Original Study
Concurrent Chemoradiotherapy for Men With Locally Advanced Penile Squamous Cell Carcinoma Gregory R. Pond,1 Matthew I. Milowsky,2 Michael P. Kolinsky,3 Bernhard J. Eigl,4 Andrea Necchi,5 Lauren C. Harshman,6 Giuseppe Di Lorenzo,7 Tanya B. Dorff,8 Richard J. Lee,9 Guru Sonpavde10 Abstract Chemoradiotherapy is often administered for locally advanced penile squamous cell carcinoma (PSCC), an orphan malignancy, but outcomes with this approach are unclear. This retrospective analysis of 26 patients reports outcomes with concurrent chemoradiotherapy for locally advanced and advanced PSCC. The study highlights dismal outcomes with chemoradiotherapy and suggests the need for better understanding of tumor biology and evaluation of novel systemic agents. Background: Outcomes with concurrent chemoradiotherapy for penile squamous cell carcinoma (PSCC) are unclear, and only anecdotal reports have been published. This study was a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and Methods: Individual patientelevel data were obtained from 5 institutions for outcomes with concurrent chemoradiotherapy for PSCC. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors on progression-free survival (PFS) and overall survival (OS). Results: A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was III in 9 patients (36%) and stage IV in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients, and the median (range) of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The median OS was 6.9 months (95% CI, 5-14), and the median PFS was 5.1 months (95% CI, 2.5-7.0). When excluding patients with M1 disease, the remaining patients (n ¼ 21) had a median OS and PFS of 10.0 months (95% CI, 5-14) and 6.0 months (95% CI, 2.0-7.0), respectively. Baseline neutrophil to lymphocyte ratio (NLR) was significantly associated with survival, and visceral metastasis showed a trend for association with OS. Conclusions: Concurrent chemoradiotherapy demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Chemoradiation, Locally advanced, Outcomes, Penile squamous cell carcinoma, Prognosis
Introduction Penile squamous cell carcinoma (PSCC) is relatively rare in the western world, but developing countries exhibit higher incidences. In the United States, 1640 new cases and 320 deaths from PSCC were expected in 2014.1 The majority of patients are diagnosed at a 1
McMaster University, Hamilton, Ontario, Canada University of North Carolina, Chapel Hill, NC 3 University of Alberta, Edmonton, Alberta, Canada 4 BC Cancer Agency, Vancouver, British Columbia, Canada 5 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 6 Dana-Farber Cancer Institute, Boston, MA 7 University Federico II, Napoli, Italy 8 University of Southern California, CA 9 Massachusetts General Hospital Cancer Center, Boston, MA 2
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.009
localized stage and are generally managed by single-modality therapy with surgery or radiation therapy, although selected patients may be offered concurrent chemoradiotherapy. However, PSCC can exhibit aggressive biology with locoregional lymphatic spread and subsequent distant metastasis. Patients with distant metastatic disease 10 University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL
Submitted: Jan 17, 2014; Revised: Mar 01, 2014; Accepted: Mar 11, 2014 Address for correspondence: Guru Sonpavde, MD, Associate Professor of Medicine, Division of Hematology-Oncology, UAB Comprehensive Cancer Center, 1802 6th Ave S, NP2540, Birmingham, AL 35294 E-mail contact: [email protected]
Clinical Genitourinary Cancer Month 2014
-1
Chemoradiotherapy for Penile Cancer Table 1 Continued
Table 1 Baseline Patient Characteristics
n (%)
n (%) Patient Characteristics (n ¼ 26 Unless Otherwise Noted)
Tumor Characteristics Clinical Stageb
Site Alberta
8 (30.8)
2
British Columbia
6 (23.1)
3
4 (15.4)
North Carolina
8 (30.8)
4
16 (61.5)
Dana-Farber
2 (7.7)
Unknown
Milan
2 (7.7) 60.3 (12.4)
Smoking Status Never
8 (30.8)
3 (11.5)
1
2 (7.7)
2
18 (69.2)
3 Visceral Metastases
3 (11.5) c
9 (34.6)
Current
5 (19.2)
Yes
2 (7.7)
Unknown
4 (15.4)
Unknown
6 (23.1)
No
Soft Tissue Metastases 17 (65.4)
Yes, Neonatal
0 (0.0)
Yes, Postneonatal
3 (11.5)
Unknown
6 (23.1)
ECOG Performance Status 0
1 (3.8)
1
5 (19.2)
2 3 Unknown
3 (11.5) 3 (11.5) 14 (53.8)
Mean (SD)
12.8 (1.5)
Neutrophils (n ¼ 25) Mean (SD)
7.7 (3.9) 1.5 (0.5) 4.4 (1.5-16.2)
Albumin (n ¼ 20) Mean (SD)
6 (23.1)
Pathology Papillary
1 (3.9)
Verrucous
1 (3.9)
Sarcomatoid
1 (3.9)
Not Specified
23 (88.5)
Lymphovascular Invasion Yes Unknown
13 (50.0) 4 (15.4)
Chemotherapy Regimen No Platinum
24 (92.3) 2 (7.7)
Specific Chemotherapy Regimen
Neutrophils/Lymphocytes Ratio (n ¼ 25) Median (range)
7 (26.9)
Unknown
Cisplatin-Based
Lymphocytes (n ¼ 25) Mean (SD)
Yes
Treatment Characteristics
Hemoglobin
3.6 (0.6)
5-FU and Cisplatin
10 (38.5)
Cisplatin Only
14 (53.8)
5-FU Only
1 (3.9)
Bleomycin
1 (3.9)
External Beam Radiation Dose 60 Gy
5 (19.2)
Asian
4 (15.4)
Unknown
1 (3.9)
Hispanic/Latin American
1 (3.8)
Unknown
7 (26.9)
Race White
Family History of PSCC None
26 (100.0)
History of Precancerous Lesion n (%)
Outcomes Overall Survival (mo) n (%) Censored
8 (30.8)
Median (95% CI)
6.9 (5, 14)
1-year (95% CI) 2 (7.7)a
HIV Positive
-
Grade
Past
Circumcision
2
1 (3.8)
0
Age Mean (SD)
5 (19.2)
32.6 (14.2, 52.6)
Progression-Free Survival (mo) n (%) Censored
7 (26.9)
Negative
17 (65.4)
Median (95% CI)
5.1 (2.5, 7.0)
Unknown
9 (34.6)
1-year (95% CI)
18.7 (5.9, 36.9)
Clinical Genitourinary Cancer Month 2014
Gregory R. Pond et al Table 1 Continued n (%) Outcomes (Excluding Patients With Metastases) Overall Survival (mo) n (%) Censored
6 (28.6)
Median (95% CI)
10.0 (5, 14)
1-year (95% CI)
36.9 (16.0, 58.1)
Progression-Free Survival (mo) n (%) Censored
5 (23.8)
Median (95% CI)
6.0 (2.0, 7.0)
1-year (95% CI)
20.5 (6.4, 40.1)
Abbreviations: CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; 5-FU ¼ 5-fluorouracil; mo ¼ month; PSCC ¼ penile squamous cell carcinoma; SD ¼ standard deviation. a One patient had previous balanitis xerotica obliterans; one had an undefined precancerous lesion. b American Joint Committee on Cancer 7th edition: stage 1, T1aN0M0; stage II, T1b-T3N0M0; stage III, T1-T3N1-N2M0; stage IV, any T4, any N3, or M1; T1a, tumor invades subepithelial connective tissue without lymphovascular invasion (LVI) and is not high grade 3-4; T1b, tumor invades subepithelial connective tissue with LVI or is grade 3-4; T2, tumor invades corpus spongiosum or cavernosum; T3, tumor invades urethra; T4, tumor invades other adjacent structures; N1, mobile unilateral inguinal lymph node; N2, mobile multiple or bilateral inguinal lymph nodes; N3, palpable fixed inguinal nodal mass or pelvic lymphadenopathy; M1, distant metastasis. Among 16 patients with stage IV disease, 5 had M1 disease and 11 had T4 disease, N3 disease, or both. c These include bone, lung, and liver disease.
are generally treated with systemic cisplatin-based combination chemotherapy.2-15 In the spectrum between local therapy alone and systemic therapy alone, multimodality therapy plays a major role. In patients with locally advanced or locoregional but operable disease, neoadjuvant cisplatin-based combination chemotherapy followed by surgery is offered.4,8,16,17 Patients with high-risk disease after initial surgery have been considered for adjuvant chemotherapy, radiotherapy, or both. Selected patients with inoperable locally advanced or locoregional disease with bulky or fixed lymphadenopathy (with or without prior surgery) are considered appropriate for a concurrent chemoradiotherapy approach, although high disease burden may lead to the institution of systemic chemotherapy alone. However, no prospective studies have been conducted to investigate outcomes with concurrent chemoradiotherapy for locoregionally advanced disease, and only anecdotal reports exist.18,19 Hence, this study was a retrospective analysis of patients with PSCC receiving concurrent chemoradiotherapy for unresectable locoregionally advanced or advanced disease to examine clinical outcomes and potential prognostic factors.
Patients and Methods Patient Population This study identified consecutive patients with PSCC who were treated between the years 2000 and 2012 at referral medical centers in North America and Europe. Eligibility required patients who had received concurrent systemic therapy with external beam radiotherapy without subsequent surgery for localized, locoregionally advanced, or metastatic disease. However, patients may have undergone previous surgery before recurrence and presentation with locoregional or advanced disease. Patients who received perioperative chemoradiotherapy were excluded. The following patient and disease characteristics at baseline were requested: Eastern
Cooperative Oncology Group performance status, American Joint Committee on Cancer 7th edition clinical stage, sites of metastases (soft tissue vs. visceral), hemoglobin, race, smoking status, circumcision status, peripheral blood neutrophil count, peripheral blood lymphocyte count, albumin, family history of penile cancer, history of precancerous lesion, HIV status, lymphovascular invasion, histologic subtype, systemic therapy regimen, and the duration to tumor progression and death from the initiation of chemoradiotherapy. The study was conducted after approval by the Institutional Review Board at the University of Alabama, Birmingham (UAB) and other participating institutions.
Statistical Methods Individual patientelevel data were combined, and patient, disease, and outcome characteristics were summarized using descriptive statistics. Durations to event outcomes were calculated using the Kaplan-Meier method. Neutrophil and lymphocyte count were assessed individually, as well as using the neutrophil/lymphocyte ratio. Dichotomization of selected categorical or ordinal variables and application of a logarithmic transformation for non-normal continuous variables were applied for statistical purposes. Univariate Cox proportional hazards regression analysis was conducted to examine the prognostic effect of the aforementioned candidate factors on overall survival (OS) and progression-free survival (PFS). Given the small sample size and limited statistical power available, it was decided a priori not to perform multivariate statistical modeling. All tests were 2-sided, and a value of P .05 was considered statistically significant.
Results Patient Characteristics Patient data for 26 patients treated with chemoradiotherapy were captured from 5 institutions (Table 1): the University of North Carolina (Chapel Hill, NC) (n ¼ 8); the University of Alberta (Edmonton, Alberta, Canada) (n ¼ 8); the British Columbia Cancer Agency (Vancouver, British Columbia, Canada) (n ¼ 6); Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy) (n ¼ 2); and the Dana-Farber Cancer Institute (Boston, MA) (n ¼ 2). All patients had squamous cell carcinoma, although the histologic subtype was not available for most patients. The mean age of these patients was 60.3 years; 16 (61.5%) had clinical stage IV disease; and 5 patients overall had M1 disease (19.2%). Soft tissue and visceral disease were present in 26.9% and 7.7% of patients, respectively. The majority of patients (92.3%) received cisplatin-based regimens. The median dose of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The radiotherapy fields were variable between patients and institutions. After chemoradiotherapy, none of the patients underwent surgical excision.
Clinical Outcomes The 1-year OS was 32.6% (95% CI, 14.2%-52.6%), and PFS was 18.7% (95% CI, 5.9%-36.9%) (Table 1; Fig. 1A, B). When excluding patients with M1 disease, the remaining patients (n ¼ 21) exhibited 1-year OS and PFS of 36.9% (95% CI, 16.0%58.1%) and 20.5% (95% CI, 6.4%-40.1%), respectively (Table 1; Fig. 2A, B). Regarding staging, 5, 4, and 16 patients had stage II,
Clinical Genitourinary Cancer Month 2014
-3
Chemoradiotherapy for Penile Cancer Figure 1 Survival Analysis. A, Overall Survival. B, ProgressionFree Survival
III, and IV disease, with 1-year OS of 40.0% (95% CI, 5.2%75.3%), 37.5% (1.1%-80.8%), and 22.4% (4.1%-49.8%), respectively; the median OS was 10 (6-16), 5 (2.5-14), and 6.9 (3-10) months, respectively. The 6-month PFS was 20.0% (0.8%-58.2%), 0%, and 39.0% (15.1%-62.5%), respectively; the median PFS was 6 (2-7), 2.25 (1-not reached), and 5.1 (2-8) months, respectively. Only 2 patients attained durable PFS and OS > 2 years.
Univariable Analyses
4
-
On univariable analyses, baseline neutrophil to lymphocyte ratio (NLR) was the only variable that attained statistical significance as a prognostic factor for OS (hazard ratio [HR] ¼ 2.84; 95% CI, 1.157.02; P ¼ .023) (Table 2). NLR also showed a trend for association with PFS (HR ¼ 1.89 [0.84-4.21]; P ¼ .12). A trend for an unfavorable effect of visceral disease on both OS (HR ¼ 3.35 [0.6916.21]; P ¼ .13) and PFS (HR ¼ 3.40 [0.70-16.52]; P ¼ .13) was observed (Table 3). Notably, the dose of radiation was associated with a 20%-30% decreased hazard of both OS and PFS for every 10-Gy increase in dose; however, neither attained statistical significance.
Clinical Genitourinary Cancer Month 2014
Figure 2 Survival Analysis for Patients With M0 Disease. A, Overall Survival for Patients With M0 Disease. B, Progression-Free Survival for Patients With M0 Disease
Discussion Guidelines, such as from the NCCN (National Comprehensive Cancer Network), and case reports have advocated or reported chemoradiotherapy as a viable approach for locally advanced PSCC despite the lack of published data on the use of this treatment modality.18-22 The present study is the first to report outcomes in a cohort of patients receiving concurrent chemotherapy and radiotherapy for locally advanced or advanced PSCC. For this study, 26 patients from 5 institutions had data available, despite a review of databases from 13 centers, which together contributed 140 patients toward the authors’ previously reported study of chemotherapy alone as first-line therapy for locally advanced or advanced PSCC.23 These data suggest that concurrent chemoradiotherapy is seldom being considered for unresectable locoregionally advanced disease. This study’s population can be characterized as having considerably advanced and bulky disease, with stage IV disease in 61.5%, M1 disease in 19.2%, and visceral metastases in 7.7% of patients, implying that therapy was administered with palliative intention in
Gregory R. Pond et al Table 2 Univariable Analyses for Overall Survival All Data Definition
n
Hazard Ratio (95% CI)
P
/Decade /unit /unit /unit /log(unit) /unit 4 versus
Concurrent Chemoradiotherapy for Men With Locally Advanced Penile Squamous Cell Carcinoma Gregory R. Pond,1 Matthew I. Milowsky,2 Michael P. Kolinsky,3 Bernhard J. Eigl,4 Andrea Necchi,5 Lauren C. Harshman,6 Giuseppe Di Lorenzo,7 Tanya B. Dorff,8 Richard J. Lee,9 Guru Sonpavde10 Abstract Chemoradiotherapy is often administered for locally advanced penile squamous cell carcinoma (PSCC), an orphan malignancy, but outcomes with this approach are unclear. This retrospective analysis of 26 patients reports outcomes with concurrent chemoradiotherapy for locally advanced and advanced PSCC. The study highlights dismal outcomes with chemoradiotherapy and suggests the need for better understanding of tumor biology and evaluation of novel systemic agents. Background: Outcomes with concurrent chemoradiotherapy for penile squamous cell carcinoma (PSCC) are unclear, and only anecdotal reports have been published. This study was a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and Methods: Individual patientelevel data were obtained from 5 institutions for outcomes with concurrent chemoradiotherapy for PSCC. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors on progression-free survival (PFS) and overall survival (OS). Results: A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was III in 9 patients (36%) and stage IV in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients, and the median (range) of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The median OS was 6.9 months (95% CI, 5-14), and the median PFS was 5.1 months (95% CI, 2.5-7.0). When excluding patients with M1 disease, the remaining patients (n ¼ 21) had a median OS and PFS of 10.0 months (95% CI, 5-14) and 6.0 months (95% CI, 2.0-7.0), respectively. Baseline neutrophil to lymphocyte ratio (NLR) was significantly associated with survival, and visceral metastasis showed a trend for association with OS. Conclusions: Concurrent chemoradiotherapy demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Chemoradiation, Locally advanced, Outcomes, Penile squamous cell carcinoma, Prognosis
Introduction Penile squamous cell carcinoma (PSCC) is relatively rare in the western world, but developing countries exhibit higher incidences. In the United States, 1640 new cases and 320 deaths from PSCC were expected in 2014.1 The majority of patients are diagnosed at a 1
McMaster University, Hamilton, Ontario, Canada University of North Carolina, Chapel Hill, NC 3 University of Alberta, Edmonton, Alberta, Canada 4 BC Cancer Agency, Vancouver, British Columbia, Canada 5 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 6 Dana-Farber Cancer Institute, Boston, MA 7 University Federico II, Napoli, Italy 8 University of Southern California, CA 9 Massachusetts General Hospital Cancer Center, Boston, MA 2
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.009
localized stage and are generally managed by single-modality therapy with surgery or radiation therapy, although selected patients may be offered concurrent chemoradiotherapy. However, PSCC can exhibit aggressive biology with locoregional lymphatic spread and subsequent distant metastasis. Patients with distant metastatic disease 10 University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL
Submitted: Jan 17, 2014; Revised: Mar 01, 2014; Accepted: Mar 11, 2014 Address for correspondence: Guru Sonpavde, MD, Associate Professor of Medicine, Division of Hematology-Oncology, UAB Comprehensive Cancer Center, 1802 6th Ave S, NP2540, Birmingham, AL 35294 E-mail contact: [email protected]
Clinical Genitourinary Cancer Month 2014
-1
Chemoradiotherapy for Penile Cancer Table 1 Continued
Table 1 Baseline Patient Characteristics
n (%)
n (%) Patient Characteristics (n ¼ 26 Unless Otherwise Noted)
Tumor Characteristics Clinical Stageb
Site Alberta
8 (30.8)
2
British Columbia
6 (23.1)
3
4 (15.4)
North Carolina
8 (30.8)
4
16 (61.5)
Dana-Farber
2 (7.7)
Unknown
Milan
2 (7.7) 60.3 (12.4)
Smoking Status Never
8 (30.8)
3 (11.5)
1
2 (7.7)
2
18 (69.2)
3 Visceral Metastases
3 (11.5) c
9 (34.6)
Current
5 (19.2)
Yes
2 (7.7)
Unknown
4 (15.4)
Unknown
6 (23.1)
No
Soft Tissue Metastases 17 (65.4)
Yes, Neonatal
0 (0.0)
Yes, Postneonatal
3 (11.5)
Unknown
6 (23.1)
ECOG Performance Status 0
1 (3.8)
1
5 (19.2)
2 3 Unknown
3 (11.5) 3 (11.5) 14 (53.8)
Mean (SD)
12.8 (1.5)
Neutrophils (n ¼ 25) Mean (SD)
7.7 (3.9) 1.5 (0.5) 4.4 (1.5-16.2)
Albumin (n ¼ 20) Mean (SD)
6 (23.1)
Pathology Papillary
1 (3.9)
Verrucous
1 (3.9)
Sarcomatoid
1 (3.9)
Not Specified
23 (88.5)
Lymphovascular Invasion Yes Unknown
13 (50.0) 4 (15.4)
Chemotherapy Regimen No Platinum
24 (92.3) 2 (7.7)
Specific Chemotherapy Regimen
Neutrophils/Lymphocytes Ratio (n ¼ 25) Median (range)
7 (26.9)
Unknown
Cisplatin-Based
Lymphocytes (n ¼ 25) Mean (SD)
Yes
Treatment Characteristics
Hemoglobin
3.6 (0.6)
5-FU and Cisplatin
10 (38.5)
Cisplatin Only
14 (53.8)
5-FU Only
1 (3.9)
Bleomycin
1 (3.9)
External Beam Radiation Dose 60 Gy
5 (19.2)
Asian
4 (15.4)
Unknown
1 (3.9)
Hispanic/Latin American
1 (3.8)
Unknown
7 (26.9)
Race White
Family History of PSCC None
26 (100.0)
History of Precancerous Lesion n (%)
Outcomes Overall Survival (mo) n (%) Censored
8 (30.8)
Median (95% CI)
6.9 (5, 14)
1-year (95% CI) 2 (7.7)a
HIV Positive
-
Grade
Past
Circumcision
2
1 (3.8)
0
Age Mean (SD)
5 (19.2)
32.6 (14.2, 52.6)
Progression-Free Survival (mo) n (%) Censored
7 (26.9)
Negative
17 (65.4)
Median (95% CI)
5.1 (2.5, 7.0)
Unknown
9 (34.6)
1-year (95% CI)
18.7 (5.9, 36.9)
Clinical Genitourinary Cancer Month 2014
Gregory R. Pond et al Table 1 Continued n (%) Outcomes (Excluding Patients With Metastases) Overall Survival (mo) n (%) Censored
6 (28.6)
Median (95% CI)
10.0 (5, 14)
1-year (95% CI)
36.9 (16.0, 58.1)
Progression-Free Survival (mo) n (%) Censored
5 (23.8)
Median (95% CI)
6.0 (2.0, 7.0)
1-year (95% CI)
20.5 (6.4, 40.1)
Abbreviations: CI ¼ confidence interval; ECOG ¼ Eastern Cooperative Oncology Group; 5-FU ¼ 5-fluorouracil; mo ¼ month; PSCC ¼ penile squamous cell carcinoma; SD ¼ standard deviation. a One patient had previous balanitis xerotica obliterans; one had an undefined precancerous lesion. b American Joint Committee on Cancer 7th edition: stage 1, T1aN0M0; stage II, T1b-T3N0M0; stage III, T1-T3N1-N2M0; stage IV, any T4, any N3, or M1; T1a, tumor invades subepithelial connective tissue without lymphovascular invasion (LVI) and is not high grade 3-4; T1b, tumor invades subepithelial connective tissue with LVI or is grade 3-4; T2, tumor invades corpus spongiosum or cavernosum; T3, tumor invades urethra; T4, tumor invades other adjacent structures; N1, mobile unilateral inguinal lymph node; N2, mobile multiple or bilateral inguinal lymph nodes; N3, palpable fixed inguinal nodal mass or pelvic lymphadenopathy; M1, distant metastasis. Among 16 patients with stage IV disease, 5 had M1 disease and 11 had T4 disease, N3 disease, or both. c These include bone, lung, and liver disease.
are generally treated with systemic cisplatin-based combination chemotherapy.2-15 In the spectrum between local therapy alone and systemic therapy alone, multimodality therapy plays a major role. In patients with locally advanced or locoregional but operable disease, neoadjuvant cisplatin-based combination chemotherapy followed by surgery is offered.4,8,16,17 Patients with high-risk disease after initial surgery have been considered for adjuvant chemotherapy, radiotherapy, or both. Selected patients with inoperable locally advanced or locoregional disease with bulky or fixed lymphadenopathy (with or without prior surgery) are considered appropriate for a concurrent chemoradiotherapy approach, although high disease burden may lead to the institution of systemic chemotherapy alone. However, no prospective studies have been conducted to investigate outcomes with concurrent chemoradiotherapy for locoregionally advanced disease, and only anecdotal reports exist.18,19 Hence, this study was a retrospective analysis of patients with PSCC receiving concurrent chemoradiotherapy for unresectable locoregionally advanced or advanced disease to examine clinical outcomes and potential prognostic factors.
Patients and Methods Patient Population This study identified consecutive patients with PSCC who were treated between the years 2000 and 2012 at referral medical centers in North America and Europe. Eligibility required patients who had received concurrent systemic therapy with external beam radiotherapy without subsequent surgery for localized, locoregionally advanced, or metastatic disease. However, patients may have undergone previous surgery before recurrence and presentation with locoregional or advanced disease. Patients who received perioperative chemoradiotherapy were excluded. The following patient and disease characteristics at baseline were requested: Eastern
Cooperative Oncology Group performance status, American Joint Committee on Cancer 7th edition clinical stage, sites of metastases (soft tissue vs. visceral), hemoglobin, race, smoking status, circumcision status, peripheral blood neutrophil count, peripheral blood lymphocyte count, albumin, family history of penile cancer, history of precancerous lesion, HIV status, lymphovascular invasion, histologic subtype, systemic therapy regimen, and the duration to tumor progression and death from the initiation of chemoradiotherapy. The study was conducted after approval by the Institutional Review Board at the University of Alabama, Birmingham (UAB) and other participating institutions.
Statistical Methods Individual patientelevel data were combined, and patient, disease, and outcome characteristics were summarized using descriptive statistics. Durations to event outcomes were calculated using the Kaplan-Meier method. Neutrophil and lymphocyte count were assessed individually, as well as using the neutrophil/lymphocyte ratio. Dichotomization of selected categorical or ordinal variables and application of a logarithmic transformation for non-normal continuous variables were applied for statistical purposes. Univariate Cox proportional hazards regression analysis was conducted to examine the prognostic effect of the aforementioned candidate factors on overall survival (OS) and progression-free survival (PFS). Given the small sample size and limited statistical power available, it was decided a priori not to perform multivariate statistical modeling. All tests were 2-sided, and a value of P .05 was considered statistically significant.
Results Patient Characteristics Patient data for 26 patients treated with chemoradiotherapy were captured from 5 institutions (Table 1): the University of North Carolina (Chapel Hill, NC) (n ¼ 8); the University of Alberta (Edmonton, Alberta, Canada) (n ¼ 8); the British Columbia Cancer Agency (Vancouver, British Columbia, Canada) (n ¼ 6); Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy) (n ¼ 2); and the Dana-Farber Cancer Institute (Boston, MA) (n ¼ 2). All patients had squamous cell carcinoma, although the histologic subtype was not available for most patients. The mean age of these patients was 60.3 years; 16 (61.5%) had clinical stage IV disease; and 5 patients overall had M1 disease (19.2%). Soft tissue and visceral disease were present in 26.9% and 7.7% of patients, respectively. The majority of patients (92.3%) received cisplatin-based regimens. The median dose of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The radiotherapy fields were variable between patients and institutions. After chemoradiotherapy, none of the patients underwent surgical excision.
Clinical Outcomes The 1-year OS was 32.6% (95% CI, 14.2%-52.6%), and PFS was 18.7% (95% CI, 5.9%-36.9%) (Table 1; Fig. 1A, B). When excluding patients with M1 disease, the remaining patients (n ¼ 21) exhibited 1-year OS and PFS of 36.9% (95% CI, 16.0%58.1%) and 20.5% (95% CI, 6.4%-40.1%), respectively (Table 1; Fig. 2A, B). Regarding staging, 5, 4, and 16 patients had stage II,
Clinical Genitourinary Cancer Month 2014
-3
Chemoradiotherapy for Penile Cancer Figure 1 Survival Analysis. A, Overall Survival. B, ProgressionFree Survival
III, and IV disease, with 1-year OS of 40.0% (95% CI, 5.2%75.3%), 37.5% (1.1%-80.8%), and 22.4% (4.1%-49.8%), respectively; the median OS was 10 (6-16), 5 (2.5-14), and 6.9 (3-10) months, respectively. The 6-month PFS was 20.0% (0.8%-58.2%), 0%, and 39.0% (15.1%-62.5%), respectively; the median PFS was 6 (2-7), 2.25 (1-not reached), and 5.1 (2-8) months, respectively. Only 2 patients attained durable PFS and OS > 2 years.
Univariable Analyses
4
-
On univariable analyses, baseline neutrophil to lymphocyte ratio (NLR) was the only variable that attained statistical significance as a prognostic factor for OS (hazard ratio [HR] ¼ 2.84; 95% CI, 1.157.02; P ¼ .023) (Table 2). NLR also showed a trend for association with PFS (HR ¼ 1.89 [0.84-4.21]; P ¼ .12). A trend for an unfavorable effect of visceral disease on both OS (HR ¼ 3.35 [0.6916.21]; P ¼ .13) and PFS (HR ¼ 3.40 [0.70-16.52]; P ¼ .13) was observed (Table 3). Notably, the dose of radiation was associated with a 20%-30% decreased hazard of both OS and PFS for every 10-Gy increase in dose; however, neither attained statistical significance.
Clinical Genitourinary Cancer Month 2014
Figure 2 Survival Analysis for Patients With M0 Disease. A, Overall Survival for Patients With M0 Disease. B, Progression-Free Survival for Patients With M0 Disease
Discussion Guidelines, such as from the NCCN (National Comprehensive Cancer Network), and case reports have advocated or reported chemoradiotherapy as a viable approach for locally advanced PSCC despite the lack of published data on the use of this treatment modality.18-22 The present study is the first to report outcomes in a cohort of patients receiving concurrent chemotherapy and radiotherapy for locally advanced or advanced PSCC. For this study, 26 patients from 5 institutions had data available, despite a review of databases from 13 centers, which together contributed 140 patients toward the authors’ previously reported study of chemotherapy alone as first-line therapy for locally advanced or advanced PSCC.23 These data suggest that concurrent chemoradiotherapy is seldom being considered for unresectable locoregionally advanced disease. This study’s population can be characterized as having considerably advanced and bulky disease, with stage IV disease in 61.5%, M1 disease in 19.2%, and visceral metastases in 7.7% of patients, implying that therapy was administered with palliative intention in
Gregory R. Pond et al Table 2 Univariable Analyses for Overall Survival All Data Definition
n
Hazard Ratio (95% CI)
P
/Decade /unit /unit /unit /log(unit) /unit 4 versus
