M.J. Terrier-Lacombe

Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84

The second International Society of Paediatric Oncology (SIOP) study for rhabdomyosarcoma (MMT84) had several goals. The two principal aims were: (1) to improve the survival of children with rhabdomyosarcoma; and (2) to reduce the late effects from therapy by restricting the indications for surgery and/or radiotherapy after good response to initial chemotherapy. A further aim was to investigate the role of high-dose chemotherapy in young patients with parameningeal primary tumours. 186 previously untreated eligible patients entered the study. Patients with completely resected primary tumour received three courses of IVA (ifosfamide, vincristine and actinomycin D). Patients with incompletely resected tumour received six to 10 courses of IVA according to stage. Patients achieving complete remission with chemotherapy alone did not usually receive radiotherapy or undergo extensive surgery, but patients remaining in partial remission received local therapy with surgery and/or radiotherapy. Only patients over 5 years of age with parameningeal disease and patients over 12 years with tumours at any site were given systematic irradiation. Complete remission was achieved in 91% (170/186) of all patients. With a median follow-up of 8 years, the 5-year overall survival was 68% (+/- 3% standard error of the mean (SEM) and the 5-year event-free survival 53% (+/- 4% SEM). These results show an improvement over previous SIOP study (RMS75) in which survival was 52% and event-free survival was 47%. Among the 54 patients who exhibited isolated local relapse, 35% (19/54) survived in further remission longer than 2 years after retreatment, including local therapy (surgery +/- radiotherapy). Analysis of the overall burden of therapy received by all surviving children (including primary treatment and treatment for relapse if required) showed that 24% (28/116) were treated by limited surgery followed by three courses of IVA, 29% (34/116) were treated by chemotherapy alone (after initial biopsy) and 13% (15/116) received chemotherapy plus conservative local treatment (limited surgery or radiotherapy for residual disease). Only 34% (39/116) received intensive local therapy defined as radical wide field radiotherapy or radical surgery or both. Compared with the results obtained in the previous SIOP study, treatment in MMT84 was based on response to initial chemotherapy and, despite an overall reduction of the use of local therapy, significantly improved survival for patients with non-metastatic disease. This trial, also for the first time, provides evidence that retreatment after local relapse can achieve long-term second remissions.

The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients

Growing teratoma syndrome (GTS) is defined as an increase in tumour size during or after chemotherapy for germ cell tumour (GCT), and only mature teratoma at histological analysis of the resected tumour specimen. Between 1985 and 1997, 30 male patients fulfilling GTS criteria were included in the present study. 3 female patients were also included but analysed separately. A mature teratoma component was found in 86% of the primary GCT. 3 male patients (10%) had a complication at diagnosis of GTS. One male patient (4%) having undergone complete resection (n=24) had a recurrent GTS, compared with all but 1 patient (83%) in whom resection was partial (n=6) (P<0.001). 2 (8%) and 3 (50%) male patients treated with complete and partial resection subsequently developed a malignant NSGCT respectively (P=0.01). 2 female patients treated with partial resection presented a recurrent GTS. One of them died of this recurrent GTS. GTS is an entity in its own right with respect to complications and the natural history of the disease. Complete surgical resection is the treatment of choice for GTS.

Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: A phase II study of the genitourinary group of the French federation of cancer centers

PURPOSE We assessed the efficacy and toxicity of a chemotherapy regimen combining doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma. MATERIALS AND METHODS Of the 25 patients included in a prospective multicenter phase II trial 23 were evaluable for efficacy and toxicity studies after pathological review. RESULTS A median of 3 cycles per patient (range 1 to 8) was administered. No objective response was observed. Median time to progression was 2.2 months and median overall survival was 3.9 months. A single patient died of toxicity. CONCLUSIONS The results do not support the standard use of doxorubicin/ifosfamide chemotherapy in patients with metastatic sarcomatoid renal cell carcinoma.

Stage I non-seminomatous germ-cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse

There is no consensus about a reproducible prognostic model capable of distinguishing between clinical stage I non-seminomatous germ cell tumour (NSGCT) carrying a high and low risk of relapse. The aim of this study was to assess the prognostic value of histological parameters in patients with stage I NSGCT undergoing surveillance after orchiectomy. We retrospectively evaluated tumour specimens from 88 consecutive stage I NSGCT patients undergoing surveillance in our institution between 1984 and 1996. 24 patients relapsed (27%). Multivariate analysis singled out vessel invasion (VI) (relative risk (RR)=3.8; 95% confidence interval (CI) 1.4-10.4) and the presence of mature teratoma (RR= 0.2; 95% CI 0.1-0.6) as independently correlated with relapse-free survival (RFS). Patients can be classified accordingly into three prognostic groups with a low (27 patients with mature teratoma but without VI), intermediate (34 patients with both VI and mature teratoma or with neither VI or mature teratoma) and a high risk (23 patients with VI, but without mature teratoma) of relapse. Relapse rates in these three groups were 0%, 29% (95% CI: 23-35%) and 61% (95% CI: 55-67%), respectively. This prognostic index, based on two standard pathological parameters, identified a subgroup with a very low risk of relapse that represents approximately one third of stage I patients. Patients who belong to this subgroup should be managed by surveillance only, instead of retroperitoneal lymph node dissection (RPLND) or adjuvant chemotherapy.

Adult Wilms' tumour: Review of 22 cases

The Institut Gustave Roussy experience with nephroblastoma in 22 patients older than 16 years during a 19-year period (1973-1992) was retrospectively reviewed. All patients underwent a nephrectomy. There were 4 stage I, 8 stage II, 3 stage III and 7 stage IV patients. Initial postnephrectomy therapy included single modality approach in 7 patients (radiotherapy in 1 and chemotherapy in 6) and combined modality approach (radiotherapy and chemotherapy) in 15 patients. The agents used most often were actinomycin, vincristine and doxorubicin. 2 of 7 (29%) and 7/15 (47%) patients are disease-free survivors after first-line treatment. Salvage chemotherapy was given in 13 patients. Only 1 patient experienced a subsequent sustained complete remission. After a mean follow-up of 100 months (range 10-240), 12/22 patients (55%) are alive, including 10 who are disease-free (45%). We confirm that adult patients are likely to have more advanced disease and poorer prognosis than children. The combined modality approach is more active than one-modality therapy. Aggressive treatment, including the three-drug regimen actinomycin+vincristine+doxorubicin, regardless of stage, associated to irradiation starting from stage II, is recommended.

Primary Chemotherapy in Patients with Nonseminomatous Germ Cell Tumors of the Testis and Biological Disease Only After Orchiectomy

PURPOSE We assessed the efficacy of primary chemotherapy in patients with nonseminomatous germ cell tumors of the testis and elevated serum tumor markers as the only evidence of disease after orchiectomy. MATERIALS AND METHODS We analyzed the outcome of 20 patients with biological disease only who received cisplatin-based (16) or carboplatin-based (4) chemotherapy as primary treatment following orchiectomy. RESULTS Serum tumor markers returned to normal levels in all 20 patients. One patient required subsequent surgery for recurrent retroperitoneal mature teratoma. Two patients experienced a relapse with active disease, 1 of whom died of progressive germ cell tumor. Of the patients 19 remained free of disease 18 to 116 months after the end of treatment. CONCLUSIONS Since results with primary retroperitoneal lymph node dissection suggest that elevated serum tumor markers usually reflect systemic metastases rather than retroperitoneal disease, primary chemotherapy seems to be the most appropriate strategy to consider in patients with biological disease only following orchiectomy.

Initial management of primary mediastinal seminoma: radiotherapy or cisplatin-based chemotherapy?

Primary mediastinal seminoma is an uncommon neoplasm, the optimal management of which is still debated. Radiotherapy produces a 65% disease-free survival rate. We assess whether these results have been improved with the advent of cisplatin-based chemotherapy. Data from 14 patients treated at the Institut Gustave-Roussy were reviewed. 9 had received cisplatin-based chemotherapy (Group 1): their outcome was compared with that of 5 patients treated with radiotherapy without chemotherapy (Group 2). We also reviewed data from the English literature using strict criteria, and report results concerning patients who received cisplatin-based chemotherapy and those who received radiotherapy. 8 of the 9 patients (89%) in Group 1 are long-term disease-free survivors and only 3 of 5 patients in Group 2. The patient who died in Group 1 was the only one who refused surgical resection of residual masses after chemotherapy. The review of the literature revealed that 59 of 68 (87%) patients initially managed with cisplatin- or carboplatin-based chemotherapy and for whom sufficient data are available, are long-term survivors and free of disease. Some of these patients had also received radiotherapy. Only 64 of 103 (62%) treated with thoracic radiotherapy without chemotherapy were long-term disease-free survivors. The disease-free survival rate of 51 patients who received cisplatin-based chemotherapy (excluding those who received carboplatin) was 86%. The difference in survival between patients administered cisplatin-based chemotherapy and those who underwent radiotherapy is apparently not due to unbalanced prognostic factors, the effect of time or non-specific medical management. We conclude that cisplatin-based chemotherapy allows long-term disease-free survival in approximately 85% of patients. These results seem to be higher than those obtained without cisplatin-based chemotherapy. However, a randomised study is required for definitive conclusions, but it is very unlikely that such a study will be performed due to the rarity of this neoplasm. Another alternative would be a meta-analysis based on individual data.

Are 3 Cycles of Bleomycin, Etoposide and Cisplatin or 4 Cycles of Etoposide and Cisplatin Equivalent Optimal Regimens for Patients with Good Risk Metastatic Germ Cell Tumors of the Testis? The Need for A Randomized Trial

PURPOSE Standard chemotherapy for good prognosis metastatic nonseminomatous germ cell tumors of the testis currently includes etoposide and cisplatin. The optimal number of cycles and the need for bleomycin remain matters of debate. Three cycles of bleomycin, etoposide and cisplatin (BEP) or 4 cycles of etoposide and cisplatin are supposed to represent equivalent optimal regimens. MATERIALS AND METHODS We analyzed the therapeutic outcome of 75 patients with good risk metastatic nonseminomatous germ cell tumor of the testis who were routinely treated at our institute. The chemotherapy regimens consisted of 4 cycles of BEP in 17 patients, 3 cycles of BEP in 23 patients, and 4 cycles of etoposide and cisplatin in 35 patients. RESULTS All 75 patients achieved a complete or partial response with normal serum tumor markers. After a median followup of 3.5 years (range 2 to 7.5) the overall no evidence of disease rate was 91% (100, 96 and 83% in patients treated with 4 cycles of BEP, 3 cycles of BEP, and 4 cycles of etoposide and cisplatin, respectively). When considering the number of adverse events in each treatment group, that is the number of surgical complete responses or relapses after complete remission, results appeared similar with 3 or 4 cycles of BEP (2 and 3, respectively) but lower in patients who received 4 cycles of etoposide and cisplatin (11 adverse events). Of the 35 patients treated with etoposide and cisplatin 4 (11%) died of disease while only 1 of the 40 (3%) treated with BEP died of disease. CONCLUSIONS Four cycles of etoposide and cisplatin could yield inferior results compared to 3 cycles of BEP in patients with good risk nonseminomatous germ cell tumor of the testis. Our results highlight the need for a randomized trial addressing the question of therapeutic equivalence between these 2 chemotherapy regimens.

Chemotherapy in stage II nonseminomatous germ cell tumors of the testis: The institut Gustave roussy experience.

To assess the role of chemotherapy in the treatment of stage II nonseminomatous germ-cell tumors of the testis, the outcomes of 154 patients who were included in prospective trials and standard treatment programs at Institut Gustave Roussy between 1984 and 1993 were reviewed. The median follow-up is 5.5 years. Cisplatin-based primary chemotherapy was the treatment regimen for 108 patients. Elevated serum tumor marker levels were found in 27 patients only while 81 had radiologic evidence of retroperitoneal disease. Primary chemotherapy was followed by retroperitoneal lymph node dissection (RPLND) in 41 % of cases. Long-term nonevolutive disease (NED) was diagnosed in 101 (93%) patients. Primary RPLND and adjuvant chemotherapy was the treatment regimen for 46 patients, 100% of whom are long-term NED. Patients with normal serum tumor marker levels following orchiectomy and radiologic evidence of low volume retroperitoneal disease should undergo primary RPLND. Patients with persistently elevated serum tumor marker levels without retroperitoneal involvement should be treated by primary chemotherapy, as should patients with large volume retroperitoneal disease. In patients with elevated serum tumor marker levels and low volume retroperitoneal disease who may benefit equally from up-front chemotherapy or primary RPLND, assessment of risk-benefit, cost-benefit, and quality of life is warranted in future trials.

Cisplatin-Based Chemotherapy in Advanced Seminoma: The Institut Gustave Roussy Experience

The aim of this study was to report the results of cisplatin-based combination chemotherapy for patients with pure seminomatous tumours. 72 patients with advanced seminoma were treated with various cisplatin-based chemotherapy regimens. 61 (85%) patients achieved a sustained durable response. 11 relapses were observed with a median time to failure of 6 months. Overall, 60 (83%) of the 72 patients remain alive and free of disease after a median follow-up of 64 months. Initial clinical (age, site of primary, prior radiotherapy, extent of disease) and biological (serum human chorionic gonadotrophin levels, serum lactic dehydrogenase levels, p53 immunostaining) features which could be of predictive value for survival, were analysed in a univariate analysis. No variable retained statistical significance. High cure rates are expected after chemotherapy with standard cisplatin-based combinations in advanced seminoma. Renewed efforts are required to identify markers of chemosensitivity.