. In another study, paclitaxel, ifosfamide, and cisplatin was given to patients with metastases limited to the inguinal and pelvic lymph nodes (62). In this neoadjuvant study, patients with response or stable disease after four courses underwent surgery with curative intent. The response rate was 50%, and the safety profile of this regimen was an improvement over BMP, with no treatment-related deaths. In another study of taxane drugs for the treatment of metastatic penile cancer, docetaxel, 5-fluorouracil, and cisplatin resulted in a response rate of 38.5% (63). The response rate was not high enough to recommend this regimen in preference to 5-fluorouracil and cisplatin, and grade 3 and 4 toxicities were frequent.
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5-Fluorouracil and cisplatin were studied in a retrospective series of patients with metastatic penile cancer (64). Partial responses had been seen in 8 of 25 evaluable patients (32%). While there have been no randomized controlled trials to establish a single standard of chemotherapy treatment for metastatic penile cancer, either 5-fluorouracil plus cisplatin or paclitaxel, ifosfamide, and cisplatin have been endorsed by contemporary guidelines (42,43).
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Multimodality Therapy
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Neoadjuvant Chemotherapy
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As discussed in the section on therapeutic lymph node dissection, the 5-year overall and disease-free survival rates with surgery alone are as high as 80% for unilateral, superficial inguinal lymph node involvement with no more than two nodes (stage N1 or limited N2), only 10% to 20% for stages N2 and N3 (multiple, bilateral, or pelvic lymph nodes involved), and less than 10% in the presence of extranodal extension (66). Nearly all recurrences are detected within 2 years of surgery, and an aggressive, multimodality approach to the treatment of high-risk patients could result in better overall survival (37,57,67).
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In 1988, a team of Italian investigators reported their experience with adjuvant or preoperative (neoadjuvant) bleomycin, vincristine, and methotrexate for patients with penile carcinoma and metastases confined to the inguinal lymph nodes (68). In the neoadjuvant group, five patients with fixed inguinal nodes received weekly bleomycin (30 mg intramuscularly), vincristine (1 mg intravenously), and methotrexate (30 mg orally). Three of those five patients had a sufficient tumor response that they could undergo surgical consolidation, and they were reported to be alive and disease free at 20, 27, and 72 months after surgery. The other two patients experienced less-than-partial responses, did not undergo surgery, and survived less than 12 months. This study, although small, demonstrated that perioperative chemotherapy for locally advanced penile carcinoma was feasible.
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A group from the Netherlands reported on their retrospective analysis of 20 patients who had received preoperative chemotherapy to downstage unresectable disease (69). Seventeen patients had had bulky lymph node metastases (Tx, N3), and the other three had had advanced primary tumors (T3-T4, N0-N1). The most commonly used regimens in the Dutch series, which spanned a 34-year period, had been BMP (n = 10); bleomycin, vincristine, and methotrexate (n = 5); and single-agent bleomycin (n = 3). Severe toxicity had occurred in four patients, including three treatment-related deaths. Twelve patients had experienced an objective tumor response; nine of the twelve had undergone surgery, and eight had achieved long-term disease-free survival. Two patients had no residual tumor in the surgical specimen. The finding of pathologic complete responses suggested that this finding could be used as a screen for efficacy.
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A retrospective study from MD Anderson Cancer Center reported a series of 10 patients who had received neoadjuvant chemotherapy (70). The reported experience spanned a 15-year period at one institution and was limited to patients who had undergone aggressive lymph node dissections after having experienced a response or stable disease after chemotherapy. The regimens given preoperatively had been BMP (n = 3); paclitaxel and carboplatin (n = 2); and paclitaxel, ifosfamide, and cisplatin (n = 5). Four patients had complete responses, and one had a partial response. Three patients had a pathologic complete response in the lymph nodes; all of these patients had received paclitaxel, ifosfamide, and cisplatin, and all had biopsy-confirmed metastases prior to chemotherapy. Four patients had experienced long-term disease-free survival.
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Neoadjuvant chemotherapy was next studied prospectively in a phase II clinical trial conducted at MD Anderson Cancer Center (62). Thirty patients with clinical TX N2-N3, M0 penile cancer received four courses of paclitaxel, ifosfamide, and cisplatin prior to a planned complete bilateral inguinal lymph node dissection and uni- or bilateral pelvic lymph node dissection. Fifteen patients (50%) experienced a partial or complete response to chemotherapy. Twenty-two patients (73%) were able to complete the neoadjuvant chemotherapy and surgery, of whom there were three patients (14%) with a pathologic complete response in the lymph nodes (see Fig. 38-4). Objective response to chemotherapy, absence of bilateral residual tumor, and absence of extranodal extension in residual tumor were associated with a higher rate of overall and progression-free survival in a univariable analysis (Fig. 38-5).
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The overall and progression-free survival rates in N2-N3 disease achieved with neoadjuvant paclitaxel, ifosfamide, and cisplatin are an improvement over the expected survival with surgery alone. Despite the absence of a randomized controlled trial, contemporary guidelines have recommend neoadjuvant paclitaxel, ifosfamide, and cisplatin for patients presenting with bulky/high-risk regional lymph node metastases (42).
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Adjuvant Chemotherapy
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Adjuvant chemotherapy has the advantage of allowing patient selection based on accurate pathologic staging. Unfortunately, a randomized controlled trial of adjuvant chemotherapy would not be feasible due to the low incidence of penile carcinoma and the large number of patients necessary to power such a trial. The development of neoadjuvant chemotherapy as standard treatment appears to be more achievable and has advantages of downstaging to facilitate surgery, better tolerance of chemotherapy in the preoperative setting, and earlier exposure of micrometastases to the chemotherapy agents. Tumor response can be detected in the neoadjuvant setting, but not in the adjuvant setting, and the histopathologic findings of postchemotherapy surgery provide an early indicator of the treatment effect and prognosis (Fig. 38-6) (71).
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In cases where patients have undergone surgery without neoadjuvant chemotherapy and are found to have multiple inguinal or any pelvic lymph nodes involved or extranodal extension, then a regimen such as paclitaxel, ifosfamide, and cisplatin can be administered as adjuvant therapy on the basis of extrapolation from the neoadjuvant data.
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Radiotherapy Combined With Surgery or Chemotherapy
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Studies of radiotherapy in penile carcinoma have included penis-sparing treatment for small (T1-T2, <4 cm) primary tumors, treatment of lymph node metastases, postoperative radiotherapy, and chemoradiotherapy (54,57). There are no published randomized trials of multimodality treatment with radiotherapy in penile cancer, as there are in squamous cell carcinomas from other sites. For example, radiotherapy with surgical lymphadenectomy has been studied in women with cancer of the vulva, a disease site that has natural history and nodal drainage similar to those of the penis. On the basis of these studies, the standard of care for metastatic vulvar cancer is radiotherapy to the pelvis rather than pelvic lymph node dissection (72). Pelvic lymph node dissection remains the standard of care for penile cancer patients following definitive treatment of inguinal lymph node metastases (42). Thus, a randomized trial in penile cancer would be informative concerning the optimal method for consolidation of pelvic lymph nodes.
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International Randomized Trial
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It has not been possible to conduct randomized controlled trials in penile cancer to answer basic questions. One of the studies currently being developed and discussed by the International Rare Tumors Initiative (IRCI) is a 400-patient trial to be conducted in the United Kingdom, United States, and Canada (73). The International Penile Advanced Cancer Trial (InPACT) uses a Bayesian design for randomized treatment of patients with inguinal lymph node metastases from penile cancer. The trial has two independent randomizations, addressing key questions in the clinical pathway: first, the role of neoadjuvant therapy prior to standard surgery, by randomizing to chemotherapy, chemoradiotherapy, or no neoadjuvant therapy; and second, the role of prophylactic pelvic lymph node dissection following the standard surgery with therapeutic inguinal lymph node dissection. The primary outcome measure of the InPACT study is overall survival.