Primary Penile Cancer: The Role of Adjuvant Radiation Therapy in the Management of Extranodal Extension in Lymph Nodes

E U R O P E A N U R O L O GY F O C U S 5 ( 2 0 19 ) 7 3 7 – 741

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Penile Cancer

Primary Penile Cancer: The Role of Adjuvant Radiation Therapy in the Management of Extranodal Extension in Lymph Nodes Peter A.S. Johnstone a,*, David Boulware b, Rosa Djajadiningrat c, Sarah Ottenhof c, Andrea Necchi d, Mario Catanzaro d, Dingwei Ye e, Yao Zhu e, Nicola Nicolai d, Simon Horenblas c, Philippe E. Spiess f a

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA; b Department of Bioinformatics and Biostatistics, Moffitt Cancer Center, Tampa

FL, USA; c Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; d Department of Urology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy; e Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; f Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA

Article info

Abstract

Article history: Accepted October 8, 2018

Background: In head and neck cancer, the presence of extranodal extension (ENE) in lymph nodes (LNs) has been shown prospectively to require adding chemotherapy to postoperative radiation therapy (RT). Limited data exist regarding ENE in LNs from primary penile cancer (PeCa). Objective: To determine the association of RT and ENE in PeCa. Design, setting, and participants: We retrospectively analyzed the outcomes of 93 patients with pT1–4 N3 M0 (American Joint Committee on Cancer 7th edition) squamous cell carcinoma of the penis across four international centers. Intervention: If the inguinal nodal specimen had ENE or two or more positive inguinal LNs, RT was delivered to an ipsilateral inguinal field. An ipsilateral pelvic field was added for positive pelvic LNs on dissection. The delivered dose was usually 50 Gy in 25 daily fractions. Outcome measurements and statistical analysis: Clinical and demographic characteristics of relapse-free (RFS), disease-specific (DSS), and overall (OS) survival were compared by ENE status and receipt of adjuvant RT. Results and limitations: Seventy-two percent of patients had inguinal ENE, and 49% had pelvic ENE. On multivariable analysis (MVA) of ENE-negative patients, an OS benefit was noted with postoperative chemotherapy (p = 0.038) and inguinopelvic RT (p = 0.037). RFS suffered with worsening grade of the lesion (moderately: p = 0.027; poorly: p = 0.038), but was improved with groin (p = 0.016) and inguinopelvic (p = 0.006) RT. On MVA of patients with ENE, inguinopelvic RT was associated with better DSS (p = 0.041). Grade impacted DSS (moderately: p = 0.043; poorly: p = 0.033), and poorly differentiated lesions impacted RFS (p = 0.013). Conclusions: Inguinopelvic RT may benefit regional control in PeCa patients with positive pelvic LNs, but this appears to be limited to those without ENE. Patient summary: For patients with penile cancer and positive pelvic lymph nodes, postoperative radiation therapy was found to decrease the likelihood of disease recurrence in the groin or pelvis only if extranodal extension was absent. © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Associate Editor: Richard Lee Keywords: Penile cancer Extranodal extension Lymph node

* Corresponding author. Radiation Oncology Department, Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612, USA. Tel. +1 (813)745-1075; Fax: +1 (813) 745-7231. E-mail address: Peter.Johnstone@Moffitt.org (Peter A.S. Johnstone). https://doi.org/10.1016/j.euf.2018.10.007 2405-4569/© 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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1.

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Introduction

penis were collected; all patients had at least unilateral LN dissection. Details of therapy have been described previously [19]. Performance of

In head and neck cancer (HNCa), involvement of cervical lymph nodes (LNs) is critically important; Johnson and colleagues [1] reported that 5-yr survival is reduced by about half with LN involvement. Extranodal extension (ENE) of LN metastasis portends an even worse prognosis. In a subsequent report, Johnson and associates [2] described a further 50% survival decrement among patients with ENE in cervical LN metastases. Another study [3] documented ENE as having a threefold risk of neck recurrence. ENE similarly has been implicated in poorer outcomes in carcinoma of the bladder [4,5], breast [6], pancreas [7], stomach [8], and cervix [9]. In HNCa, radiation therapy (RT) has become the standard of care postoperatively for ENE. A classic report in HNCa by Peters and associates [10] described 48% local-regional failure after RT of 57.6 Gy if ENE was present. This was reduced to 26% by increasing the RT dose to 63 Gy. Chemotherapy may be necessary for ENE+ patients as well. In a prospective randomized trial in HNCa patients [11], RT alone for ENE allowed a 68% local recurrence rate, compared with 48% for concurrent chemoradiation. Results from two large cooperative group trials in the USA [12] and Europe [13] reported separately that ENE necessitates the addition of cisplatin to postoperative RT. In fact, a combined analysis of those two trials [14] clarified that ENE and positive surgical margins were the only two pathologic factors for which postoperative chemotherapy added to RT improved outcomes. Given a similar complex relationship with human papillomavirus (HPV) and similar histology, some have tried to extrapolate from the HNCa literature to clinical therapy of penile cancer (PeCa), since far fewer data exist in that experience. Graafland and colleagues [15] have shown in prospectively collected data that ENE contributes to decreased cancer-specific survival in PeCa. However, unlike HNCa, there is a distinct lack of data showing the benefit of postoperative RT for pN1 or pN2 PeCa [16]. This may explain why a recent examination of the National Cancer Database has revealed that adjuvant RT is more commonly delivered for pN1 or pN2 disease in the community than in academic centers [17]. Currently, the European Association of Urology guidelines for PeCa recommend that RT be considered in selected patients with ENE [18]. The international consortium represented here has previously contributed to a better understanding of the role of adjuvant RT [19] and adjuvant chemotherapy [20] in the subset of patients with positive pelvic LNs (PLNs) from primary PeCa. We therefore sought to analyze the relationship between ENE and the role of adjuvant RT. 2.

Patients and methods

Following appropriate institutional review board approval, four collaborating institutions in Italy, The Netherlands, the People's Republic of China, and the USA contributed patient data to this retrospective review. Patient data pertaining to stage pT1–4 N3 M0 (according to the TNM 2009 classification system, 7th edition) squamous cell carcinoma of the

PLN dissection was according to the institutional policy, but in general included two or more positive inguinal LNs, ENE, or suspicious pelvic imaging. Techniques were similar across all institutions and required open resection of all lymphatic tissue in the obturator and the internal and external iliac regions. Patients from Moffitt and the Netherlands Cancer Institute undergoing unilateral inguinal LN dissection had a dynamic sentinel LN biopsy of the clinically nonpalpable side, with no suspicious nodes on preoperative imaging on that ipsilateral side. Our data are not specific enough to confirm for the other sites. Radiation was provided at the discretion of the attending radiation oncologist. As previously described [21], if the inguinal nodal specimen had ENE or two or more positive inguinal LNs, RT was delivered to an ipsilateral inguinal field. An ipsilateral pelvic field was added for positive PLN on dissection. Delivered dose was usually 50 Gy in 25 daily fractions [21]. Of note, despite the fact that all patients had pelvic node–positive disease, the variables of ENE, RT, and regional recurrence were collated and analyzed separately for both inguinal and pelvic beds. Chemotherapy was delivered to 46 patients. Cisplatin and 5FU were delivered in 23 cases, with other platinum-based regimens in 19 and methotrexate + bleomycin in nine cases. Some patients received more than one regimen. Basic descriptive statistics were used to summarize the patient cohort (n = 93). For categorical comparisons, either the chi-square test or the Fisher’s exact test was used. For numeric variables, the Kruskal-Wallis test was used. Overall survival (OS), disease-specific survival (DSS), and disease recurrence were examined using the Kaplan–Meier curves (with log-rank test) and Cox proportional hazards regression multivariate models (including RT, chemotherapy, and grade). Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported along with the p values for the Cox regression. All analyses were performed in SAS v. 9.4 or R.

3.

Results

Records of 93 patients were available (see Table 1). Median age at the time of LN dissection was 65.3 yr (range 35.9–90.2 yr). Median follow-up was 9.4 mo (interquartile range: 5.4– 19.4). The median number of involved inguinal LNs was 4 (range 1–12), and median positive PLNs was 2 (range 1–21). Median OS was 10.58 mo and median DSS was 11.10 mo. Seventy-two percent of patients had ENE in the inguinal area and 49% had ENE in the pelvis. Infield failure occurred in 52 of 64 sites with ENE and in 18 of 28 sites without ENE (p = 0.08). In the presence of ENE, infield failure was experienced by 32/39 patients receiving RT and by 20/25 patients not receiving RT (p = 1.0). In the absence of ENE, infield failure was observed in eight of 16 cases after RT and in 10 of 12 cases without RT (p = 0.11). Multivariable analysis of the patient cohort without ENE shows that postoperative chemotherapy benefitted OS (Table 2; p = 0.038). Inguinopelvic RT improved OS and conferred a decreased recurrence risk both in the groin (p = 0.016; HR 0.04, 95% CI 0.003, 0.54) and in the pelvis (p = 0.006; HR 0.03, 95% CI 0.002, 0.363). In this patient cadre, there were too few reference (well-differentiated) lesions to allow for multivariable analysis of survival endpoints by grade. A similar subset analysis of the ENE+ cohort yielded no effect of grade, chemotherapy, or RT on OS. Moderately and

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Table 1 – Patient demographics.

Patients, na Age, median (range) Stage pT1 pT2 pT3 pT4 pTx Grade Well Moderately Poorly Unknown Median positive pelvic LN (IQR) Chemotherapy No Preop Postop

Total n (%)

No XRT (%)

XRT both (%)

XRT pelvis only (%)

XRT groin only (%)

93 (100) 65.3 (36–90)

31 65.4 (36–84)

38 65.4 (37–86)

2 50.5 (45–56)

18 63.9 (35–90)

13 (14.0) 57 (61.3) 13 (14.0) 1 (1.1) 9 (9.7)

3 (9.7) 15 (48.4) 5 (16.1) 1 (3.2) 7 (22.6)

7 (18.4) 27 (71.0) 3 (7.9) 0 1 (2.6)

0 1 (50.0) 1 (50.0) 0 0

3 (16.7) 13 (72.2) 2 (11.1) 0 0

0.109

20 (21.5) 36 (38.7) 31 (33.3) 6 (6.5) 2 (1–3)

8 (25.8) 13 (41.9) 8 (25.8) 2 2(1–5)

7 (19.4) 15 (41.7) 14 (38.9) 2 2 (1–3)

0 1 (50.0) 1 (50.0) 0 2 (1–3)

4 6 7 1 1

(22.2) (33.3) (38.9)

0.938

(1–2)

0.080

47 (50.5) 14 (15.1) 32 (34.4)

20 (64.5) 5 (16.1) 6 (19.4)

18 (47.4) 6 (15.8) 14 (36.8)

1 (50.0) 0 1 (50.0)

7 (38.9) 3 (16.7) 8 (44.4)

0.484

p value

0.435

IQR = interquartile range; LN = lymph node; XRT = external beam radiotherapy. Four patients could not be assigned to an XRT group due to incomplete information.

a

poorly differentiated lesions had poorer disease-free survival than well-differentiated lesions (respectively, p = 0.043; HR 2.43, 95%CI 1.03, 5.75 and p = 0.033; HR 2.65, 95% CI 1.08, 6.48), although only poorly differentiated lesions conferred significantly worse regional recurrence (p = 0.013; HR 3.08, 95% CI 1.27, 7.45). RT to the pelvis + groin, but not groin alone for inguinal involvement, was associated with better DSS (p = 0.041; HR 0.48, 95% CI 0.24, 0.97). Figure 1 reveals Kaplan–Meier analyses of OS (Fig. 1A), DSS (Fig. 1B), and recurrence-free survival (Fig. 1C). In no cases, ENE impacts the survival or recurrence endpoints. 4.

Discussion

These data confirm the negative prognostic value of LN involvement after nodal basin dissection for PeCa. The

presence of positive LNs in a basin led to an increasing frequency of regional failure there. ENE was not associated with an increased risk of failure, likely because that risk was very high at baseline. Grade of the primary lesion certainly impacts outcomes: relapse-free survival (RFS) in ENE( ) patients and also DSS in ENE(+) patients. Here, the extranodal extent of disease is shown to be associated with poor outcomes. In the case of patients without ENE, RT was found to contribute to better RFS (p = 0.016 for groin RTand p = 0.006 for inguinopelvic RT). OS was improved by adjuvant chemotherapy (p = 0.038) and inguinopelvic RT (p = 0.037). However, ENE(+) patients saw no benefit to chemotherapy and no local-regional benefit to RT, only a DSS benefit to inguinopelvic RT (p = 0.041). The provision of inguinopelvic RT showed a benefit but in a peculiar pattern. For ENE( ) patients, OS and RFS

Table 2 – Cox proportional hazards regression (multivariable). OS HR (95% CI) ENE patients (n = 18) Chemotherapy (ref = no) Chemotherapy (ref = no) Grade (ref = well) Grade (ref = well) XRT (ref = no XRT) XRT (ref = no XRT) ENE+ patients (n = 64) Chemotherapy (ref = no) Chemotherapy (ref = no) Grade (ref = well) Grade (ref = well) XRT (ref = no XRT) XRT (ref = no XRT)

p value

DSS HR (95% CI)

p value

RFS HR (95% CI)

p value

Preop Postop Moderate Poorly XRT both XRT groin only

– 0.07 (0.006, 0.86) – – 0.04 (0.002, 0.62) 0.11 (0.01, 1.57)

– 0.038 – – 0.037 0.132

– 0.12 (0.009, 1.70) – – 0.06 (0.004, 1.02) 0.11 (0.007, 1.59)

– 0.118 – – 0.052 0.104

0.05 (0.003, 1.033) 1.61 (0.32, 8.21) 0.02 (0, 0.621) 0.03 (0.001, 0.826) 0.03 (0.002, 0.363) 0.04 (0.003, 0.54)

0.052 0.566 0.027 0.038 0.006 0.016

Preop Postop Moderate Poorly XRT both XRT groin only

1.49 (0.66, 3.32) 1.19 (0.59, 2.43) 1.94 (0.89, 4.26) 2.06 (0.89, 4.75) 0.54 (0.28, 1.06) 0.87 (0.37, 2.09)

0.333 0.624 0.097 0.090 0.072 0.761

1.30 (0.57, 2.97) 1.14 (0.55, 2.37) 2.43 (1.03, 5.75) 2.65 (1.08, 6.48) 0.48 (0.24, 0.97) 0.97 (0.37, 2.08)

0.534 0.714 0.043 0.033 0.041 0.756

1.27 (0.56, 2.89) 1.89 (0.94, 3.81) 2.25 (0.98, 5.16) 3.08 (1.27, 7.45) 0.51 (0.26, 1.02) 0.62 (0.26, 1.47)

0.571 0.075 0.054 0.013 0.056 0.274

CI = confidence interval; DSS = disease-specific survival; ENE = extranodal extension; HR = hazard ratio; OS = overall survival; ref = references; RFS = relapsefree survival; RT = radiation therapy; XRT = external beam radiotherapy. Bold indicates statistical significance. Nine patients with missing information and two receiving RT only to the pelvis were excluded from this analysis.

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Fig. 1 – Kaplan–Meier analyses by the presence or absence of extranodal extension (ENE): (A) overall survival, (B) disease-specific survival, (C) recurrence-free survival.

The fact that RT confers a uniform RFS benefit only in patients without ENE implies that the disease burden in ENE-positive patients may be too extreme for tolerable RT doses. In our recent analysis of the role of HPV and chemoradiotherapy in PeCa [22], we found that the only factor associated with local/regional control (LRC) was positive LN status. Of those LN+ patients, both HPV+ status and adjuvant chemoradiation provided increased LRC [22]. The present study investigated the role of chemotherapy in a different cohort of patients; the fact that here chemotherapy was found on multivariable analysis to impact OS only in ENE( ) patients reveals the difficulty of finding coherent data in this rare disease and mirrors the data reported by Necchi and colleagues [23]. We acknowledge several shortcomings in this study. First, it is retrospective, multi-institutional, and multinational; all of these convey potential for a patient bias in selection for therapy. Dose, timing, and sophistication of RT, as well as the reasons for its administration may confound these results. We are unable to take into account a small number of patients not undergoing surgery after progression or intolerance of preoperative systemic chemotherapy. Sparse data were available on patient comorbidities. Finally, comparison of data from different studies at different institutions is prone to variability as to what is considered ENE. Many published studies will overestimate ENE frequency because those patients undergoing nodal dissections have been preselected to be at a high risk of nodal involvement. Further, some standard pathologic techniques for the examination of dissection specimens may miss microscopic ENE. Finally, the number of ENEnegative patients in our study is somewhat small, which is not unexpected given the sample of patients with pelvic involvement. These data do not completely mirror what has been learned in the case of HNCa, but a positive LN remains a critically poor prognostic factor in PeCa. ENE does not occur infrequently. While a recent meta-analysis has confirmed no reproducible benefit to adjuvant groin RT [16], these findings support a potential benefit of pelvic and groin RT in terms of regional control in patients with positive PLNs after dissection. A conceptual benefit may be inferred of prophylactic pelvic RT to patients with ENE in groin nodes alone, although they were not included in this review. Certainly, ENE+ patients need different therapeutic strategies from ENE patients, as shown by their lack of response to current strategies. Clinical trials, as in HNCa, should investigate the role of combined chemoradiation in this population as is currently being coordinated and in the early stages of accrual in the International Penile Advanced Cancer Trial (ECOG-EA 8134)..

5. were improved, and the p value for disease-free survival was 0.052. It is tempting to think that a larger patient number might contribute to a benefit across all metrics.

Conclusions

LN metastases are a critically poor prognostic factor in PeCa and ENE is frequent. Adjuvant RT appears to benefit local control only in patients without ENE.

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Author contributions: Peter A.S. Johnstone had full access to all the data

[9] Horn LC, Hentschel B, Galle D, Bilek K. Extracapsular extension of

in the study and takes responsibility for the integrity of the data and the

pelvic lymph node metastases is of prognostic value in carcinoma of

accuracy of the data analysis. Study concept and design: Johnstone. Acquisition of data: Djajadiningrat, Ottenhof, Necchi, Catanzaro, Ye, Zhu,

the cervix uteri. Gynecol Oncol 2008;108:63–7. [10] Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first

Nicolai, Horenblas, Spiess.

report of a prospective randomized trial. Int J Radiat Oncol Biol

Analysis and interpretation of data: Johnstone, Boulware, Horenblas,

Phys 1993;26:3–11.

Spiess.

[11] Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-

Drafting of the manuscript: Johnstone, Boulware.

Schveitzer N. Combined postoperative radiotherapy and weekly

Critical revision of the manuscript for important intellectual content: John-

cisplatin infusion for locally advanced head and neck carcinoma:

stone, Boulware, Ottenhof, Necchi, Horenblas, Spiess.

final report of a randomized trial. Int J Radiat Oncol Biol Phys

Statistical analysis: Boulware. Obtaining funding: Johnstone, Spiess.

1996;36:999–1004. [12] Cooper J, Pajak T, Forastiere A, et al. Postoperative concurrent

Administrative, technical, or material support: Johnstone.

radiotherapy and chemotherapy for high-risk squamous-cell carci-

Supervision: Johnstone, Spiess, Horenblas.

noma of the head and neck. N Engl J Med 2004;350:1937–44.

Other: None.

[13] Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced

Financial disclosures: Peter A.S. Johnstone certifies that all conflicts of

head and neck cancer. N Engl J Med 2004;350:1945–52.

interest, including specific financial interests and relationships and

[14] Bernier J, Cooper J, Pajak T, et al. Defining risk levels in locally

affiliations relevant to the subject matter or materials discussed in the

advanced head and neck cancers: a comparative analysis of con-

manuscript (eg, employment/affiliation, grants or funding, consultan-

current postoperative radiation plus chemotherapy trials of the

cies, honoraria, stock ownership or options, expert testimony, royalties,

EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843–50.

or patents filed, received, or pending), are the following: None.

[15] Graafland NM, van Boven HH, van Werkhoven E, Moonen LM, Horenblas S. Prognostic significance of extranodal extension in

Funding/Support and role of the sponsor: None.

patients with pathological node positive penile carcinoma. J Urol 2010;184:1347–53. [16] Robinson R, Marconi L, MacPepple E, et al. Risks and benefits of

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