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Another good review. Abstract, treatment/survival, and conclusions posted below
Journal of Clinical Oncology, Vol 24, No 35 (December 10), 2006: pp. 5503-© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.08.1836
REVIEW ARTICLE
Late Relapses of Germ Cell Malignancies: Incidence, Management, and Prognosis
Jan Oldenburg, Jarad M. Martin, Sophie D. Fosså
From the Department of Clinical Cancer Research, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; Department of Radiation Oncology, Princess Margaret Hospital, Toronto, ON, Canada
Address reprint requests to Jan Oldenburg, MD, Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; e-mail: [email protected]
Late relapses of malignant germ cell tumors (MGCTs) are rare and occur, by definition, 2 years or later after successful treatment. They represent a major challenge of today's treatment of MGCTs. Because of the rarity and heterogeneity of late relapses, many aspects of their main characteristics remain obscure. We present relevant literature on relapsing MGCTs to highlight the following issues: incidence, impact of initial treatment on the subsequent risk of late relapse, treatment, and survival. In a pooled analysis, the incidence is 1.4% and 3.2% in seminoma and nonseminoma patients, respectively. The predominant site of relapse is the retroperitoneal space in both histologic types. The initial treatment appears to be important for the risk and localization of late relapses. The treatment of late relapses should be based on a representative presalvage biopsy and includes radical surgery and salvage chemotherapy in most cases. Five-year cancer-specific survival is above 50% in the recent large series and reaches 100% in case of single-site teratoma. Diagnosis and treatment of late-relapsing MGCT patients is challenging and should be performed in experienced centers only. Referral of late-relapsing patients to high-volume institutions ensures the best chances of cure and enables increasing understanding of tumor biology and the clinical course of these patients.
TREATMENT AND SURVIVAL
Optimal treatment for the individual patient requires careful evaluation and planning by an experienced interdisciplinary team of urologic surgeons, oncologists, and radiologists and possibly also vascular, thoracic, orthopedic and neurosurgeons. It has been shown that survival of poor-prognosis patients is increased by treatment in high-volume centers.We are convinced that this rationale also applies to late-relapsing patients.
Patients with late-relapsing MGCT should be treated according to a representative presalvage biopsy. Teratoma may be found in both initial seminoma and nonseminoma, and a cure is achieved only by a complete resection in these patients. Also, in patients with somatic differentiated teratoma, a complete resection is the treatment of choice because salvage chemotherapy has only limited effect.
Seminoma
Late-relapsing seminoma patients on surveillance are cured by radiotherapy, cisplatin-based chemotherapy, or, more rarely, surgery.
After radiation in seminoma CS I, relapses occur nearly exclusively outside the prior radiation field and are usually cured by cisplatin-based chemotherapy. However, in case of inguinal localized relapse, further radiation or pelvic lymph node dissection may be sufficient.
Relapses after single-agent carboplatin are mostly salvaged by cisplatin-based chemotherapy or by radiotherapy. Relapse after cisplatin-based chemotherapy in advanced seminoma is very rare. Approximately 50% of these patients are cured by alternative salvage chemotherapy.Salvage surgery should always be considered, although it seems to be less often applied than in nonseminoma.
Nonseminoma
Surgery is considered the most important part of treatment in late-relapsing, previously chemotherapy-treated nonseminoma patients and increases the chances of cure. Even patients with chemorefractory germ cell tumors have a definitive chance to be cured by salvage "desperation" surgery.Incomplete resection of viable residual tumor portends a poor prognosis. Sharp et al demonstrated in a recent series a 5-year disease-free survival of 79% in patients with complete resection lesions compared with 36% in patients with incomplete resection. Repeated operations, because of incomplete resection of viable tumor, are technically very challenging and should probably best be avoided by ensuring that only surgeons with especial expertise operate on relapsing patients in the first place.
Chemotherapy-naïve patients have the best chances to be cured, whereas the response to salvage chemotherapy in patients with prior chemotherapy exposure is low.
In previously chemotherapy-treated patients with relapse alternative cytotoxic-agents should preferentially be used. Ifosfamide, vinblastine, and cisplatin (VeIP) achieved a continuously disease-free status in only a minority of patients (15% to 24%). More recently, the combination of paclitaxel, ifosfamide, and cisplatin (TIP) has been demonstrated to yield durable complete responses in 63% to 73% of patients with relapse after initial chemotherapy for testicular cancer.
After four cycles of TIP and resection of residual masses, Kondagunta et al report progression-free survival rates of 50% and 78% in late- and early-relapsing patients, respectively.
Growing experience in treatment of late-relapsing MGCT patients combined with enhanced vigilance toward detection might have contributed to improving cure rates during the last decades (1995, 26%; 1997, 36%; 2002, 69%; 2003, 47%; 2005, 63%; 2006, 68%).
CONCLUSION
MGCT patients suspected to have a late relapse should be referred to an experienced hospital for diagnosis and treatment. Such policy not only provides the best chances of cure, but also enables collection of data that increase our understanding of this rare condition.
Postchemotherapy residual retroperitoneal masses should be removed completely as part of initial treatment. Follow-up of all MGCT patients should be continued for at least 10 years. Lifelong follow-up for the detection of late relapses is a controversial issue and may, in our view, be indicated in patients with previous relapse after chemotherapy, high amounts of teratoma and primary metastases, and primary EGGCT.
These conclusions are based on approximately 500 cases reported in several rather heterogeneous series over the last 20 years. A retrospective uniform analysis of these cases would be worthwhile, and prospective registration of new cases is recommended
Journal of Clinical Oncology, Vol 24, No 35 (December 10), 2006: pp. 5503-© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.08.1836
REVIEW ARTICLE
Late Relapses of Germ Cell Malignancies: Incidence, Management, and Prognosis
Jan Oldenburg, Jarad M. Martin, Sophie D. Fosså
From the Department of Clinical Cancer Research, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; Department of Radiation Oncology, Princess Margaret Hospital, Toronto, ON, Canada
Address reprint requests to Jan Oldenburg, MD, Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; e-mail: [email protected]
Late relapses of malignant germ cell tumors (MGCTs) are rare and occur, by definition, 2 years or later after successful treatment. They represent a major challenge of today's treatment of MGCTs. Because of the rarity and heterogeneity of late relapses, many aspects of their main characteristics remain obscure. We present relevant literature on relapsing MGCTs to highlight the following issues: incidence, impact of initial treatment on the subsequent risk of late relapse, treatment, and survival. In a pooled analysis, the incidence is 1.4% and 3.2% in seminoma and nonseminoma patients, respectively. The predominant site of relapse is the retroperitoneal space in both histologic types. The initial treatment appears to be important for the risk and localization of late relapses. The treatment of late relapses should be based on a representative presalvage biopsy and includes radical surgery and salvage chemotherapy in most cases. Five-year cancer-specific survival is above 50% in the recent large series and reaches 100% in case of single-site teratoma. Diagnosis and treatment of late-relapsing MGCT patients is challenging and should be performed in experienced centers only. Referral of late-relapsing patients to high-volume institutions ensures the best chances of cure and enables increasing understanding of tumor biology and the clinical course of these patients.
TREATMENT AND SURVIVAL
Optimal treatment for the individual patient requires careful evaluation and planning by an experienced interdisciplinary team of urologic surgeons, oncologists, and radiologists and possibly also vascular, thoracic, orthopedic and neurosurgeons. It has been shown that survival of poor-prognosis patients is increased by treatment in high-volume centers.We are convinced that this rationale also applies to late-relapsing patients.
Patients with late-relapsing MGCT should be treated according to a representative presalvage biopsy. Teratoma may be found in both initial seminoma and nonseminoma, and a cure is achieved only by a complete resection in these patients. Also, in patients with somatic differentiated teratoma, a complete resection is the treatment of choice because salvage chemotherapy has only limited effect.
Seminoma
Late-relapsing seminoma patients on surveillance are cured by radiotherapy, cisplatin-based chemotherapy, or, more rarely, surgery.
After radiation in seminoma CS I, relapses occur nearly exclusively outside the prior radiation field and are usually cured by cisplatin-based chemotherapy. However, in case of inguinal localized relapse, further radiation or pelvic lymph node dissection may be sufficient.
Relapses after single-agent carboplatin are mostly salvaged by cisplatin-based chemotherapy or by radiotherapy. Relapse after cisplatin-based chemotherapy in advanced seminoma is very rare. Approximately 50% of these patients are cured by alternative salvage chemotherapy.Salvage surgery should always be considered, although it seems to be less often applied than in nonseminoma.
Nonseminoma
Surgery is considered the most important part of treatment in late-relapsing, previously chemotherapy-treated nonseminoma patients and increases the chances of cure. Even patients with chemorefractory germ cell tumors have a definitive chance to be cured by salvage "desperation" surgery.Incomplete resection of viable residual tumor portends a poor prognosis. Sharp et al demonstrated in a recent series a 5-year disease-free survival of 79% in patients with complete resection lesions compared with 36% in patients with incomplete resection. Repeated operations, because of incomplete resection of viable tumor, are technically very challenging and should probably best be avoided by ensuring that only surgeons with especial expertise operate on relapsing patients in the first place.
Chemotherapy-naïve patients have the best chances to be cured, whereas the response to salvage chemotherapy in patients with prior chemotherapy exposure is low.
In previously chemotherapy-treated patients with relapse alternative cytotoxic-agents should preferentially be used. Ifosfamide, vinblastine, and cisplatin (VeIP) achieved a continuously disease-free status in only a minority of patients (15% to 24%). More recently, the combination of paclitaxel, ifosfamide, and cisplatin (TIP) has been demonstrated to yield durable complete responses in 63% to 73% of patients with relapse after initial chemotherapy for testicular cancer.
After four cycles of TIP and resection of residual masses, Kondagunta et al report progression-free survival rates of 50% and 78% in late- and early-relapsing patients, respectively.
Growing experience in treatment of late-relapsing MGCT patients combined with enhanced vigilance toward detection might have contributed to improving cure rates during the last decades (1995, 26%; 1997, 36%; 2002, 69%; 2003, 47%; 2005, 63%; 2006, 68%).
CONCLUSION
MGCT patients suspected to have a late relapse should be referred to an experienced hospital for diagnosis and treatment. Such policy not only provides the best chances of cure, but also enables collection of data that increase our understanding of this rare condition.
Postchemotherapy residual retroperitoneal masses should be removed completely as part of initial treatment. Follow-up of all MGCT patients should be continued for at least 10 years. Lifelong follow-up for the detection of late relapses is a controversial issue and may, in our view, be indicated in patients with previous relapse after chemotherapy, high amounts of teratoma and primary metastases, and primary EGGCT.
These conclusions are based on approximately 500 cases reported in several rather heterogeneous series over the last 20 years. A retrospective uniform analysis of these cases would be worthwhile, and prospective registration of new cases is recommended
