Japanese Journal of Clinical Oncology 33:592-594 (2003)
© 2003 Foundation for Promotion of Cancer Research
Non-invasive Management of Invasive Bladder Cancer: Lectures by Professor William U. Shipley
Division of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT THE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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This report summarizes lectures by Professor William U. Shipley on the non-invasive management of invasive bladder cancer with chemoradiotherapy and transurethral resection, presented at the 60th Meeting of the International Lectureship, in the international lectureship program of the FPCR.
The 60th Meeting of the International Lectureship was held at the International Conference Hall on March 25, 2003, inviting Professor William U. Shipley, Harvard University and Massachusetts General Hospital, under the auspices of the Foundation for the Promotion for Cancer Research. Professor William U. Shipley, one of the outstanding radiation oncologists in the world, especially in the uro-radiation oncology field, visited Japan from March 22 to 31, 2003, as a lecturer in the lectureship program of the Foundation for Promotion of Cancer Research (Fig. 1).
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William Shipley graduated from Harvard Medical School, Boston, in 1966. He spent his surgical internship at Massachusetts General Hospital (MGH). He took the residency plan of the Joint Center for Radiation Therapy, MGH, in 1971 and became Assistant Professor of Radiation Therapy in 1974. Since 1985 he has also been appointed to several administrative posts and has been Professor of Radiation Oncology since 1991. Currently he is Deputy Head for Cancer Research, Department of Radiation Oncology, MGH.
Professor Shipley’s main academic concern has been towards uro-radiation oncology, with many academic and clinical achievements in radiation therapy for bladder and other urinary tract cancers. He has conducted intraoperative radiotherapy for pancreatic cancer and also bladder cancer in the USA. He was the first to introduce the application of protons to prostate cancer, using protons at the Harvard Cyclotron Laboratory. He also conducted chemoradiation therapy for bladder cancer mainly using cisplatin and full-dose radiotherapy. He has organized several Radiation Therapy Oncology Group studies as Chairman of the Genitourinary Site Committee since 1987.
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THE MANAGEMENT OF INVASIVE BLADDER CANCER |
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TOPABSTRACTTHE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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The lecture was entitled ‘Surgery plus chemoradiotherapy for invasive bladder cancer’. There is concern about sparing the bladder when treating muscle-invading tumors of the bladder in uro-oncology. Superficial recurrence is common and can be managed by transurethral resection (TUR) as with relapses. Overall survival does not change irrespective of the existence or absence of the superficial recurrence. Professor Shipley’s visit was an important opportunity for us to consider organ preservation studies for bladder cancer specifically and also for other organs for the management of cancer in general.
Bladder cancer can be divided into three major categories of presentation, superficial, invasive (of the bladder wall) and metastatic, which must be taken into account when determining prognosis and primary treatment. With a superficial tumor, the goal is to prevent superficial relapses and progression to an incurable stage. For a metastatic tumor, the main clinical issue is how to choose the most effective palliation. For muscle-invading bladder cancer, superficial relapse is common after chemoradiation therapy, but can be controlled by transurethral resection.
For the management of invasive bladder cancer, radical cystectomy is viewed as the gold standard and is the only treatment recommended, with a few exceptions, in the USA. An early approach at bladder preservation was via aggressive transurethral resection alone done selectively only for patients with small tumors, which represented less than 20% of all muscle-invasive tumors. All patients with muscle-invasive tumors were referred for external beam radiotherapy. However, local failure rates with conventional radiotherapy alone were disappointingly high and this approach as monotherapy has largely been abandoned. Professor Shipley’s major motif of clinical study is that a potential bladder-sparing approach should be taken for muscle-invading tumors and is based on his experience and results that a combination regimen of radiation therapy and platinum-containing chemotherapy yielded far better local control results than expected. Also, the trend in the 1990s has changed towards organ preservation using combined chemotherapy and radiation, with or without conservative local surgery, in many other areas of cancer treatment, e.g. for patients with cancer of the breast, esophagus, anus and larynx and the limb sarcomas.
The trimodality therapy with selective bladder preservation is not designed to replace radical cystectomy, but it can be offered as a reasonable alternative to patients with invasive bladder cancer who are not willing to undergo radical cystectomy and urinary diversion. A bladder-sparing strategy can be offered appropriately to highly selected patients with the understanding that radical cystectomy is an available option in those who fail combined radiation and chemotherapy with no diminution in survival related to the delay in cystectomy.
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RESULTS OF TRIMODALITY THERAPY FOR MUSCLE-INVASIVE BLADDER CANCER AT MGH |
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TOPABSTRACTTHE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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Substantial improvements in local control have more recently been achieved with combined modality therapy: TURBT followed by radiotherapy with concurrent tumor-sensitizing chemotherapy. The combination of TURBT with MVAC, but without RT, was reported earlier at the Memorial Sloan-Kettering Cancer Center (MSKCC), which resulted in lower rates of bladder preservation. Professor Shipley added external radiotherapy to platinum-based chemotherapy, with far better local control results.
Professor Shipley recently reported long-term follow-up data for 190 patients on conservative treatment of muscle-invasive bladder cancer at MGH from 1986 to 1997 (1). All patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor; candidates managed by TUR and concurrent chemoradiation were included in the analysis. The median follow-up was 6.7 years for all surviving patients. Of these, 121 patients with a complete response by cytological and histological examination and those medically unfit for cystectomy received boost chemoradiation up to 64–65 Gy; 60% of patients who had a CR after induction therapy developed no further bladder tumors, 24% subsequently developed only a superficial recurrence and 16% developed an invasive tumor. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors.
The results showed that the 5- and 10-year actuarial overall survival rates were 54 and 36%, respectively (stage T2, 62 and 41%; stage T3–T4a, 47 and 31%, respectively). The overall 5- and 10-year disease-specific survival rates were 63 and 59%, respectively, and the 5- and 10-year disease-specific survival rates for patients with an intact bladder were 46 and 45%, respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity.
The University of Southern California (USC) recently reported on 633 patients undergoing contemporary radical cystectomy with pathological stage T2–T4a, with an actuarial overall survival rate at 5 years of 48% and at 10 years of 32% (2). The reports on cystectomy at MSKCC were also similar to those at USC. The similarity of the results of radical cystectomy cases and those of bladder preservative chemoradiation with TUR was due to the prompt use of salvage cystectomy when necessary. In conclusion, the 10-year overall survival and disease-specific survival rates are comparable to the results reported for contemporary radical cystectomy for patients of similar clinical and pathological stages. One-third of patients treated on protocol with the goal of bladder sparing required cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders.
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RESULTS OF RTOG STUDIES (1985–2001) |
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TOPABSTRACTTHE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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Professor Shipley promoted clinical studies for patients with muscle-invasive bladder cancer who were cystectomy candidates in the Radiation Therapy Oncology Group (RTOG) and other international inter-groups. The RTOG has conducted many multi-institutional clinical trials concerning radiation therapy since 1976. Since 1985, RTOG has conducted six clinical studies with T2–T4a muscle-invasive bladder cancer patients who were cystectomy candidates. Bladder preservation with intravesical surgery, chemotherapy and radiation therapy are combined as initial treatment via trimodality therapy and radical cystectomy was recommended for incomplete responders. Five of the RTOG protocols were phase I/II trials of current chemotherapy and radiation and one protocol was a phase III trial testing the efficacy of adjuvant MCV chemotherapy. A total of 415 patients were entered in these six trials. The 5-year overall survival is ~50% and three-quarters of those patients were cured of their cancer while maintaining a functioning bladder. The current RTOG protocol and its successor are directed towards better tolerated and potentially more effective chemotherapy regimens that will result in a high protocol compliance rate and possibly a higher overall survival rate (3).
Within the RTOG, the protocols have been restricted to patients with muscle-invading bladder tumors. The issues are identifying patients who are in need of a radical cystectomy for cure, those who can be successfully cured without radical surgery and those who are at such a high risk for occult metastases that systemic chemotherapy is required to improve the chance of cure.
The first study (RTOG 85-12) accrued 42 patients and yielded very encouraging results of a complete response rate of 66% and 4-year overall survival of 64% for stage T2 and 24% for T3–T4 patients (4). The subsequent study, RTOG 88-02, was based on an MGH pilot study that indicated that the addition of MCV chemotherapy for two cycles prior to this regimen was well tolerated and yielded a 75% response rate and a 51% 5-year survival rate. RTOG 88-02 was followed promptly by RTOG 89-03, which was a phase III trial to assess the efficacy of neoadjuvant MCV chemotherapy (5). This study was stopped short of its projected accrual of 174 patients owing to poor patient tolerance of the MCV regimen. Toxicity was mostly severe leucopenia and sepsis, which resulted in three treatment-related deaths. With a median follow-up of 60 months, the actuarial 5-year overall survival rate for the 123 entered patients was 49% with no difference with regard to treatment arm. A total of 35% of the patients had evidence of distant metastasis in 5 years; 33% of those were in the MCV arm and 40% in the non-MCV arm. None of these differences were significant. Two cycles of MCV neoadjuvant chemotherapy were shown not to be beneficial with regard to overall survival, freedom from metastatic disease and in the complete response rate achieved by induction therapy. Beginning in 1995, the RTOG evaluated via phase I/II protocols accelerated radiation hypofractionation schemes in combination with concurrent outpatient 5-fluorouracil (5-FU)–cisplatin chemotherapy in RTOG 95-06.
The RTOG Genitourinary (GU) translational research group is now evaluating by immunohistochemical staining the significance of the overexpression of p53, p21, pRB, p16, Erb-1(epidermal growth factor receptor) and Erb-2 (HER-2) proteins. To date, tumors from 73 patients completing treatment on RTOG 88-02, 89-03, 95-06 and 97-06 have been studied and multivariate analysis for correlation with complete response, overall survival, disease-specific survival and disease-specific survival with an intact bladder are under way. The findings do not as yet confirm that abnormal expressions of any of these proteins predict tumor response to chemoradiation.
Professor Shipley presented two lectures and held other scientific discussions with many doctors during his stay in Japan. The first informal lecture was given on March 24, entitled ‘An update of radiation therapy in the curative treatment of patients with localized prostate cancer in the PSA era’ at the Meeting Hall of NCCH and the last, formal one was on March 26, entitled ‘Our results for combined conservative surgery plus concurrent radiation and chemotherapy for invasive bladder cancer with organ preservation’ at the Lecture Hall of Kyoto University Hospital, Kyoto. The audiences at the two locations, including medical doctors in cancer clinics and basic researchers, especially radiation oncologists and urologists, were very interested and motivated by the lectures.
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Acknowledgments |
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TOPABSTRACTTHE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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The Second Term Comprehensive 10-Year Strategy for Cancer Control is conducted and supported by the Ministry of Health, Labor and Welfare of Japan. The lectureship program of the Foundation for Promotion of Cancer Research, one of the projects of ‘the 10-Year Strategy for Cancer Control’, has been subsidized by the Japan Motorcycle Racing Organization through its promotion funds from Autorace. We greatly appreciate Professor Shipley’s visit with Mrs Shipley and his distinguished lectures in Japan in spite of his busy schedule. We thank Mr Masataka Kohda, President, and Dr Michiya Ohtaka, Executive Director of the Foundation for Promotion of Cancer Research for their support of the lectureship program. We are also grateful to Dr Tadao Kakizoe, President, National Cancer Center and Dr Takashi Sugimura, President Emeritus, National Cancer Center, for their valuable advice.
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FOOTNOTES |
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+ For reprints and all correspondence: Hiroshi Ikeda, Division of Radiation Oncology, National Cancer Center Hospital, 5–1–1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: hikeda{at}ncc.go.jp
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REFERENCES |
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TOPABSTRACTTHE MANAGEMENT OF INVASIVE...RESULTS OF TRIMODALITY THERAPY...RESULTS OF RTOG STUDIES...AcknowledgmentsREFERENCES |
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1 Shipley WU, Kaufman DS, Zehr E, Heney NM, Lane SC, Thakral HK, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62–8.[ISI][Medline]
2 Stein JP, Liescovsky G, Cote R, Groshen S, Feng A, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol 2001;19:666–75.
3 Shipley WU, Kaufman DS, Tester WJ, Pilepich MV, Sandler HM. Overview of bladder cancer trials in the Radiation Therapy Oncology Group. Cancer 2003;97:2115–9.[CrossRef][ISI][Medline]
4 Shipley WU, Prout GR Jr, Einstein AB Jr, Coombs LJ, Wajsman Z, Soloway MS, et al. Treatment of invasive bladder cancer by cisplatin and irradiation in patients unsuited for surgery: a high success rate in clinical stage T2 tumors in a National Bladder Cancer Group trial. JAMA 1987;258:931–5.[Abstract]
5 Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WJ, et al. A phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of RTOG 89-03. J Clin Oncol 1998;16:3576–83.[Abstract]
Received August 19, 2003; accepted October 6, 2003
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