Pieter H.M. de Mulder

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVESnThe first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands.nnnMETHODSnMedical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update.nnnRESULTSnThe first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma.nnnCONCLUSIONSnWhereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Ondansetron Compared with High-Dose Metoclopramide in Prophylaxis of Acute and Delayed Cisplatin-Induced Nausea and Vomiting: A Multicenter, Randomized, Double-Blind, Crossover Study

OBJECTIVEnTo compare the efficacy and side effects of ondansetron with those of high-dose metoclopramide in treating acute and delayed cisplatin-induced nausea and vomiting.nnnDESIGNnRandomized, double-blind, crossover trial.nnnSETTINGnConducted at two university hospitals, a cancer institute, and six community hospitals.nnnPATIENTSnOf 125 patients, 95 were evaluable for the acute phase and 79 for the delayed phase. Major reasons for not being evaluable were no second course (14 patients), protocol violation (5 patients), and change in cisplatin dose (3 patients) for the acute phase, and rescue medication on day 1 (7 patients), protocol violation (3 patients), and inadequate data (4 patients) for the delayed phase.nnnINTERVENTIONSnAll patients received cisplatin, 50 to 100 mg/m2 body surface area (median, 75 mg/m2); none had previously received chemotherapy. Thirty minutes before the cisplatin administration, ondansetron was given intravenously over 15 minutes, at a loading dose of 8 mg followed by a continuous infusion of 1 mg/h for 24 hours. Metoclopramide was given at a loading dose of 3 mg/kg body weight, followed by a continuous infusion for 8 hours (4 mg/kg). For the delayed phase (days 2 through 6), the first oral dose was given as soon as the infusion was completed; the oral dose consisted of either metoclopramide, 20 mg three times daily, or ondansetron, 8 mg three times daily for another 5 days.nnnMEASUREMENTS AND MAIN RESULTSnIn the acute phase, a major or complete response was seen in 72% of the ondansetron-treated and 41% of the metoclopramide-treated patients (P less than 0.001). Nausea was significantly better controlled among the ondansetron-treated patients (P = 0.04). In the delayed phase, no statistically significant difference was seen between ondansetron- and metoclopramide-treated patients. Nausea was significantly better controlled with metoclopramide (P = 0.016).nnnCONCLUSIONSnOndansetron is significantly more effective than metoclopramide in preventing acute nausea and vomiting. In the delayed phase, the results of both drugs were disappointing, although metoclopramides effect on delayed nausea was superior. Patients preferred ondansetron.

Immunotherapy for renal cell carcinoma.

Renal cell carcinoma (RCC) is the most prevalent malignancy within the kidney and the incidence is rising. Due to improved radiological evaluation over 50% of the renal cancers are found incidentally. Despite the fact that these incidentalomas are often confined to the kidney, around 50% of all patients diagnosed with kidney cancer will develop systemic disease. Metastatic RCC has a poor prognosis. Traditional treatment modalities like chemo- and radiotherapy show overall response percentages of 2-6%. In view of the observed spontaneous remissions of advanced renal cancer, immune mechanisms have been suggested to play a role in the natural disease course of RCC. At present, several non-specific cytokine regimens are used in the treatment of mRCC, e.g. interleukin-2 and interferon-alpha, in combination or as monotherapy or in combination with substances like 13-cis-retinoic acid and/or 5-fluorouracil. Collective data of trials evaluating cytokine-based therapies for mRCC show an overall response rate of approximately 15%, with 5% of the patients showing complete responses. More importantly, cytokine treatment clearly translates into a significant survival benefit in a subset of patients. Nevertheless, the toxicity profile of these cytokine regimens is significant. With the enhanced knowledge of tumor-immunology, the identification of immunogenic tumor proteins, and antibodies recognizing tumor-associated antigens, new treatment strategies with increased specificity and fewer side effects are of interest. Here we review the different immunotherapeutical modalities currently used as well as new approaches for the treatment of advanced RCC.

Quality of Life in Good Prognosis Patients With Metastatic Germ Cell Cancer: A Prospective Study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20)

PURPOSEnTo describe global quality of life (GLQL) in patients with metastatic testicular cancer (TC) treated with four different schedules of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (four v three cycles given over 5 v 3 days).nnnPATIENTS AND METHODSnQuality-of-life data were prospectively collected in 666 patients with metastatic TC entered into the European Organization for Research and Treatment of Cancer (EORTC) Trial 30941/United Kingdom Medical Research Council Trial TE20, using the EORTC Quality-of-Life Questionnaire C30 and a TC module. Data were analyzed by a mixed effects model and by evaluation of clinically relevant changes at 2 years.nnnRESULTSnThe pattern of GLQL changes was similar in the four groups. Two years after chemotherapy, 36% of patients displayed improved GLQL as compared with baseline, whereas GLQL had deteriorated in 13%. At 3 months, patients receiving the 3-day regimen experienced increased gastrointestinal (GI) toxicity more than those receiving the 5-day regimen, with the difference reaching the level of clinical relevance (>or = 10-point change) if four cycles were given. The 3-day schedule increased the 2-year risk of tinnitus, with clinical relevance demonstrated after four cycles. Long-term peripheral neuropathy and Raynaud-like phenomena were not associated with the number of cycles or days per cycle. At 2 years, Raynaud-like phenomena, tinnitus, or reduced hearing were reported by 21% to 26% of the patients.nnnCONCLUSIONnBecause of the excess of acute GI toxicity and the increased risk of tinnitus after the 3-day regimen, we recommend the 5-day regimen if four cycles of BEP are planned. If only three cycles are to be given, then the 3-day regimen is acceptable, even given the increased risk of nausea/vomiting at 3 months.

Randomized Phase II/III Trial of Interferon Alfa-2a With and Without 13-cis-Retinoic Acid in Patients With Progressive Metastatic Renal Cell Carcinoma: The European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951)

PURPOSEnA randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma.nnnPATIENTS AND METHODSnThree hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-alpha-2a.nnnRESULTSnMedian time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-alpha-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-alpha-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-alpha-2a and 13-CRA, and 13.2 months for patients treated with IFN-alpha-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-alpha-2a.nnnCONCLUSIONnProgression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-alpha-2a plus 13-CRA were significantly longer compared with patients on IFN-alpha-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.

Lack of Efficacy of Two Consecutive Treatments of Radioimmunotherapy With 131I-cG250 in Patients With Metastasized Clear Cell Renal Cell Carcinoma

PURPOSEnA previous activity dose-escalation study using 131I-labeled chimeric monoclonal antibody cG250 in patients with progressive metastatic renal cell carcinoma (RCC) resulted in occasional therapeutic responses. The present study was designed to determine the safety and therapeutic efficacy of two sequential high-dose treatments with 131I-cG250.nnnPATIENTS AND METHODSnPatients (n = 29) with progressive metastatic RCC received a low dose of (131)I-cG250 for assessment of preferential targeting of metastatic lesions, followed by the first radioimmunotherapy (RIT) with 2220 MBq/m2 131I-cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low-dose 131I-cG250 (n = 20) was given 3 months later. When blood clearance was not accelerated, a second RIT of 131I-cG250 was administered at an activity-dose of 1110 MBq/m2 (n = 3) or 1665 MBq/m2 (n = 16). Patients were monitored weekly for toxicity, and tumor size was evaluated by computed tomography once every 3 months intervals.nnnRESULTSnThe maximum-tolerated dose (MTD) of the second RIT was 1,665 MBq/m2 because of dose-limiting hematological toxicity. Based on an intention-to-treat analysis, after two RIT treatments, the disease stabilized in five of 29 patients, whereas it remained progressive in 14 of 29 patients. Two patients received no RIT, and eight of 29 received only one 131I-cG250 RIT because of grade 4 hematologic toxicity, formation of human antichimeric antibodies, or disease progression.nnnCONCLUSIONnIn patients with progressive end-stage RCC, the MTD of the second treatment was 75% of the MTD of the first RIT. In the majority of patients, two cycles of 131I-cG250 could be safely administered without severe toxicity. No objective responses were observed, but occasionally two RIT doses resulted in stabilization of previously progressive disease.

Commonly Used Imaging Techniques for Diagnosis and Staging

Imaging plays a vital role in the management of patients with cancer. Not only is it important for diagnosis, indicating sites of abnormality, and guiding biopsies, but it is also crucial in assessing disease extent and thereby determining treatment. In this review, conventional imaging techniques such as ultrasound, computed tomography, magnetic resonance imaging, and [18F]fluorodeoxyglucose-positron emission tomography are described, with attention to their mechanisms of action, and their strengths and weaknesses in diagnosis and staging of tumors. New developments are addressed and radiation safety issues are highlighted. In addition, we describe current and expected future uses of imaging techniques in oncology. Given that each technique has its inherent strengths and weaknesses, the combination of the methods will result in improved diagnosis, staging, and treatment prediction and monitoring.

Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon : an unexpectedly frequent complication

Background. In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects.

Radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell cancer: dosimetric analysis and immunologic response.

Purpose: A study was designed to define the therapeutic efficacy, safety, and toxicity of two sequential high-dose treatments of radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell carcinoma. Here, we report the dosimetric analysis and the relationship between the development of a human antichimeric antibody response and altered pharmacokinetics. Experimental Design: Patients (n = 29) with progressive metastatic renal cell carcinoma received a low dose (222 MBq) of [131I]cG250 for dosimetric analysis, followed by the first radioimmunotherapy with 2,220 MBq/m2 [131I]cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low dose of [131I]cG250 (n = 20) was given 3 months later. Provided that no accelerated blood clearance was observed, a second radioimmunotherapy of [131I]cG250 was administered at an activity-dose level of 1,110 MBq/m2 (n = 3) or 1,665 MBq/m2 (n = 16). After each administration, whole-body images were obtained and the pharmacokinetics and the development of human antichimeric antibody responses were determined. Radiation-absorbed doses were calculated for whole body, red marrow, organs, and metastases. Results: No correlation was found between hematologic toxicity and radiation-absorbed dose to the whole body or bone marrow, nor administered activity (MBq and MBq/kg). The tumor-absorbed doses varied largely. An inverse relation between tumor size and radiation-absorbed dose was found. Most tumor lesions received <10 Gy, whereas only lesions <5 g absorbed >50 Gy. A relatively high number of patients developed a human antichimeric antibody response (8 of 27) with altered pharmacokinetics, hampering additional radioimmunotherapies in four of these patients. Conclusions: Dosimetric analysis did not adequately predict the degree of bone marrow toxicity. When human antichimeric antibody developed, the rapid clearance of radioactivity from the blood and body prohibited further treatment. According to the calculated absorbed dose in metastatic lesions, future radioimmunotherapy studies with radiolabeled cG250 should aim at treatment of small-volume disease or treatment in an adjuvant setting.

Interferon-α-2a with or without 13-Cis retinoic acid in patients with progressive, measurable metastatic renal cell Carcinoma: Results of a randomized phase II study (European Organization for Research and Treatment of Cancer Study 30951)

In patients with metastatic renal cell carcinoma (MRCC), interferon‐α (IFN) monotherapy leads to response rates of 5–15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13‐cis retinoic acid (CRA).