T indicates tumor; N0, no regional lymph node involvement; and M1, distant metastasis.
A, Survival by receipt of lymph node dissection (LND) in all 1123 patients. B, Survival among 373 patients who did not receive LND. C, Survival among 750 patients who received LND. D, Survival by receipt of LND, chemotherapy (CT), and radiotherapy (XRT) in all 1123 patients. CT+ indicates received CT; CT−, no CT; LND+, received LND; LND−, no LND; mOS, median overall survival; XRT+, received XRT; and XRT−, no XRT.
eFigure 1. Treatments by Time
eFigure 2. Utilization Trends by Treatment Combination
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Joshi SS, Handorf E, Strauss D, et al. Treatment Trends and Outcomes for Patients With Lymph Node–Positive Cancer of the Penis. JAMA Oncol. 2018;4(5):643–649. doi:10.1001/jamaoncol.2017.5608
What are the national trends and survival benefits for the use of lymph node dissection, chemotherapy, and radiotherapy in patients with advanced penile cancer?
In this review of data for 1123 patients from the US National Cancer Database, the use of chemotherapy increased over the past decade but remained below 50%, older patients were less likely to receive chemotherapy, and patients with a higher node category and those who received radiotherapy were more likely to receive chemotherapy. Neither the receipt of chemotherapy nor of radiotherapy was associated with overall survival.
There is opportunity for improvement in guideline-recommended care, and prospective clinical trials are needed to better understand the utility of these treatments.
Penile cancer is an uncommon disease with minimal level I evidence to guide therapy. The National Comprehensive Cancer Network (NCCN) guidelines advocate a lymph node dissection (LND) or radiotherapy with consideration of perioperative chemotherapy for all patients with lymph node–positive (LN+) penile cancer without metastasis.
To determine temporal trends in use of chemotherapy for patients with LN+ penile cancer without metastasis and to evaluate outcomes between those who did or did not receive LND, chemotherapy, and radiotherapy.
Design, Setting, and Participants
The US National Cancer Database (NCDB) was queried for all 1123 patients with LN+, squamous cell carcinoma of the penis without metastasis from January 1, 2004, through December 31, 2014. Temporal trends were assessed using Cochran-Armitage tests. Multivariable logistic models were used to examine the association between treatments, clinicopathologic variables, and receipt of chemotherapy. Kaplan-Meier analyses with log-rank tests and multivariable Cox regressions were used to analyze overall survival. Data were analyzed between January 2017 and September 2017.
Main Outcomes and Measures
Use of chemotherapy over time. Survival outcomes by receipt or nonreceipt of LND, radiotherapy, and chemotherapy.
Of 1123 patients identified, most were white (924 [82.3%]) vs African American (141 [12.6%]) or of other or unknown race (58 [5.2%]). The age of most patients (727 [64.7%]) was between 50 and 75 years, and 750 patients (66.8%) underwent an LND. From 2004 to 2014, the use of systemic therapy significantly increased (26 of 68 patients, 38.2% vs 65 of 136, 47.8%; P < .001). However, only 177 of 335 patients with N3 disease (52.8%) received chemotherapy (N1: 106 of 338, 31.4%; N2: 178 of 450, 39.6%). Following adjustment, older patients (>76 years: OR, 0.28; 95% CI, 0.15-0.50; P < .001) were less likely to receive chemotherapy. Patients who received radiotherapy (OR, 4.38; 95% CI, 3.10-6.18; P < .001) and those patients with N2 (OR, 1.62; 95% CI, 1.16-2.27; P = .005) or N3 (OR, 2.32; 95% CI, 1.67-3.22; P < .001) cancer were more likely to receive chemotherapy. On multivariable analysis, LND (HR, 0.64; 95% CI, 0.52-0.78; P < .001) was associated with better overall survival, while neither chemotherapy (HR, 1.01; 95% CI, 0.80-1.26; P = .95) nor radiotherapy (HR, 0.85; 95% CI, 0.70-1.04; P = .11) was associated with overall survival.
Conclusions and Relevance
In hospitals reporting to the NCDB, only 66.8% of patients with LN+ penile cancer received an LND. While chemotherapy use has increased since 2004, rates remain low (52.8% for patients with N3 cancer). Receipt of LND, but not chemotherapy or radiotherapy, is associated with overall survival. This may reflect the aggressive natural history of penile cancer as well as the inherent analysis limitation of a relatively small sample size. These data highlight opportunities to improve adherence to guideline-recommended care.
Squamous cell carcinoma of the penis is a rare disease with aggressive clinical features. In 2017, approximately 2100 cases were diagnosed; 5-year survival for locally-advanced or lymph node–positive (LN+) disease is approximately 59%.1 It has long been appreciated that inguinal and/or pelvic lymph node dissection (LND) for patients with LN+ penile cancer results in improved survival.2,3 Accumulated retrospective and limited prospective evidence for the use of chemotherapy for patients with LN+ penile cancer also suggests a survival benefit to perioperative, cisplatin-based chemotherapy regimens.4-6
Although little level I evidence exists to guide recommendations, there appears to be a clear advantage to aggressive, often multimodal, therapy. In 2013, the National Comprehensive Cancer Network (NCCN) consensus panel recommended that all patients with a clinical presentation of LN+ penile cancer undergo LND and/or radiotherapy with consideration of perioperative chemotherapy.7 Several studies evaluating the use of treatment have previously shown that, despite evidence and guidelines, there continues to be inadequate use of LND in these patients.8,9
Less is known about the national trends for the use of perioperative chemotherapy and radiotherapy. In conjunction with publication of NCCN guidelines, use of LND appears to be increasing; a similar trend can be hypothesized with the use of perioperative chemotherapy for patients with LN+ penile cancer.8 Using the National Cancer Database (NCDB), a large national cancer registry, we sought to analyze the practices and temporal trends of chemotherapy use for patients with nonmetastatic, LN+ penile cancer. Differences in survival outcomes were evaluated for patients who did receive or did not receive lymph node dissection (LND+ vs LND−), who did receive or did not receive chemotherapy (CT+ vs CT−), and who did receive or did not receive radiotherapy (XRT+ vs XRT−).
The NCDB, a jointly sponsored program by the American College of Surgeons and the American Cancer Society, is a national cancer registry established in 1989 that serves as a comprehensive clinical surveillance resource for cancer care in the United States. The NCDB compiles data from more than 1500 Commission on Cancer–accredited cancer programs in the United States and Puerto Rico and captures approximately 70% of all newly diagnosed cancer cases.10 Institutional review board approval by Fox Chase Cancer Center was obtained for use of national deidentified registry data. Patient consent was waived by Fox Chase Cancer Center.
Patients with squamous cell carcinoma of the penis were identified in the NCDB based on International Classification of Diseases for Oncology, Third Edition (ICD-O-3) site codes. Cases were selected based on squamous cell histology (ICD-O-3 histology codes 8070-8072). Our study cohort included 11 469 patients who were diagnosed with penile cancer between January 1, 2004, and December 31, 2014. Patients were selected based on positive lymph node status. Patients who died within 30 days of diagnosis, who had an inpatient stay longer than 30 days, who did not have treatment at the reporting hospital, and for whom receipt of chemotherapy was unknown were excluded from study (Figure 1). We identified patients using the NCDB analytical staging variable, which preferentially assigns pathological stage unless not reported; otherwise, clinical stage is used. Our primary outcome measures were receipt of chemotherapy and overall survival based on receipt of LND, chemotherapy, or radiotherapy.
Patients were evaluated using variables available in the NCDB. Variables included patient characteristics, such as age, race, year of cancer diagnosis, Charlson-Deyo comorbidity classification,11 status of insurance, median household income, and urban vs rural setting. Disease characteristics included histologic grade, node category, receipt of LND, and receipt of radiotherapy. Hospital characteristics included type of facility and center volume (number of cases per year). Although extranodal extension may be an important prognostic clinical variable,12 this information was available for a small number of patients (28.8%) and was not included in the analysis.
Temporal trends in the use of LND and chemotherapy were assessed for the period from January 1, 2004, to December 31, 2014, using Cochran-Armitage tests. We determined the association between use of chemotherapy and receipt of LND and/or radiotherapy as well as patient and tumor characteristics using χ2 tests. After adjusting for covariates, multivariable logistic regression models were used to examine the association between clinical and pathological variables and receipt of chemotherapy. We accounted for within-hospital clustering using the method of generalized estimating equations with robust standard errors.13 Hospital center volume (cases per year) was modeled both as a continuous variable and categorically, with different thresholds for case volume. Kaplan-Meier analyses with log-rank tests and multivariable Cox proportional hazards regression models were used to analyze overall survival for patients from January 1, 2004, to December 31, 2013. Given the possibility that only patients with N2/N3 cancer might benefit from chemotherapy, we performed a sensitivity analysis on the effect of radiotherapy and chemotherapy by restricting the cohort to these patients and repeating the survival analysis. Statistical analysis was conducted with SAS, version 9.3 (SAS Institute Inc), with 2-sided P < .05 considered statistically significant.
From 11 469 patients assessed for eligibility, the analytic cohort identified 1123 patients with LN+ penile cancer who met the inclusion criteria (Figure 1). Table 1 demonstrates select demographic and clinical characteristics of the cohort. Most patients were white (924 [82.3%]) vs African American (141 [12.6%]) or of other or unknown race (58 [5.2%]). The age of most patients (727 [64.7%]) was between 50 and 75 years.
Of the 1123 patients, 750 (66.8%) underwent an LND. The use of chemotherapy was similar for patients who received an LND and those who did not receive an LND (303 of 750 [40.4%] vs 158 of 373 [42.4%]; P = .53). The use of chemotherapy increased from years 2004 to 2014 (26 of 68 patients [38.2%] vs 65 of 136 [47.8%]; P < .001). Although the use of radiotherapy increased to 36.8% (32 of 87 patients) by 2007, it fell to 23.5% (32 of 136 patients) by 2014. The yearly use of LND, chemotherapy, and radiotherapy are demonstrated in eFigure 1 in the Supplement, whereas eFigure 2 in the Supplement demonstrates the yearly use of each treatment combination. Patients with a higher node category were more likely to receive chemotherapy, although only 177 of 335 patients (52.8%) with N3 cancer, 178 of 450 (39.6%) with N2 cancer, and 106 of 338 (31.4%) with N1 cancer received chemotherapy.
Table 2 displays select elements of the multivariable model used to predict the use of chemotherapy. After adjustment, older patients (≥76 years; OR, 0.28; 95% CI, 0.15-0.50; P < .001) were less likely to receive chemotherapy. Receipt of radiotherapy was strongly associated with chemotherapy use (OR, 4.38; 95% CI, 3.10-6.18; P < .001). Nodal status predicted an increased likelihood of receiving chemotherapy as the node category increased: N2 (OR, 1.54; 95% CI, 1.08-2.19; P = .02) and N3 (OR, 2.15; 95% CI, 1.52-3.04; P < .001).
We also examined the association between the use of chemotherapy and hospital center volume (cases per year of penile cancer). As an example, centers with 4 or more cases/y of penile cancer (accounting for 325 of 1123 [28.9%] of LN+ cases) were less likely to deliver chemotherapy than were centers with fewer than 4 cases/y, although this difference did not reach statistical significance (OR, 0.76; 95% CI, 0.52-1.10; P = .15). However, centers with 4 or more cases/y represented only 37 of 1113 centers (3.3%) evaluated; only 3 centers (0.3%) saw at least 10 cases/y. Defining hospital center volume of 5 or more cases/y as “high volume” resulted in only 1.7% of centers meeting the threshold. We thus modeled hospital center volume as a continuous variable, but there was no significant association between hospital center volume and receipt of chemotherapy.
The multivariable survival analysis is displayed in Table 3. Overall survival was higher in patients undergoing LND (HR, 0.64; 95% CI, 0.52-0.78; P < .001). Age of 76 years or older (HR, 1.92; 95% CI, 1.29-2.85; P = .001) and node categories N2 (HR, 1.44; 95% CI, 1.17-1.78; P = .001) and N3 (HR, 1.93; 95% CI, 1.52-2.45; P < .001) were significantly associated with poorer survival.
The median overall survival based on subgroups of patients with LND− and LND+ is shown in Figure 2B and C. Median overall survival varied from 14.5 months (95% CI, 8.6-17.5 months) in the LND−/CT+/XRT− group to 44.6 months (95% CI, 23.5-114.6 months) in the LND+/CT+/XRT− group. Figure 2A demonstrates the overall survival for patients based on receipt or nonreceipt of LND, whereas Figure 2D demonstrates the Kaplan-Meier survival estimates and median overall survival for patients based on receipt of LND, chemotherapy, and radiotherapy. The receipt of chemotherapy (HR, 1.01; 95% CI, 0.80-1.27; P = .95) and radiotherapy (HR, 0.85; 95% CI, 0.70-1.04; P = .11) were not associated with overall survival on multivariable survival analysis, and there was no significant survival effect of chemotherapy by node category. After performing a sensitivity analysis by restricting the cohort to patients with N2/N3 cancer, no significant differences in treatment effect were detected. Treatments of chemotherapy (HR, 0.91; 95% CI, 0.71-1.18; P = .49) and radiotherapy (HR, 0.88; 95% CI, 0.71-1.10; P = .26) were still not associated with improved survival. Concurrent chemoradiotherapy did not have a demonstrable association with survival (137 patients [12.2%]; HR, 0.97; 95% CI, 0.88-1.07; P = .53). The association of LND with survival did not differ by receipt of chemotherapy (P = .77) or radiotherapy (P = .99).
This retrospective evaluation of data from the NCDB suggests that chemotherapy use among patients with LN+ penile cancer remains considerably low, even among patients with N2 (39.6%) and N3 (52.8%) disease for whom the NCCN guidelines more explicitly recommend chemotherapy. Over the 10-year analysis period, perioperative chemotherapy use for these patients increased from 38.2% to 47.8%. Only 66.8% of patients underwent LND, which is consistent with previous work examining the rate of LND use for patients with LN+ penile cancer.8
The survival benefit of LND in patients with locally aggressive and LN+ penile cancer has been repeatedly demonstrated over several decades. McDougal et al2 showed in 1986 that, following LND, patients with stage II cancer had 5-year recurrence-free survival of 88% and patients with stage III cancer had 5-year recurrence-free survival of 66%. Those rates dropped dramatically in men not receiving LND (38% in patients with stage II cancer vs 0% with stage III cancer). Many large retrospective series have since shown the importance of LND for T2 through T4 penile cancers; work using sentinel node biopsy results shows that occult metastatic disease, if not properly managed, has a deleterious association with survival.3,14,15 Our analysis of 1123 patients supports this conclusion with, to our knowledge, one of the largest cohorts evaluating the association of LND with survival.
Campbell et al8 found that, in a contemporary cohort of patients whose hospitals reported to the NCDB, only 63% of patients with N1 and N2 penile cancer underwent LND; patients were less likely to receive LND in nontertiary community hospital centers. Another study9 evaluating NCDB and American Board of Urology case logs for penile surgery found that only 4.1% of practicing urologists performed penile surgery and LND specifically for penile cancer, and only 1.5% performed LND. There appears to be an “informal centralization,” as the authors note, of care for patients with LN+ penile cancer in the United States, although our analysis found that only 29% of cases are managed at centers that perform 4 or more cases/y. Because penile cancer is such a rare disease, only 3.3% of centers met this threshold of 4 or more cases/y. The rarity of this disease highlights the possible need for more centralization of care to optimize the multidisciplinary management of advanced penile cancer.
Cancer of the penis is a disease of stepwise progression, and effective management relies on aggressive, stage-specific treatment. Some advocate for more aggressive LND based on data suggesting that the extent of LND in patients with LN+ penile cancer correlates with survival.16 Cisplatin-based chemotherapy also appears to affect survival, either through its effects on occult distant metastatic disease or by directly affecting nodal progression. Pagliaro et al6 conducted a phase 2 study of neoadjuvant paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy for patients with N2 and N3 cancer. An objective response to chemotherapy significantly improved time to progression and overall survival, and 36.7% of patients treated with this regimen were recurrence free at a median follow-up of 34 months. A more recent retrospective analysis of neoadjuvant TIP chemotherapy followed by LND found that patients with N2 and N3 disease who had an objective response to chemotherapy had a 5-year survival rate of 50%.5 The NCCN guidelines do not specify whether neoadjuvant therapy is superior to adjuvant therapy because there is no clear evidence to support the superiority of either approach, although efforts at clarifying this have been attempted.4,5,17
The International Penile Advanced Cancer Trial (InPACT), estimated to be completed in 2023, may provide important answers regarding the optimal treatment for patients with LN+ penile cancer.18 In this prospective phase 3 trial, patients with advanced penile cancer will be randomized to 1 of 3 arms: (1) inguinal LND, (2) neoadjuvant TIP chemotherapy followed by inguinal LND, or (3) neoadjuvant chemoradiotherapy followed by inguinal LND. Those patients with a high risk of relapse following inguinal LND will be randomized to undergo prophylactic pelvic LND vs no prophylactic pelvic LND; the primary outcome will be overall survival at 5 years. The outcome will help define the optimal treatment sequence for advanced penile cancer. More important, it will determine the value of surgery, chemotherapy, and radiotherapy with regard to lymph node progression and metastasis.
To our knowledge, this study is the first to analyze the broad national trends of chemotherapy use in patients with LN+ penile cancer. It also confirms previous work showing an inadequate, though improving, use of LND for these patients. We found that chemotherapy use was roughly equal at 40% for patients who received or did not receive LND. Consistent with expectations, a higher node category correlated with higher likelihood of receiving chemotherapy, although chemotherapy use in patients with N1 and N2 disease remains well below 50%.
Other notable findings from the multivariable analyses include the association of age with chemotherapy use and survival. We found that older patients are less likely to receive chemotherapy and to have poorer survival. Although we controlled for comorbidity, it is difficult to completely eradicate the age-related treatment bias inherent to these findings. Practitioners are less likely to give chemotherapy to older patients, even though no evidence suggests decreased tolerability or response to chemotherapy in this population.
There appears to be a survival benefit to LND, as demonstrated in Figure 2A and the multivariable survival analysis in Table 3, acknowledging the effect of selection bias on these findings. We did not demonstrate an overall survival advantage to receiving chemotherapy in the survival analysis. Interpreting this finding is difficult because of the small sample size and lack of control for adjuvant and neoadjuvant chemotherapy regimens used in this population. It is also possible that the lack of a survival benefit reflects the aggressive nature of LN+ penile cancer. Studies suggesting a benefit to chemotherapy have historically included only patients with N2/N3 disease. Our survival analysis included all patients with LN+ penile cancer. To account for the possibility that the inclusion of patients with N1 disease affected the analysis, we performed a sensitivity analysis on patients with N2/N3 disease that failed to demonstrate a survival attributable to chemotherapy administration.
No prospective randomized clinical trials have shown survival benefit to perioperative chemotherapy in penile cancer, although the InPACT study may shed light on this clinical question. There is opportunity for improvement in adhering to guideline-directed therapy that can offer survival benefits for some patients. If future trials suggest survival benefits to multimodal therapies, our study can serve as a baseline from which to measure changes in treatment use over time.
Strengths and pitfalls of studying cancer care by using data from the NCDB have been previously described.19 Data from the NCDB are retrospective and offer a limited scope of patient information for analysis. Thus, we could not identify and evaluate specific chemotherapy regimens and could not evaluate the association of early vs late LND with survival outcomes. We were also unable to meaningfully differentiate inguinal from pelvic LND because of procedure recordkeeping in the NCDB. Although LND was associated with improved survival, the specific utility of pelvic LND could not be ascertained from these data; therefore, we are unable to endorse the use of pelvic LND in all patients with penile cancer. The InPACT study has the potential to greatly improve our understanding of the effectiveness of pelvic LND in patients with high-risk disease and adverse inguinal node pathologic findings, for whom NCCN guidelines already recommend pelvic LND. This observational study is subject to selection bias; healthier patients with less aggressive disease who may live longer might also receive more care. Although we adjusted for all known patient factors, residual biases may remain. This data set offers a cohort of 1123 patients with LN+ penile cancer from which to identify treatment and temporal trends. The survival estimates generated by this analysis also provide a more accurate look at the outcomes of patients undergoing various treatment regimens; this knowledge may be useful for patient counseling.
In hospitals that report to the NCDB, only two-thirds of patients with LN+ penile cancer receive an LND. Temporal trends demonstrate increasing national use of chemotherapy, although levels remain low at 48%. There is a significant difference in overall survival in groups who receive different treatment combinations. Although LND is associated with improved survival, neither chemotherapy nor radiotherapy appears to correlate with overall survival in this heterogeneous cohort, potentially because of a small sample size. These data can be used as a benchmark from which to develop strategies that might improve adherence to guideline-recommended care and influence future clinical trials.
Corresponding Author: Shreyas S. Joshi, MD, Division of Urologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Ave, Philadelphia, PA 19111 (firstname.lastname@example.org).
Accepted for Publication: December 6, 2017.
Published Online: March 1, 2018. doi:10.1001/jamaoncol.2017.5608
Author Contributions: Drs Joshi and Handorf had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Joshi, Correa, Smaldone, Geynisman.
Acquisition, analysis, or interpretation of data: Joshi, Handorf, Strauss, Kutikov, Chen, Viterbo, Greenberg, Uzzo, Smaldone, Geynisman.
Drafting of the manuscript: Joshi, Handorf, Strauss, Correa, Geynisman.
Critical revision of the manuscript for important intellectual content: Joshi, Handorf, Correa, Kutikov, Chen, Viterbo, Greenberg, Uzzo, Smaldone, Geynisman.
Statistical analysis: Joshi, Handorf, Strauss, Smaldone.
Administrative, technical, or material support: Joshi, Correa, Viterbo, Geynisman.
Study supervision: Chen, Viterbo, Greenberg, Uzzo, Smaldone, Geynisman.
Conflict of Interest Disclosures: Dr Handorf reported receiving research funding from Pfizer outside the scope of this work. No other disclosures were reported.
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