Annals of Oncology Advance Access originally published online on April 15, 2008
Annals of Oncology 2008 19(7):1304-1307; doi:10.1093/annonc/mdn149
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urogenital tumors |
A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992)
1 Department of Medicine, Institut Gustave Roussy, Villejuif, France
2 Department of Urology, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
3 Department of Medicine, National Institute of Oncology, Budapest, Hungary
4 Department of Oncology, St James’s University Hospital, Leeds, UK
5 Department of Oncology, Netherlands Cancer Institute/Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands
6 Statistic Department, European Organization for Research and Treatment of Cancer, Brussels, Belgium
7 Department of Oncology, St Bartholomews, London, UK
* Correspondence to: Dr C. Theodore, Department of Medicine, Institut Gustave Roussy—Medecinerue camille desmoulins none, Villejuif 4800, France. Tel: +33-142114898; Fax: +33-142115238; E-mail: c.theodore{at}hopital-foch.org
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Abstract |
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Background: The aim of this study is to determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer.
Patients and methods: Patients with T3, T4, N1, N2, N3 or M1 cisplatin advanced penile cancer were treated with a combination of irinotecan (60 mg/m2) on days 1, 8 and 15 and cisplatin (80mg/m2) administered every 28 days. Patients were treated either in the neo-adjuvant setting for T3 or N1–N2 disease with a maximum of four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. The study was designed with the aim to exclude a response rate (complete response + partial response) <30% (
= 10%, power = 95%).
Results: Twenty-eight patients were included and evaluated for toxicity, and 26 eligible patients were evaluated for response. Toxicity was acceptable with three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever. There were eight responses (two complete response and six partial response) (30.8%, 80% confidence interval 18.8% to 45.1%): three patients undergoing histological verification after chemotherapy had no evidence of malignancy.
Conclusion: The study fails to demonstrate a response rate significantly >30%.The observation regarding M0 patients suggests to repeat this study in the neo-adjuvant setting.
Key words: advanced penile cancer, chemotherapy, cisplatin, irinotecan
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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The last decade has witnessed considerable progress with less morbidity caused by surgical treatment of penile carcinoma and the development of plastic surgery techniques for gland reconstruction [1] and sentinel node sampling [2]. In contrast, despite advances in other tumour types, with the development of novel more active and less toxic chemotherapy which are ideally suited to older patients such as those who develop penis cancer, there has been limited improvement of chemotherapy for penile cancer since the reports on the 5-fluorouracil (5-FU)–cisplatin [3] or methotrexate–bleomycin–cisplatin combinations [4]. The reported response rates were in the range of 25%–32.5% for both combinations, with limiting toxic effects for the latter. The most interesting advantage, however, is the high durable complete remission rate at 5 years obtained in patients with locally advanced nodal and soft tissue disease treated with neo-adjuvant chemotherapy and surgical removal of residual disease since it renders patients eligible for reconstruction with low morbidity [5–7].
Prompted by reports of irinotecan being well tolerated in combination with csplatin [8] and synergizing with another platinum analogue in a variety of solid tumours [9], the EORTC Genito-Urinary Tract Cancer Group set out to undertake a phase II study of this combination in penile cancer patients with locally advanced disease or recurrence after treatment of local disease.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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This open, nonrandomised, prospective phase II study involved six centres belonging to the EORTC Genito-Urinary Tract Cancer Group.
eligibility
Eligible patients had histologically confirmed squamous cell penile carcinoma, either locally advanced or metastatic corresponding to UICC-TNM 1997 categories T3, T4, N1, N2, N3 or M1 [10] and at least one measurable lesion 
20 mm on computed tomography (CT) scan. For patients with T3 and/or N1 and/or N2 disease, neo-adjuvant chemotherapy was planned before radical surgery. Eligible patients were also 
75 years old with a World Health Organisation performance status of zero, one or two were chemotherapy naive, had received no radiotherapy during the last 4 weeks, had no other malignancy (except basal squamous cell skin cancer), no symptomatic brain or leptomeningeal metastases, no chronic diarrhoea or unresolved bowel obstruction or chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis and no other serious medical condition. Laboratory eligibility criteria included: absolute neutrophil count (ANC) 2 x 109/l, platelet count 100 x 109/l, total bilirubin 1.5 upper limit of normal (ULN) serum alanine aminotransferase, aspartate aminotransferase 2.5 ULN in the absence of liver metastases or 5 if there were liver metastases and adequate renal function with a glomerular filtration rate (GFR) 60 ml/mn. The GFR was to be either directly measured or calculated according to the Cockcroft and Gault formula.
A clinical history and physical examination with CT scan imaging of the abdomen, pelvis and thorax and blood tests were carried out within 14 days before inclusion. All patients gave their written informed consent, and the study was approved by an Ethics Committee in accordance with national standards of Good Clinical Practice.
treatment
Patients received irinotecan on days 1, 8 and 15 of every 28-day cycle at a dose of 60 mg/m2 over 30 min in an i.v. infusion and cisplatin at a dose of 80 mg/m2 on day 1, after irinotecan, as a 1–3 h infusion administered in keeping with guidelines at each investigator site, to insure that adequate hydration was given. Patients were treated either in the neo-adjuvant setting for T3 or N1–N2 disease with a maximum of four cycles before surgery or up to 8 cycles for T4 or N3 or M+ distant metastatic disease.
supportive care
Antiemetic medication was that prescribed locally in routine practice. Systematic premedication with atropine as of the first cycle of treatment was at the investigator's discretion but was not recommended.
dosage modifications
Treatment was administered on day 1 if the white blood cell count was 3 x 109/l and the platelet count was 100 x 109/l. The full dose of irinotecan was given on day 8 or 15 to patients with an ANC 1 x 109/l and a platelet count 50 x 109/l and withheld otherwise. If a patient required 2 weeks for haematological recovery, or if grade 4 thrombocytopaenia (PLT <10 x 109/l) or grade 4 neutropenia (ANC <0.5 x 109/l) or grades 3–4 febrile neutropenia (ANC <1.0 x 109/l with fever >38.1) had occurred at the nadir, treatment was continued with 60 mg/m2 of cisplatin and irinotecan was administered only twice per cycle (skipping day 8), provided the ANC was >1.5 x 109/l and platelets were >75 x 109/l. If grade 3 diarrhoea occurred, irinotecan was withheld until recovery and if grade 4 diarrhoea occurred, irinotecan was discontinued. In the event of cholinergic syndrome, reported to occur with irinotecan, atropine (0.25 mg s.c.) was administered at a single dose. Treatment delays (of up to 2 weeks) were allowed.
safety and responses
The primary end point of the trial was the objective response to treatment, as defined by ‘response evaluation criteria in solid tumors’ criteria [11].
Toxicity was graded according to the Common Toxicity Criteria version 3.0 [12].
The tumour was re-evaluated every two cycles during treatment as well as at the end of chemotherapy and at least 4 weeks after the first observation of a complete or partial response. After discontinuation of protocol treatment, patients who had not progressed or had not undergone local treatment were re-evaluated every 8 weeks, unless they had started a new anticancer therapy.
study design
The statistical design aimed at excluding a response rate 30% with a power of 90% and a one-sided type I error rate of 10% using a two-stage Simon Optimum design [13]. Under those hypotheses, the total sample size required 28 eligible patients receiving at least one dose of treatment. The trial could have been discontinued if four or less objective responses were observed in the first 13 treated eligible patients. The secondary end points of the trial were the duration of response and tolerance of the drug combination.
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results |
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patient characteristics
Twenty-eight patients were included between May 2004 and January 2006 among whom seven in the neo-adjuvant setting. Two patients were ineligible, (one patient was >75 and another supposedly had metastatic mediastinal lymph nodes which were later histologically proven to be related to previously undiagnosed sarcoidosis instead of cancer).
The 28 treated patients were assessable for treatment administration and toxicity and 26 eligible patients were assessable for response. Baseline patient characteristics are summarised in Table 1.
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treatment administration
Treatment administration and modifications are summarised in Table 2. Altogether, treatment was administered as planned with a median number of four cycles and a median relative dose intensity of 89.1% for irinotecan and 101.1% for cisplatin.
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adverse events
Toxicity, summarised in Table 3, was acceptable with only three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever, all recovering rapidly. One patient with advanced disease stopped treatment after one cycle because of toxicity (pneumonia with grade 4 neutropenia).
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response rates
The evaluation of response of the 26 eligible patients is summarised in Table 4. Two complete and six partial responses were obtained. Two responses were observed among the seven patients treated in the neo-adjuvant setting versus six among the 19 assessable patients with advanced disease. However, three patients treated in the neo-adjuvant setting underwent a lymphadenectomy after chemotherapy and no evidence of malignancy was found at the pathological examination. The overall response rate was 30.8% (confidence interval 80% 18.8% to 45.1%) which does not statistically exclude that the true response rate may be >30% but the lower bound of the two-sided 80% confidence interval being 18.8% indicated that the study was negative.
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discussion |
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Penile cancer is a relatively rare cancer worldwide, but less rare in Eastern Europe, parts of Africa, the West Indies and South America [14]. The epidemiology of penile cancer is known to be related to human papillomavirus (HPV) infection, previous long-lasting premalignant lesions, smoking habits and hygiene [15]. It is the first cancer for which a public health initiative, circumcision, has substantially reduced the risk, though not totally eliminated its occurrence [16]. Even when penile cancer occurs in countries where health care is readily available, it is most often diagnosed at an early stage where limited local treatments like conservative surgery, laser therapy or brachytherapy may be curative with function preservation [17–19]. It is against this background that the results of this study should be assessed. Indeed, the first reports of chemotherapy in advanced penile cancer are recent compared with those published in almost any other malignant disease. Furthermore, they were initially retrospective and concerned only a few patients [20–22]. The only possible conclusion then was that chemotherapy was potentially active in advanced penile cancer [7].
However, as soon as chemotherapy was used in advanced penile cancer, the adjuvant/neo-adjuvant strategy was explored since it appeared unlikely that chemotherapy alone could cure advanced disease [7].
Two trials reported on the bleomycin–methotrexate–cisplatin combination. The first included 14 patients with squamous cell carcinoma of the genital tract, 12 of whom had a penile primary. Among the 14 patients, 11 were treated i.v. and the other three intra-arterially. A 72% overall response rate was reported [24].
The second more recent study using the same combination with updated evaluation criteria reported a 32.5% response rate in 40 assessable patients with five treatment-related deaths [4]. It was concluded that toxicity was prodigious and that future research should focus on decreasing toxicity [4].
The 5-FU–cisplatin combination was investigated in only a very small series of patients [3, 22]. In the most recent study, two of eight patients achieved a partial response (RR 25), both of whom required secondary local treatments to obtain a complete response [3].
Although better tolerated than the bleomycin–methotrexate–cisplatin combination, clearly, the irinotecan–cisplatin combination is no more active than its predecessors.
Although the study was underpowered for a subgroup analysis, the most interesting observation with a potential for future studies is the fact that three patients treated in the neo-adjuvant setting had a pathologically disease-free lymphadenectomy [3]. There is an increasing number of mainly small reports of similar results with combined modality treatment [5–7]. This suggests that further trials in patients with earlier disease, combining an organ-preserving approach, short chemotherapy courses and possibly HPV vaccination, may be a way to maximise benefits from all these components which, separately, show promise 25]. International collaboration will, however, be required to recruit sufficiently large patient cohorts in the neo-adjuvant setting with histological confirmation of response in all patients.
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funding |
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National Cancer Institute, Bethesda, MD (5U10 CA11488-34 through 5U10 CA11488-37).
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Irinotecan (CPT 11) was supplied by SANOFI AVENTIS Pharmaceuticals, 12 Quai de la Rapée, 75012 Paris, France at the beginning of the study and by PFIZER Pharmaceuticals, 235 East 42nd Street, NY 10017, NY, at the end of the trial. The authors thank Ms Lorna Saint Ange for editing.
Received for publication February 24, 2008. Accepted for publication March 5, 2008.
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References |
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1. Smith Y, Hadway P, Biedrzycki O, et al. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol (2007) 52:1179–1185.[CrossRef][Web of Science][Medline]
2. Leijte JA, Kroon BK, Valdés Imos RA, et al. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol (2007) 52:170–177.[CrossRef][Web of Science][Medline]
3. Shammas FV, Ous S, Fössa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol (1992) 147:630–632.[Web of Science][Medline]
4. Haas GP, Blumenstein BA, Gagliano R, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol (1999) 161:1823–1825.[CrossRef][Web of Science][Medline]
5. Bermejo C, Busby JE, Spiess PE, et al. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol (2007) 177:1335–1338.[CrossRef][Web of Science][Medline]
6. Leijte JA, Kerst JM, Bais E, et al. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol (2007) 52:488–494.[CrossRef][Web of Science][Medline]
7. Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol (1988) 27(66):823–824.
8. De Jonge MJ, Sparreboom A, Planting AS, et al. Phase I study of the 3 week schedule of irinotecan combined with cisplatin in patients with advanced solid tumors. J Clin Oncol (2000) 18:187–194.
9. Boku N, Ohtsu A, Shimada Y, et al. Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol (1999) 17:319–323.
10. Hermaneck P, Sobi H, eds. Union Internationale contre le Cancer: TNM Classification of Malignant Tumours (1997) 5th edition. Berlin: Springer. 130–132.
11. Therasse P, et al. New guidelines to evaluate the response to treatment in solid tumors. J. Natl. Cancer Inst (2000) 92:205–216.
12. CTC version 3 : http://ctep.info.nih.gov/reporting/ctc_v30.html.
13. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials (1989) 10:1–10.[Web of Science][Medline]
14. Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol (2004) 5:240–247.[CrossRef][Web of Science][Medline]
15. Goodman MT, Hernandez BY, Schvtsov YB. Demographic and pathologic differences in the incidence of invasive penile cancer in the United States, 1995–2003. Cancer Epidemiol Biomarkers Prev (2007) 16:1833–1839.
16. Schoen EJ. Neonatal circumcision and penile cancer. Evidence that circumcision is protective is overwhelming. BMJ (1996) 313(7048):46.[Web of Science][Medline]
17. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int (2005) 96:911–912.[CrossRef][Web of Science][Medline]
18. Tamari M, Tumar M, Shukla HS, et al. YAG laser treatment of early stage carcinoma of the penis preserves form and function of penis. Asian J Surg (2007) 30:126–130.[Web of Science][Medline]
19. Crook JM, Grimard L, Tsihlias J, et al. Penile brachytherapy: results for 49 patients. Int J Radiat Oncol Biol Phys (2005) 62:460–467.[Web of Science][Medline]
20. Sklaroff RB, Yagoda A. Methotrexate in the treatment of penile carcinoma. Cancer (1980) 45:214–216.[Medline]
21. Ahmed T, Sklaroff RB, Yagoda A. Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer. J Urol (1984) 132:465–468.[Web of Science][Medline]
22. Hussein A, Benedetto P, Sridhar KS. Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer (1990) 65:433–438.[Medline]
23. Eisenberger MA. Chemotherapy for carcinomas of the penis and urethra. Urol Clin North Am (1992) 19:333–338.[Web of Science][Medline]
24. Dexeus FH, Logothetis CJ, Sella A, et al. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol (1991) 146:1284–1287.[Web of Science][Medline]
25. Brinkman JA, Hughes SH, Stone P, et al. Therapeutic vaccination for HPV induced cervical cancers. Dis Markers (2007) 23:337–352.[Web of Science][Medline]
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