Objective. Results. Patients and Methods. Conclusions. Keywords <squamous cell carcinoma of the penis, prognostics, cancerspecific mortality, nomogram

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1 Development and external validation of a prognostic tool for prediction of cancer-specific mortality after complete loco-regional pathological staging for squamous cell carcinoma of the penis Maxine Sun, Rosa S. Djajadiningrat*, Hussain M. Alnajjar, Quoc-Dien Trinh, Niels M. Graafland*, Nick Watkin, Pierre I. Karakiewicz and Simon Horenblas* Department of Urology, Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada, *Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, and Penile Cancer Centre, St George s Healthcare NHS Trust, London, UK Objective To develop a novel postoperative prognostic tool, which attempts to integrate both pathological tumour stage and histopathological factors, for prediction of cancer-specific mortality (CSM) of squamous cell carcinoma of the penis (SCCP). Patients and Methods Patients with SCCP treated with inguinal lymph node dissection (ILND) or sentinel LN biopsy at a single institution were used for nomogram development and internal validation (n = 434), while a second cohort was used for external validation (n = 338). Multivariable Cox proportional hazards were used to examine the prognostic ability of patient age, a modified tumour staging that distinguishes between spongiosum and cavernosum body ingrowth tumours, a modified LN staging that integrates information on presence/ absence of LN metastasis, extent of inguinal LN metastases, pelvic LN involvement, and extranodal involvement, and tumour grade. Model performance was quantified using measures of discrimination and calibration. Results Overall, 36% of patients had positive LN metastases (n = 156). In univariable analyses, the modified tumour and LN staging systems were statistically significantly associated with CSM, and remained in the final model with a discrimination of 89% within internal validation, and 95% within external validation. Calibration was nearly perfect. Conclusions The newly developed model integrates important prognostic factors, which existing models do not consider. Its performance was highly accurate using measures of discrimination and calibration. Keywords <squamous cell carcinoma of the penis, prognostics, cancerspecific mortality, nomogram Introduction Squamous cell carcinoma of the penis (SCCP) is a rare disease [1]. Due to a better understanding of the natural history of the disease, significant progress has been made, and staging and treatment have improved. Nonetheless, the prognosis for men with SCCP remains variable, which reflects the heterogeneity of the disease [2,3]. Consequently, contemporary series have pursued better prognostic stratification in order to improve subsequent management of patients [4 6]. In that regard, several authors have sought to develop a model for prediction of cancer-specific mortality (CSM) in patients with SCCP [7 9]. First in 2006, Kattan et al. devised a nomogram using a cohort of Italian men (n = 175). Relying on overtly detailed pathological information (i.e. tumour thickness, growth pattern or venous and/or lymphatic embolization), the model achieved a discrimination of 73% and 75% respectively using clinical or pathological lymph node (LN) status within an internal validation. Subsequently in 2009, Zini et al. [9] developed a simpler model using a cohort of men originating from North America (n = 856). BJU Int 2014; 116: wileyonlinelibrary.com BJU International 2014 BJU International doi:1111/bju Published by John Wiley & Sons Ltd.

2 SCCP and cancer control Fig. 1 Identification and exclusion of men with SCCP who were surgically staged by sentinel LN biopsy and/or therapeutic ILND between January 1994 and December 2010 at a single institution. Patients with SCCP surgically staged by sentinel LN biopsy and/or ILND, n = 473 Exclusions: Distant metastases (n = 7) Unknown pathological stage (n = 6) Unknown tumour grade (n = 23) Unknown extent of LN metastases (n = 4) Presence of pelvic metastases without a pelvic LND (n = 1) Patients with unknown follow-up information (n = 5) Final study cohort n = 434 The model relied on historical stage and tumour grade, and achieved 74% discrimination within an internal validation. Recently, Thuret et al. [8] devised a nomogram by using the American Joint Committee on Cancer (AJCC) staging and tumour grade, and achieved 81% discrimination also relying on an internal validation (n = 1324). Both the Zini et al. [9] and Thuret et al. models relied on conventional tumour stage and grade. In contrast, the Kattan et al. [7] model relied on complex pathological information. However, a recent study showed that cavernosa invasion is worse than individuals with spongiosum invasion [10]. Another study by the same group of collaborators showed that modifying LN staging could also improve prognostication of patients with SCCP [11]. Based on the promising prognostic value of the modified pathological tumour stage and substaging of LN status, we decided to assess their combined consideration within a novel tool for prediction of CSM in patients with SCCP. The development of such a tool could help improve risk stratification of patients with a primary diagnosis of SCCP treated with surgery in the inguinal region, thereby improving patient counselling and provide additional support for subsequent treatment planning. Patients and Methods In accordance with institutional ethical guidelines and good clinical practice, data on 473 consecutive patients with SCCP who were surgically staged by sentinel LN biopsy and/or therapeutic inguinal lymphadenectomy (ILND) between January 1994 and December 2010 at a single institution were collected prospectively and retrieved retrospectively from a penile cancer database. These 473 patients constituted our nomogram development and internal validation cohort. A unilateral pelvic LND was performed in cases of more than two tumour-positive LNs and/or extranodal extension (ENE) in the inguinal specimen or preoperatively confirmed pelvic LN positivity. Pelvic LN positivity was always confirmed by histopathology (pelvic LND) or cytology alone (when considered inoperable in a minority of cases). Exclusions are described in Figure 1. All men were treated with a standard ILND for histopathologically confirmed LN metastasis. Extent of pelvic LND consists of removal of all LNs between the following boundaries [12]: proximally the common iliac vessels, distally the passage of lymphatic vessels to the groin, laterally the ilioinguinal nerve, medially the bladder and prostate and the base is the deepest part of the obturator fossa. The obturator fossa is completely removed, especially the space behind the external iliac vessels, all the way to the sacrum (triangle of Marcille). Surgery was performed by one of four staff urologists. Patients were followed according to a standard protocol, as previously described [11]. Treatment Algorithm Surgery and adjuvant radiotherapy indications were previously described [11]. In general, T1 and T2 lesions of <2 cm were treated with penile-preserving therapies (laser excision, local excision, circumcision, glans amputation with resurfacing). T2 lesions of >2 cm, as well as T3/T4 lesions were treated with either partial amputation or total amputation, depending on the size and infiltration of the tumour. All patients staged N0 underwent sentinel LN biopsy (n = 279). All patients staged N + underwent an ILND. In some of these patients ILND was preceded by a sentinel LN BJU International 2014 BJU International 735

3 Sun et al. biopsy (n = 115). Induction chemotherapy is given in locally advanced and/or inoperable regional disease without evidence of distant metastasis. Patients presenting with, or progressed to inoperable advanced disease received chemotherapy and/or radiotherapy in the palliative setting, together with best supportive care. Histopathology LN tissue was examined by palpation, inspection and sectioning. LNs were dissected manually and completely embedded in paraffin. Until 2008, all histopathology was revised by a single experienced uro-pathologist. Since then, all histopathology examinations were not revised but reported by experienced uro-pathologists. Grade assignment was between moderately or poorly differentiated based on the amount of undifferentiated cells within the tumour on histopathological examination according to Broders [13]. Lymphovascular invasion was defined as the presence of embolic tumour cells in thin-walled vessel-like structures using routinely stained sections. Finally, ENE was defined as extension of tumour through the LN capsule into the perinodal fibrous-adipose tissue [11]. The total number of histopathologically confirmed LNs and metastatic LNs was recorded for each LND specimen. In some rare cases (five patients), LN metastases were so extensive that separate LNs were no longer countable (pn3). Covariates For the purpose of the study, a modified version of the T category was examined by distinguishing between tumours that invade the corpus spongiosum and corpora cavernosa [10]. In addition, a combined variable of pathological LN involvement and ENE was created. Specifically, a recent analysis showed that ENE and pelvic LN involvement were significantly associated with worse prognosis [11]. That same study, as well as previous publications [14 16], showed that the dichotomisation of the number of inguinal LN metastases as 2 vs 3 resultedin significant associations with CSM after ILND. Consequently, the present study created a variable that considered both the number of inguinal LN metastases, ENE, as well as pelvic LN involvement. The creation of such a combined variable was necessary, given that LN-negative patients are the same across all variables, so as to avoid singularity issue. An overview of the current and modified tumour and LN stages is provided in Table 1. Other examined variables included patient age, side positivity, and tumour grade. Statistical Analysis Internal validation The Kaplan Meier method was used to estimate CSM from ILND or sentinel LN biopsy to the date of death or last Table 1 Overview of current and proposed pathological tumour and LN classifications. Current tumour stage classification Invasion in subepithelial connective tissue only Invasion in the corpora spongiosum or cavernosum Invasion in the urethra or prostate Invasion to adjacent structures Current LN stage classification No LN metastasis 1 inguinal LN metastasis Multiple or bilateral inguinal LN metastases Pelvic LNs, uni/bilateral or ENE of regional LNs Proposed tumour stage classification Invasion in subepithelial connective tissue only Invasion in the corpora spongiosum Invasion in the corpora cavernosum Invasion to adjacent structures* Proposed LN stage classification No LN metastasis 2 inguinal LN metastases without ENE 3 inguinal LN metastases and/or ENE Pelvic LN involvement *Given the few patients in this category, these individuals were grouped with those who had invasion to the corpora cavernosum in all analyses. follow-up. Patients dead at inter-current disease or alive at the last date were censored. Differences in subgroups were assessed using the log-rank test. Multivariable Cox regression analyses were used for prediction of CSM after ILND. Backward variable selection (Akaike Information Criterion) was used to identify the most accurate and parsimonious model [17]. Model discrimination was quantified using Harrell s concordance index [18,19]. The model s internal calibration was performed and graphically illustrated. External validation For this purpose, an additional 338 patients from a second institution with similar protocol with respect to surgery type indications were included. Relying on this cohort, we compared the final nomogram-predicted CSM to the observed CSM at 2 years of follow-up. Nomogram-derived CSM mortality predictions were computed with the nomogram formula, which was calculated from the development cohort. Subsequently, the nomogram-predicted probabilities of CSM were compared with the observed CSM rates, and the discrimination of time-specific predictions was quantified using the predicted probability validation method, and graphically illustrated through a calibration plot, as described by Harrell [20]. Given that the current TNM classification scheme [21] is a widely used staging system for penile cancer, we also tested its prognostic ability in the external validation cohort. Finally, decision-curve analysis was used to quantify the net benefits related to the use of the developed nomogram and the TNM staging system for prediction of CSM. The study was performed in accordance with institutional ethical guidelines, based on good clinical practice. All analyses were performed using R software environment for statistical computing and graphics (version ). 736 BJU International 2014 BJU International

4 SCCP and cancer control Table 2 Descriptive characteristics of 434 men with SCCP used for nomogram development, and 338 men used for the external validation cohort, surgically staged by sentinel LN biopsy and/or ILND. Variable Development cohort External validation cohort P No. of patients Age, years Mean (median) 64 (65) 64 (65) Interquartile range n (%): Primary lesion management: <01 Penile preserving therapies* 189 (43.5) 255 (75.4) Partial amputation 245 (56.5) 83 (24.6) pt stage 2009 TNM: 1 pt1a 88 (2) 95 (28.1) pt1b 34 (7.8) 42 (12.4) pt2 279 (64.3) 140 (41.4) pt3/4 33 (7.6) 61 (18.1) pn stage 2009 TNM pn0 279 (64.3) 233 (68.9) pn1 49 (11.3) 25 (7.4) pn2 31 (7.1) 12 (3.6) pn3 75 (17.3) 68 (2) Modified pathological tumour stage: <01 Subepithelial connective tissue invasion (pt1) 123 (28.3) 143 (42.3) Invasion in the corpora spongiosum (pt2) 212 (48.8) 123 (36.4) Invasion in the corpora cavernosum/adjacent structures (pt3 4) 99 (22.8) 72 (21.3) ENE 2 LN-negative or none 363 (83.7) 272 (8) Unilateral/bilateral 71 (16.3) 66 (19.5) Extent of LN involvement: No LN metastasis 279 (64.1) 233 (68.9) 2 inguinal LNs 112 (25.7) 69 (2) 3 inguinal LNs 43 (9.9) 36 (1) Proposed classification: 04 No LN metastasis 279 (64.1) 233 (68.9) 2 inguinal LN metastases without ENE 74 (17.3) 33 (9.8) 3 inguinal LN metastases and/or ENE 50 (11.5) 52 (15.4) Pelvic LN involvement 31 (7.1) 20 (5.9) Tumour grade: <01 Low grade (I II) 326 (75.1) 180 (53.3) High grade (III IV) 108 (24.8) 158 (46.7) Lymphovascular invasion 123 (28.3) 101 (29.9) Chemotherapy: Neoadjuvant chemotherapy 10 (2.3) 0 () Adjuvant chemotherapy 9 (2.1) 23 (6.8) Radiotherapy 74 (17.1) 32 (9.5) <01 Mean (median) follow-up, months 52.4 (43.1) 56.8 (54.0) *includes laser excision, local excision, circumcision, glans amputation with resurfacing. Results Within the development cohort (n = 434), the mean (median) patient age was 64 (65) years (Table 2). Overall, 49% of patients had invasion in the corpora spongiosum (pt2) and 23% had invasion in the corpora cavernosum or adjacent structures (pt3 4). In all, 25% had poorly/ undifferentiated tumour grade (grade III IV). Overall, 36% of patients had positive LN metastases (n = 155). The association between LN status and pathological tumour extent is described in Table 3 [10]. The presence of ENE was recorded in 46% of patients who had positive LN metastases (n = 71). Overall, 72% and 28% of LN-positive patients had 2 and 3 inguinal LN metastases, respectively. By combining information of the number of inguinal LN metastases and ENE, overall 17% had 2 inguinal LN metastases without ENE, 12% had 3 inguinal LN metastases and/or ENE, and 7% had pelvic LN involvement. Overall, the 2-year CSM rate was 14.3% (Fig. 2). Using the modified pt stage definition, CSM rates at 2 years were 8.5%, 1%, and 3% for pt1, pt2, and pt3 4, respectively (all log-rank P < 01, except pt1 vs pt2 P = 91, Fig. A). Patients with ENE had significantly worse 2-year CSM rates than patients without ENE (57.0% vs 19.3%, log-rank P < 01, Fig. 3B). CSM rates for the same time point were 1.9%, 24.9%, and 65.6% for respectively patients without any LN metastasis, with 2 inguinal LN metastases, and with 3 inguinal LN metastases (all log-rank P < 01, Fig. 3C). BJU International 2014 BJU International 737

5 Sun et al. Table 3 Bivariate association between tumour stage and LN status. TNM classification Development cohort External validation cohort No. of patients pn+, n (%) P No. of patients pn+, n (%) P pt stage 2009 TNM 04 <01 pt1a (18.1) (1) pt1b (5) (33.3) pt (39.1) (34.2) pt (39.4) (54.1) Proposed pt stage [10] 01 <01 pt (27.6) (18.1) pt (33.0) (35.8) pt (52.5) (48.6) Fig. 2 Kaplan-Meier graph depicting overall CSM rates in patients with SCCP treated with ILND or sentinel LN biopsy, year CSM rates: 14.3% Using the proposed combination, which incorporates pathological LN status and ENE, CSM rates at 2 years were 1.9%, 19.0%, 43.3%, and 68.6% for respectively those without LN metastasis, patients 2 inguinal LN metastases without ENE, patients with 3 inguinal LN metastases and/or ENE, and those with pelvic LN involvement (all log-rank P 01, Fig. 3D). Finally, patients with high-grade SCCP had statistically significantly worse CSM than their lower grade counterparts (21.5% vs 12.0%, log-rank P = 31, Fig. 3E). In the full multivariable analyses, the associated hazard ratios (HRs) for patients with 2 inguinal LN metastases without ENE, 3 inguinal LN metastases and/or ENE, and pelvic LN involvement were 1%, 33.0%, and 67.7%, respectively (all P < 01, Table 4). Patients with cavernosa invasion (HR 3.75, P < 01) and high-grade SCCP (HR 1.79, P = 24) fared worse than their spongiosum and low-grade SCCP counterparts in univariable analyses, but failed to achieve statistical significance after adjusting for other covariates. After backward variable selection, only the proposed tumour and LN classifications remained in the model (Table 5). Discriminatory estimate quantified with the area under the curve (AUC) was 9 (Fig. 4A). In calibration measures within the development cohort, predicted and observed probabilities of CSM at 2 years were nearly perfect (Fig. 4B). We compared the discrimination of our final model with that of the TNM staging system. In the external validation cohort (n = 338), the TNM staging system had an AUC of 0.90 at 2 years vs 0.95 for our model, thus resulting in a discriminatory gain of +5 (Mantel Hansel test P < 01). The graphical comparison between the nomogram-predicted probabilities and the actual fraction surviving within the external validation cohort showed virtually a near-perfect performance (Fig. 5) [18]. Finally, decision-curve analysis showed that for the prediction of CSM at 2 years, the proposed nomogram fared comparably to the current TNM staging system, with marginally better net benefit between threshold probabilities of 18 25%, and beyond 48% (Fig. 6). Discussion To date, three models have been devised for the purpose of predicting CSM in patients diagnosed with SCCP after ILND [7 9]. Despite the pertinence of all such models, some limitations apply. First, the Kattan et al. [7] model, which included pathological data of the primary tumour and groin LNs, relies on variables that are not routinely available upon pathological assessment of penectomy specimens. The second model developed by Zini et al. [9], despite having circumvented the complexity of the Kattan et al. [7] model, relies on a historical staging method specific to the database that was used. The most recent model, developed by Thuret et al. [8], suffered from intermediate discrimination ability. In the context of SCCP, given the rarity of the disease, prediction of CSM may prove to be a difficult task. Nonetheless, an accurate assessment of the prognosis of 738 BJU International 2014 BJU International

6 SCCP and cancer control Fig. 3 Kaplan-Meier graphs depicting CSM rates stratified according to a modified pathological tumour stage (A), ENE status (B), extent of inguinal LN metastases (C), proposed LN substaging classification (D), and tumour grade (E). A 1.0 pt1 0.9 pt2 pt3-4 C 2-year CSM rates 8.5% 1% 3% year CSM rates LN-negative 1.9% inguinal metastases 3 inguinal metastases 24.9% 65.6% B 1.0 LN-negative 0.9 ENE-none ENE-unilateral or bilateral D 1.0 LN-negative inguinal metastases without ENE 3 inguinal metastases and/or ENE Pelvic LN involvement 2-year CSM rates 1.9% 19.3% 57.0% year CSM rates 1.9% 19.0% 43.3% 68.6% E 1.0 Low-grade 0.9 High-grade 2-year CSM rates 12.0% 21.5% BJU International 2014 BJU International 739

7 Sun et al. Table 4 Univariable and multivariable Cox regression models for prediction of CSM in patients with SCCP, Predictors Univariable AUC Multivariable Full model Multivariable Final model HR P HR P HR P pn stage 0.91 pn0 1.0 (ref.) <01 pn <01 pn <01 pn Extent of LN involvement: 9 None 1.0 (ref.) <01 2 inguinal LNs <01 3 inguinal LNs LN density <01 1 ENE status: 8 LN-negative/none 1.0 (ref.) <01 Unilateral/bilateral Patient age, years Tumour grade: 9 Low grade (I II) 1.0 (ref.) (ref.) 49 High grade (III IV) Proposed N classification: 0.92 No LN metastasis 1.0 (ref.) < (ref.) < (ref.) <01 2 LNs, without ENE <01 10 <01 18 <01 3 LNs and/or ENE < < <01 Pelvic LN involvement Proposed T classification: 7 pt1 1.0 (ref.) (ref.) (ref.) pt < pt AUC ref., referent category. Table 5 Approximate nomogram-derived predictions of being CSM free at 2 years after ILND for SCCP. LN-negative 2 inguinal LN metastases, without ENE 3 inguinal LN metastases, and/or ENE Pelvic LN involvement pt1 2 98% 86% 60% 40% pt3 4 97% 71% 32% 15% patients with SCCP remains essential. Consequently, several investigators have re-evaluated existing predictors, or sought to identify other variables to better risk-stratify patients with SCCP. First, and foremost, the most important prognostic factor in men with invasive SCCP is the presence of LN involvement [22]. Additionally, the prognosis of patients with LN metastases varies according to certain established factors, namely the extent of LN involvement and pelvic LN involvement. While the number of positive LNs is not currently included in the TNM staging system, several studies have documented a significant worsening of survival in the presence of >2 inguinal LN metastases [14 16]. In a recent study, the authors have reconfirmed that the best threshold of inguinal LNs to determine the poor prognosis of patients with SCCP on CSM to be three [11]. Second, some have noticed that the survival of patients with T2 tumours was often comparable or worse than the survival of patients with T3 tumours. For this purpose, Leijte et al. [10], having recognised the shortcomings of the TNM staging system, proposed a modification to the pathological tumour stage. Specifically, the authors found a clinically relevant difference with respect to CSM when distinguishing between patients with tumours invading the corpus spongiosum from those invading the corpus cavernosum. Interestingly, in the nomogram devised by Kattan et al. [7], a similar observation was recorded in the final proposed model. Previous authors postulated that the capacity to break through the relative thick tunica albuginea covering the cavernous bodies may presumably reflect the biological aggressiveness of the tumour. Third, other histopathological factors, such as ENE, have consistently been reported as risk factors. Its negative prognostic effect was first recorded by Srinivas et al. [23] in 1987, and subsequently confirmed by Ravi [16] in Contemporary data have shown similar results, where ENE was associated with up to a nine-times higher risk of CSM [24]. Recently, a study re-highlighted the prognostic potential of ENE [11]. After adjustment for all other covariates, 740 BJU International 2014 BJU International

8 SCCP and cancer control Fig. 4 Final model for prediction of CSM-free survival rates at 2 years in the format of a nomogram (A) and calibration plot for prediction of CSM where the x-axis represents nomogram-predicted probability of CSM and the y-axis represents the observed fraction with evidence of CSM. Predictions vary between 75% and 98%. Perfect prediction corresponds to the 45 line. Points estimated below the 45 line correspond to nomogram overall prediction whereas points situated above the 45 line correspond to nomogram under prediction (B). A B Points Proposed LN classification LN-negative 2 inguinal metastases without ENE pelvic LN involvement 3 inguinal metastases and/or ENE Proposed tumour classification pt1 pt2 pt3 4 Observed Total Points CSM-free at 2 years Predicted patients with ENE were 2.4-times more likely to succumb to CSM than their ENE-absent counterparts (P < 01). Interestingly in that study, patients with ENE and who had positive LNs were four-times more likely to succumb to CSM than patients with positive LNs without ENE. Based on the aforementioned considerations, there is room for improvement. As such, it prompted the current attempt aimed at the development of a more accurate model using more relevant tumour and LN substages. Our findings are several fold. First, the presence and extent of LN involvement emerged as one of the most important prognostic factors in men with SCCP. Specifically, patients with 3 inguinal LN metastases had worse CSM rate at 2 years than patients with 2 inguinal LN metastases. Furthermore, patients with pelvic LN involvement had the poorest CSM rates at 2 years. Second, our findings showed that presence of ENE, regardless of patients LN status, was associated with a significantly worse survival than patients without ENE. Third, our present results showed that the combination of both the extent of LN involvement with ENE emerged as the most informative and the most clinically relevant prognostic variable in our model. Fourth, our findings corroborate previous studies that showed a survival difference between patients with tumours invading the corpus spongiosum vs patients with tutors invading the corpus cavernosa (2-year CSM 10% vs 31%). However, it is noteworthy that its inclusion was less important given the strong prognostic influence of the proposed classification. That being said, it remained in the final model after backward variable selection. However, its clinical pertinence is clearly of less importance relative to the combined prognostic ability of LN status and ENE. In contrast, although tumour grade was an informative prognostic factor in our analyses, it failed to be included in the final model. An explanation may be that the consideration of extent of LN involvement and ENE resulted in such strong prognostic factors that it rendered the importance of other variables secondary (i.e. tumour grade). Taken together, we devised and externally validated a tool that relies on important prognostic factors, namely extent of LN involvement, pelvic LN involvement, and ENE status, as well as a modified pathological tumour stage for prediction of CSM in patients with SCCP treated with ILND. Its prognostic ability was better than that of the widely used TNM staging system when both models were subjected to external validation. This nomogram can help identify patients at high risk of succumbing to CSM 2 years after ILND. The identification of such patients can result in better cancer control outcomes for improved patient follow-up planning, BJU International 2014 BJU International 741

9 Sun et al. Fig. 5 Comparison between nomogram-predicted probability of cancerspecific survival (x-axis) and the actual observed fraction surviving (y-axis) within the external validation cohort. The calibration plot is generated by bootstrapping estimates of predicted vs observed values based on subsetting prediction into intervals, where predicted means predicted survival probability at a single time point, and observed refers to the Kaplan-Meier survival estimates [18]. Fraction Surviving 24 Month Predicted 24 Month Survival n = 434 d = 67 p = 5, 150 subjects per group Net benefit X-resampling optimism added, B = 40 Based on observed-predicted Fig. 6 Decsion-curve analysis for predictions of CSM at 2 years using the developed nomogram (black) and the conventional TNM staging system (red) Threshold probability, % and alternative (multimodal) treatment strategies if needed. The tool is less complex compared with a previously devised nomogram [7], and was highly accurate given its AUC in external validation. That said, the tool requires that an ILND has been performed and a pelvic LND in some patients. Moreover, we recommend the consideration of this novel tool for future external validations before its integration in routine clinical practice. The present study is not devoid of limitations. First, given the rarity of the disease, external validations of tools developed in the context of SCCP are more difficult to acquire. Nonetheless, it remains an integral part following the development of a model. That said, the present model having been modelled upon patients treated in Europe, may be less applicable to patients treated in other continents, as the phenotype of SCCP may differ [25 27]. Furthermore, the external validation cohort could have benefitted from an even larger sample size. Moreover, the cohort on whom the model was externally validated on was coincidentally highly homogenous in mortality patterns compared with our development cohort. For example, the proportion of patients who died within 2 years was 48% and 45% for the development and external validation cohorts, respectively, hence the nearly perfect discriminative ability of the nomogram even after external validation. Consequently, future studies may want to assess the proposed model s performance in other populations, e.g. a larger North American cohort, before its integration in to routine clinical practice. Second, the present study was based on a small sample size originating from a highly homogenous population given its single institutional nature. Ideally, the model would have benefitted from a cohort with several contributing institutions to increase its generalizability. Third, other potentially important prognostic factors, e.g. histological tumour subtype or LN density, may have been worth examining. Moreover, we could not assess the true impact of chemotherapy and/or radiotherapy on survival in this cohort. Given its retrospective nature, a treatment selection bias would have confounded the results. A randomised trial is needed to truly assess the effect of adjuvant treatment in this context. Fourth, it would have been valuable to compare our present model to existing ones. Unfortunately, the Kattan nomogram relies on parameters that we do not have in the present cohorts (e.g. growth pattern). Consequently, we could not compare the performance of the two models. With respect to the Zini et al. [9] and Thuret et al. [8] models, no external validation was possible given that the former model relied on a specific staging system unique to the Surveillance, Epidemiology, and End Results database, while the latter model relied on a more historical version of the TNM staging system. Finally, the short follow-up prevented us from examining CSM rates at an ulterior time point. Preferably, a more 742 BJU International 2014 BJU International

10 SCCP and cancer control suitable time point would have been 5 years after pathological staging. That being said, most recurrences occur within 2 years [28]. Moreover, a previous study showed that given a CSM-free period of at least 2 years after a primary tumour excision, the prognosis of patients remains relative stable thereafter [29]. In conclusion, the present study shows that the prognosis of patients with SCCP can be highly accurately predicted using modified substaging of pathological tumour and LN stages. The simultaneous consideration of extent of inguinal LN metastases and presence of ENE further improves prognostication of patients with SCCP. The proposed model holds great potential for routine clinical use. Conflicts of interest None of the authors have any conflicts of interest or disclosures to declare. Funding None received. References 1 Pizzocaro G, Algaba F, Horenblas S et al. 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Cancer 2011; 117: Correspondence: Maxine Sun, Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, 264 Blvd. Rene-Levesque East, Room 228, Montreal (QC) H2X1P1, Canada. mcw.sun@umontreal.ca Abbreviations: AUC, area under the curve; CSM, cancerspecific mortality; ENE, extranodal extension; HR, hazard ratio; (I)LND, (inguinal) lymphadenectomy; LN, lymph node; SCCP, squamous cell carcinoma of the penis. BJU International 2014 BJU International 743