Rosa S. Djajadiningrat

Contemporary management of regional nodes in penile cancer-improvement of survival?

PURPOSE The management of regional nodes of penile squamous cell carcinoma has changed with time due to improved knowledge about diagnosis and treatment. To determine whether changes in the treatment of regional nodes have improved survival, we compared contemporary 5-year cancer specific survival of patients with squamous cell carcinoma of the penis with that of patients in previous cohorts. MATERIALS AND METHODS In an observational cohort study of 1,000 patients treated during 56 years 944 were eligible for analysis. Tumors were staged according to the 2009 TNM classification, and patients were divided into 4 cohorts of 1956 to 1987, 1988 to 1993, 1994 to 2000 and 2001 to 2012, reflecting changes in clinical practice regarding regional nodes. Kaplan-Meier survival curves with the log rank test and Cox proportional hazards modeling were used to examine trends in 5-year cancer specific survival. RESULTS The 5-year cancer specific survival of patients with cN0 disease treated between 2001 and 2012 was 92% compared to 89% (1994 to 2000), 78% (1988 to 1993) and 85% (1956 to 1987). The 5-year cancer specific survival improved significantly since 1994, the year dynamic sentinel node biopsy was introduced, at 91% (1994 to 2012) vs 82% (1956 to 1993) (p = 0.021). This conclusion still holds after adjustment for pathological T stage and grade of differentiation (HR 2.46, p = 0.01). Extranodal extension, number of tumor positive nodes and pelvic involvement in node positive (pN+) cases were associated with worse 5-year cancer specific survival. CONCLUSIONS Despite less surgery being performed on regional nodes, 5-year cancer specific survival has improved in patients with cN0 disease. The number of tumor positive nodes, extranodal extension and pelvic involvement were highly associated with worse cancer specific survival in patients with pN+ disease. In this group other treatment strategies are needed as no improvement was observed.

Early Wound Complications After Inguinal Lymphadenectomy in Penile Cancer: A Historical Cohort Study and Risk-factor Analysis

BACKGROUND Complication rates after inguinal lymph node dissection (ILND) are high. Risk factors for early wound complications after ILND in patients with penile carcinoma have not yet been studied. OBJECTIVES To assess the frequency of early wound complications in a contemporary series and to identify clinical risk factors for early wound complications after ILND for penile carcinoma. DESIGN, SETTING, AND PARTICIPANTS We evaluated 237 ILNDs in 163 patients with penile cancer treated between 2003 and 2012 at the Netherlands Cancer Institute. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We assessed the occurrence of wound infection, skin-flap problems, and seroma formation and graded complications using the modified Clavien system. Univariable and multivariable penalised mixed effects logistic regression was used to identify clinical risk factors for occurrence of any complication (grade ≥ 1) and of moderate to severe complications (grade ≥ 2). RESULTS AND LIMITATIONS One complication or more occurred in 58% of the procedures, and 10% of those complications were severe. Wound infection occurred in 43%, seroma formation occurred in 24%, and skin-flap problems occurred in 16%. Palpable disease was the only factor associated with grade ≥ 1 complications in the univariable analysis (odds ratio [OR]: 0.43; p=0.02). In the multivariable model, after penalisation, no statistically significant risk factors remained. Univariable associations for grade ≥ 2 complications were present for body mass index (BMI; OR of 1.66 for a 5.8-point change in BMI; p=0.05) and sartorius muscle transposition (OR: 2.64; p=0.04). In the reduced multivariable model, the OR for sartorius muscle transposition was 2.12 (p=0.06) and for BMI was 1.76 (p=0.03). In addition, bilateral dissection approached significance in the multivariable model (OR: 2.17; p=0.06). This study is limited by its observational nature. CONCLUSIONS Wound complication rates after ILND are high in this cohort. BMI, sartorius muscle transposition, and bilateral dissection were the factors most strongly associated with the occurrence of grade ≥ 2 wound complications.

Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome.

PURPOSE The incidence of penile cancer is increasing, and is suggested to be explained by changes in sexual practice and increased exposure of men to sexually transmitted high risk human papillomavirus infection. In penile cancers from a Dutch population treated in 1963 to 2001 we found a high risk human papillomavirus prevalence of about 30%. In this study we assessed the prevalence of high risk human papillomavirus-DNA in a more recent, contemporary penile cancer cohort and its association with patient survival. MATERIALS AND METHODS High risk human papillomavirus-DNA presence was assessed by GP5+6+ polymerase chain reaction in 212 formalin fixed, paraffin embedded invasive penile tumor specimens of patients treated between 2001 and 2009. The 5-year disease specific survival was calculated using the Kaplan-Meier method with the log rank test and Cox regression. RESULTS High risk human papillomavirus-DNA was detected in a subset of penile cancer cases (25%, 95% CI 19-31). HPV16 was the predominant type, representing 79% (42 of 53) of all high risk human papillomavirus infections. The 5-year disease specific survival in the high risk human papillomavirus negative group and the high risk human papillomavirus positive group was 82% and 96%, respectively (log rank test p=0.016). Adjusted for stage, grade, lymphovascular invasion and age, human papillomavirus status was still prognostic for disease specific survival (p=0.030) with a hazard ratio of 0.2 (95% CI 0.1-0.9). CONCLUSIONS High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.

Penile sparing surgery for penile cancer-does it affect survival?

PURPOSE Management of squamous cell carcinoma of the penis changed in recent decades in favor of penile sparing surgery. We assessed whether penile sparing therapies were increasingly applied in our penile squamous cell carcinoma cohort with time and whether penile sparing affected 5-year cancer specific survival. MATERIALS AND METHODS We reviewed the records of 1,000 patients treated between 1956 and 2012, of whom 859 with invasive tumors were eligible for analysis. Tumors were staged according to the 2009 TNM classification. Binary logistic regression was used to assess penile preservation vs amputation with time. Cancer specific survival was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. Competing risk analysis was done for local recurrence. RESULTS With time significantly fewer penile amputations were performed. The 5-year cumulative incidence of local recurrence as the first event after penile preservation was 27% (95% CI 23-32) while after (partial) penectomy it was 3.8% (95% CI 2.3-6.2, Gray test p <0.0001). Patients treated with penile preservation showed no significant difference in survival compared to patients treated with (partial) amputation after adjusting for relevant covariables. Factors associated with cancer specific survival were pathological T stage, pathological N stage and lymphovascular invasion on multivariable analysis. In the penile preservation group local recurrence as a time dependent variable in a Cox model was not associated with cancer specific survival (HR 0.52, 95% CI 0.21-1.24, p = 0.13). CONCLUSIONS Significantly more penile preservation therapies were performed in more recent years. Although patients treated with penile preservation experienced more local recurrences, 5-year cancer specific survival was not jeopardized.

Adjuvant chemotherapy is associated with improved overall survival in pelvic node–positive penile cancer after lymph node dissection: A multi-institutional study

OBJECTIVES We determined whether adjuvant chemotherapy (AC) would be associated with improved survival after lymph node dissection (LND) for patients with penile cancer (PeCa) who have positive pelvic lymph nodes (PPLNs). METHODS We retrospectively identified patients across 4 centers with penile squamous cell carcinoma who underwent LND from 1978 to 2013 and were found to have PPLNs. Patients who received chemotherapy before surgery or in the presence of recurrent disease were excluded. Cox regression was used to evaluate the association of AC with overall survival (OS), which was estimated using the Kaplan-Meier method. Differences in OS were determined with the log-rank test. RESULTS During the study period, 141 patients who underwent LND for PeCa had PPLNs, and 84 of them met inclusion criteria. Median number of PPLNs was 2 (interquartile range [IQR]: 4-7), with 10% of cases occurring bilaterally and 55% having pelvic extranodal extension. AC was used in 36 (43%) patients. Patients who received AC were younger (P = 0.014), had less-aggressive penile tumor pathology (P<0.01), were less likely to receive adjuvant radiation (P<0.01), had less bilateral inguinal disease (P = 0.019), and had more inguinal extranodal extension (P = 0.042). Median follow-up was 12.1 months. Estimated median OS was 21.7 months (IQR: 11.8-104) in patients who received AC vs. 10.1 (IQR: 5.6-48.1) in those who did not (P = 0.048). AC was independently associated with improved OS on multivariate analysis (hazard ratio: 0.40; 95% CI: 0.19-0.87; P = 0.021). CONCLUSIONS AC is associated with improved OS in patients with PeCa who have PPLNs after LND. Prospective studies are needed to demonstrate causality.

Predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort

To assess the potential complications associated with inguinal lymph node dissection (ILND) across international tertiary care referral centres, and to determine the prognostic factors that best predict the development of these complications.

Neoadjuvant Taxane-Based Combination Chemotherapy in Patients With Advanced Penile Cancer

INTRODUCTION/BACKGROUND Neoadjuvant taxane-based combination chemotherapy has shown promising results in unresectable squamous cell carcinoma of the head and neck area, and the penis. Our primary aim was to assess the objective response in penile cancer patients neoadjuvantly treated with taxane-based combination chemotherapy. Secondary outcomes were progression-free survival (PFS), disease-specific survival (DSS), and toxicity. PATIENTS AND METHODS Twenty-six patients were treated within the framework of a nonrandomized institutional registration study with 4 courses of TPF (docetaxel, cisplatin, and 5-fluorouracil) for advanced penile cancer between 2008 and 2012. Response was measured using computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography/CT according to Response Evaluation Criteria in Solid Tumours 1.1 criteria and European Organisation for Research and Treatment of Cancer recommendations, respectively. Toxicity, PFS, and DSS were analyzed using either the Common Toxicity Criteria of Adverse Events version 4.0 or the Kaplan-Meier methods. To analyze possible association with survival, univariable and multivariable Cox regression analyses were performed for tumor differentiation, N-category, recurrent disease, tumor margins, and administration of radiotherapy. RESULTS During a median follow-up of 30 months, an imaging-based response was obtained in 60% (95% confidence interval [CI], 39%-79%) (15/25) of patients. However, pathologic complete response was observed in 1 of 25 evaluable patients (4%; 95% CI, 0%-20%). Toxicity was considerable with registered toxicity in every patient. The 2-year PFS and DSS probability were 12% and 28%, respectively. Patients responsive to chemotherapy had significantly better survival than nonresponsive patients. CONCLUSION Despite a fairly good response percentage, TPF chemotherapy was poorly tolerated with disappointing survival rates. Therefore, other treatment options should be considered.

Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status

Purpose: PD‐L1 (programmed death ligand 1) inhibits T‐cell function and prevents tumor eradication. This is facilitated by PD‐L1 positive tumor cells and PD‐L1 positive immune cells, and can be prevented by anti‐PD‐1 (programmed death 1)/PD‐L1 immunotherapy. In advanced penile cancer there is a need for new therapeutic strategies. We investigated PD‐L1 expression in penile cancers and compared PD‐L1 expression with disease specific survival, lymph node metastases at diagnosis and high risk HPV status in a large patient cohort. Materials and Methods: A total of 213 primary tumors were immunohistochemically stained for PD‐L1 and scored for tumor (percentage), stroma (binary) and PD‐L1 positive tumor infiltrating macrophages. Additionally, PD‐L1 positive tumors were scored for expression pattern, that is diffuse or predominantly present at the tumor‐stroma margin. Results: Staining was successful in 200 tumors, of which 75% were high risk HPV negative. Median followup was 62 months. Of 200 tumors 96 (48%) were PD‐L1 positive (scored 1% or greater), of which 59 (62%) had a marginal expression pattern and 79 (82%) were high risk HPV negative (p = 0.03). Compared to PD‐L1 negative tumors, the PD‐L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58). These results were more prominent in the high risk HPV negative subgroup (OR 0.25, HR 3.92). Conclusions: PD‐L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.

Establishing Criteria for Bilateral Pelvic Lymph Node Dissection in the Management of Penile Cancer: Lessons Learned from an International Multicenter Collaboration

PURPOSE Penile carcinoma with bilateral pelvic lymph node metastasis is a relatively rare condition with poor outcomes. There are little data available on optimal strategies for staging and treating this group of patients. We assessed factors predicting bilateral pelvic lymph node metastasis in patients with penile cancer and confirmed inguinal lymph node metastasis. MATERIALS AND METHODS Multi-institutional data from a total of 4 centers in Europe, the Peoples Republic of China and the United States were retrospectively analyzed. Patients with penile carcinoma and inguinal lymph node metastasis who underwent bilateral pelvic lymphadenectomy were included in analysis. The Kaplan-Meier and log rank tests were used to express overall survival. Logistic regression was used for multivariate analysis of factors predicting bilateral pelvic lymph node metastasis. Cox regression was done in the multivariable analysis of overall survival. RESULTS We identified 140 patients with penile carcinoma who had confirmed pelvic lymph node metastasis. Of the patients 83 had bilateral inguinal lymph node metastasis and 64 underwent bilateral pelvic lymphadenectomy. Bilateral pelvic lymph node metastasis was observed in 16 patients (25%). The ROC of the total number of inguinal lymph node metastases and the detection of bilateral pelvic lymph node metastasis had an AUC of 0.76 (p = 0.002) with 95% sensitivity for the cutoff point of 4 inguinal nodes. On logistic regression analysis the detection of 4 or more positive inguinal nodes was the only independent predictor of bilateral pelvic lymph node metastasis (OR 14.0, CI 1.71-115). On Cox regression analysis 4 or more inguinal lymph node metastases, adjuvant chemotherapy, inguinal extraprostatic extension and bilateral procedures were associated with overall survival. CONCLUSIONS Patients with bilateral inguinal lymph node metastasis who are treated with unilateral pelvic lymphadenectomy should be considered for bilateral pelvic lymphadenectomy in the presence of 4 or more metastatic inguinal nodes.

Ultrasound examination and fine needle aspiration cytology-useful for followup of the regional nodes in penile cancer?

PURPOSE Routine followup of the groins of patients with penile squamous cell carcinoma after primary treatment consists of physical examination together with ultrasound of the groins, followed by fine needle aspiration cytology if suspicious. We assessed the value of this routine followup. MATERIALS AND METHODS Using ultrasound and fine needle aspiration cytology we assessed 247 patients during followup who were treated from 2004 to 2010 and underwent dynamic sentinel node biopsy only or observation of the inguinal regions. A negative result was defined as no evidence of metastatic disease after at least 2 years of followup. We calculated the sensitivity, specificity, and positive and negative predictive values of ultrasound and ultrasound guided fine needle aspiration cytology using standard statistical methods. RESULTS Recurrence was diagnosed in 47 of 247 patients (55 groins). In 40 of 55 groins (73%) recurrence was detectable by physical examination. In 12 of 15 cases of nonpalpable recurrence (80%) ultrasound guided fine needle aspiration cytology revealed the recurrence. We considered 217 groins to be suspicious on ultrasound followed by fine needle aspiration cytology. Fine needle aspiration cytology revealed tumor in 49 groins and showed false-positive findings in 1 patient after negative completion lymphadenectomy. Sensitivity and specificity were 87.3% (48 of 55 cases) and 99.9% (1,304 of 1,305), respectively. CONCLUSIONS Although inguinal recurrence manifests clinically in most patients, ultrasound guided fine needle aspiration cytology detected 80% of metastatic disease in patients with nonpalpable disease. Therefore, it has great value for detecting lymph node metastases during followup.