Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU ml−1, or a alpha-foetoprotein level higher than 2000 mIU ml−1. Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.
British Journal of Cancer (2002) 86, 1555–1560. DOI: 10.1038/sj/bjc/6600272 www.bjcancer.com
© 2002 Cancer Research UK
chemotherapy; dose-dense chemotherapy; germ-cell tumours; International Germ-Cell Cancer Consensus Group; non-seminomatous germ cell-tumours
New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP.
intermediate and poor prognosis metastatic germ cell tumours; bleomycin; carboplatin; vincristine; cisplatin; etoposide
In this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).
Between March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.
A total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.
Radiotherapy; High-dose chemotherapy; Autologous stem cell transplantation; Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Children
We analysed outcome in 206 consecutive male patients treated for metastatic non-seminomatous germ cell tumour (NSGCT) of testicular or extragonadal origin treated with the POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) regimen after division into prognostic groups by commonly used clinical classification systems and definitions of adverse prognosis. The adverse prognostic groups of all classification systems and definitions examined showed similar, but only moderate, sensitivity (71-81%) and specificity (52-56%) in predicting death. A simple definition of poor prognosis based on raised initial levels of serum tumour markers alpha fetoprotein (aFP) and human chorionic gonadotrophin (hCG) proved at least as useful (sensitivity 80%, specificity 55%) as other more complicated systems in predicting failure to achieve long-term survival. Comparison of survival between ultra-high dose cisplatin-based combination chemotherapy and patients treated with POMB/ACE shows no advantage from this more toxic approach. This suggests that good results in adverse prognosis patients can be achieved using conventional dose regimens administered intensively.
Children with high risk medulloblastoma and non-cerebellar PNET’s were treated on a phase II study of pre-radiotherapy chemotherapy (CHT) followed by high dose, hyperfractionated craniospinal radiotherapy (CSRT). The protocol objectives were to verify feasibility and monitor progression-free (PFS) and overall survival (OS).
Methods and Materials
Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm2 post-op residual disease and all patients with non-cerebellar PNET. Treatment was initiated with 5 alternating monthly cycles of CHT [A (cisplatin, cyclophosphamide, etoposide and vincristine, B (carboplatin and etoposide), A, B and A] followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice daily 1 Gy fractions.
The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four (68%) patients completed the entire protocol within the study guidelines of 9 months and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year PFS and OS were 43 ± 5% and 52 ± 5%. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, post-op residual disease or M-stage.
The feasibility of this intensive multi-modality protocol was confirmed and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared to other studies, given the protocol design.
PNET; Medulloblastoma; High risk; Hyperfractionated radiotherapy; Pre-radiation chemotherapy
Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs). However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy.
We examined 35 patients (27 men and 8 women) diagnosed with IC-GCTs between August 2004 and April 2008 and received risk-adapted carboplatin-based chemotherapy at the Samsung Medical Center. Patients were divided into either low-risk (LR) or high-risk (HR) groups and a retrospective analysis was performed using information from the medical records.
Although hematological complications were common, hearing difficulties or grade 3 or 4 creatinine level elevation were not observed in patients who underwent carboplatin-based chemotherapy. The frequency of febrile neutropenia did not differ between the risk groups. The overall survival was 100% and event-free survival (EFS) was 95.7%. The EFS rate was 100% in the LR group and 90% in the HR group, respectively.
Despite their common occurrence in high-risk patients, no lethal hematological complications were associated with carboplatin-based treatment. The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs.
Intracranial germ cell tumor; Carboplatin; Adverse effects
Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m−2 days 1 and 2, vincristine 1.4 mg m−2 (max. 2 mg) days 2 and 8, bleomycin 30 000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported ‘quite a bit' or ‘very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 × BOP over 2 × BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.
adjuvant chemotherapy; stage I non-seminoma
High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.
chemotherapy; germ cell tumors; high-dose chemotherapy; stem cell transplantation; testicular cancer
Long-term outcome was reviewed in 266 consecutive patients with metastatic non-seminomatous germ cell tumours treated at a single institution. The overall 3 year survival was 77%, and 3 year progression-free survival was 71%. Multivariate analysis identified the following clinical features as independent prognostic factors: the presence of liver, bone or brain metastasis, serum human chorionic gonadotropin > or = 10000 U l-1 and/or alpha-fetoprotein > or = 1000 ng ml-1, a mediastinal mass > 5 cm and the presence of 20 or more lung metastases. Age was not of prognostic significance. Patients without any of the above poor-risk factors had a 3 year survival of 91% regardless of etoposide- or vinblastine-containing chemotherapy compared with 61% for the remaining patients. However, etoposide-containing protocols led to significantly improved survival in patients with at least one poor risk factor. After 612 patient-years of observation no case of secondary leukaemia was observed among 119 surviving patients who had received etoposide as part of their treatment. With a median follow-up of 93 months, five patients developed a second germ cell tumour, two patients nongerm cell malignancies. Fourteen patients relapsed after a disease-free interval of more than 2 years, and nine patients died more than 5 years after commencement of treatment underscoring the need to report long-term results. There is some evidence that cumulative experience translates into improved survival and cure rates for patients with poor-risk metastatic disease.
Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare tumor type that mainly affects young women. We report a 21-year old woman with SCCOHT. The patient initially presented with stage T3AN1MX disease and treated with surgery. The patient then received 8 cycles of multi-agent chemotherapy including cisplatin, bleomycin, cyclophosphamide, doxorubicin, and etoposide. Upon relapse, the patient underwent total abdominal hysterectomy, followed by chemotherapy with gemcitabine. The patient subsequently received radiation therapy and chemotherapy with bevacizumab, irinotecan and docetaxel. She passed away approximately 5 months after the second surgery and with her prior permission an immediate autopsy was performed. We examined the gene expression and copy number profiles of the tumor tissue samples obtained from the autopsy and compared them to normal ovary tissues. Our results indicated that although this tumor did not harbor chromosomal abnormalities nor gene copy number changes, there were significant gene expression changes in a number of genes/pathways. More than 5,000 genes showed significant differential expression in the tumor when compared to normal ovary tissue. Pathway enrichment analysis further identified several pathways/processes including the Vitamin D receptor signaling and the hedgehog signaling pathways to be significantly dysregulated. The gene expression profiling also suggests a number of agents such as pazopanib, bortezomib, 5-azacytidine, and PARP inhibitors as treatment options to possibly explore in future trials against this disease.
Small cell carcinoma; hypercalcemic type; ovarian carcinoma
Part 7 of an update of the state of the art of cancer chemotherapy of the genitourinary tract is directed to the treatment of gestational trophoblastic neoplasms. Chemotherapy is the cornerstone of treatment for gestational trophoblastic neoplasms, as these tumors are generally highly curable with chemotherapy.
In early stage disease, 40 percent of cases are cured with hysterectomy. In low-risk cases, single-agent methotrexate or dactinomycin provides cure rates of over 90 percent. In high-risk disease sequential methotrexate/dactinomycin, methotrexate plus dactinomycin plus cyclophosphamide or chlorambucil, or methotrexate plus 6-mercaptopurine, or a combination protocol consisting of cyclophosphamide, hydroxyurea, dactinomycin, methotrexate, vincristine (VCR), folinic acid, and doxorubicin (CHAMOCA) produce complete remission rates in 70 to 80 percent of patients. Newer studies are under way with etoposide (VP16), cisplatin, and investigational agents to determine whether better chemotherapy regimens can be developed.
Embryonal cell carcinoma is a rare clinical entity. We report a case of a 20-year-old patient who presented with lump lower abdomen for last two months with primary amenorrhea and poorly developed secondary sexual characteristics. Ultrasonography (USG) whole abdomen showed lower abdominal mass approximately 15×15×10 cm, probably neoplastic changes in intra-abdominal testis, with mild ascites, no uterus and ovaries. Fine needle aspiration cytology from the tumor mass reported the possibility of non-seminomatous germ cell tumor, possibly embryonal carcinoma. The patient received three cycles of neo-adjuvant chemotherapy (Regime Bleomycin, Etoposide and Cisplatin) followed by laparotomy, at laparotomy (L) orchidectomy with removal of tumor, (R) orchidectomy, omentectomy and appendisectomy was performed. Postoperatively the patient received two more cycles of chemotherapy of the same regime. The patient has been under close follow-up for the last three years with no evidence of disease.
Androgen insensitivity syndrome; karyotype; masculinisation; mosaicism; virilisation
We present the case of a congenital localised sacrococcygeal primitive neuroectodermal tumor treated aggressively with surgical resection and modified age-appropriate adjuvant chemotherapy. The conventional combination chemotherapy of vincristine, adriamycin, cyclophosphamide, ifosfamide and etoposide was modified to a regimen including vincristine, adriamicin, cyclophosphamide and actinomycin in order to minimise the predicted toxicity in this age group. Adjuvant “induction” chemotherapy commenced at 4 weeks of age and consisted of four cycles of vincristine, adriamycin and cyclophosphamide at 50%, 75%, 75% and 100% of recommended doses (vincristine 0.05 mg/kg, adriamycin 0.83 mg/kg daily × 2, cyclophosphamide 40 mg/kg) at 3-weekly intervals. This was followed by four cycles of “maintenance” chemotherapy with vincristine (0.025 mg/kg), actinomycin (0.025 mg/kg) and cyclophosphamide (36 mg/kg) at full recommended doses. Cardioxane at a dose of 16.6 mg/kg was infused immediately prior to the adriamycin. Our patient is thriving at 19 months out from end of treatment.
Chemotherapy; neonatal; peripheral primitive neuroectodermal tumor; primitive neuroectodermal tumor
This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and ⩽2 adverse prognostic factors. Patients were randomised to receive six cycles of either ACE (doxorubicin 50 mg/m2 i.v., cyclophosphamide 1 g/m2 i.v. and etoposide 120 mg/m2 i.v. on day 1, then etoposide 240 mg/m2 orally for 2 days) or PE (cisplatin 80 mg/m2 and etoposide 120 mg/m2 i.v. on day 1, then etoposide 240 mg/m2 orally for 2 days) given for every 3 weeks. For patients where cisplatin was not suitable, carboplatin (AUC6) was substituted. A total of 280 patients were included (139 ACE, 141 PE). The response rates were 72% for ACE and 77% for PE. One-year survival rates were 34 and 38% (P=0.497), respectively and 2-year survival was the same (12%) for both arms. For LD patients, the median survival was 10.9 months for ACE and 12.6 months for PE (P=0.51); for ED patients median survival was 8.3 months and 7.5 months, respectively. More grades 3 and 4 neutropenia (90 vs 57%, P<0.005) and grades 3 and 4 infections (73 vs 29%, P<0.005) occurred with ACE, resulting in more days of hospitalisation and greater i.v. antibiotic use. ACE was associated with a higher risk of neutropenic sepsis than PE and with a trend towards worse outcome in patients with LD, and should not be studied further in this group of patients.
small-cell lung cancer; chemotherapy; randomised clinical trial; cisplatin; doxorubicin
The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.
brain tumor; childhood; cyclophosphamide; high-dose chemotherapy; stem cell transplant
In a study of chemotherapy as palliative treatment, 300 patients with untreated limited and extensive stage small cell lung cancer (SCLC), who did not have progressive disease after the first cycle of chemotherapy, were randomised to receive either regular 'planned' chemotherapy or chemotherapy given 'as required' (AR). All patients received the same chemotherapy: cyclophosphamide 1 gm m-2 i.v., vincristine 2 mg i.v., and etoposide 120 mg m-2 i.v. on day 1, and etoposide 100 mg b.d. orally on days 2 and 3. Planned chemotherapy was given regularly every 3 weeks. AR chemotherapy was given for tumour-related symptoms, or for radiological progression of disease. Both groups of patients were assessed every 3 weeks and a maximum of eight cycles of chemotherapy was given. A detailed quality of life assessment was made using daily diary cards. The median survival (MS) of patients given AR chemotherapy was not significantly worse than those receiving planned treatment [MS: Planned = 36 weeks (95% C.I. 32-40 weeks), AR = 32 weeks (95% C.I. 28-37 weeks) P = 0.960]. In the AR patients the median interval between treatments was 42 days. On average AR patients received half as much chemotherapy as planned patients. AR patients with a treatment-free interval (TFI) of more than 8 weeks between the first and second cycles of chemotherapy survived longer than those in whom this interval was less than 4 weeks; [MS: TFI greater than 8 = 47 weeks (95% C.I. 32-53 weeks); TFI less than 4 = 24 weeks (95% C.I. 17-34 weeks) P = 0.013]. Contrary to expectation, in the quality of life assessment the AR patients scored themselves as having more severe symptoms than patients receiving planned treatment. AR chemotherapy is a novel method of attempting to use cytotoxic drugs palliatively, which resulted in less drug treatment for approximately equivalent survival. However the palliative effect seen with as required treatment was less satisfactory than with planned chemotherapy.
Background: To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-prognosis germ-cell cancer (GCC).
Patient and methods: Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but closed with 137, due to slow accrual.
Results: One hundred thirty-one patients were included in this analysis. The complete response rates in the HD-CT and in the BEP arm did not differ: (intention to treat) 44.6% versus 33.3% (P = 0.18). There was no difference in FFS between the two treatment arms (P = 0.057, 66 events). At 2 years, the FFS rate was 44.8% [95% confidence interval (CI) 32.5–56.4] and 58.2%, respectively (95% CI 48.0–71.9); but this 16.3% (standard deviation 7.5%) difference was not statistically significant (P = 0.060). Overall survival did not differ between the two groups (log-rank P > 0.1, 47 deaths).
Conclusion: This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy improves outcome in patients with poor-prognosis GCC.
germ-cell tumor; high-dose chemotherapy; phase III
This study was performed to determine the changes in pulmonary function in patients randomised to receive treatment with four cycles of bleomycin, etoposide and cisplatin (BEP) (27 patients) or with four cycles of etoposide and cisplatin (EP) (27 patients) for disseminated non-seminomatous testicular cancer. This enabled us to establish whether effects other than those due to bleomycin determined the detrimental effects of BEP on lung function assessments. Slow inspiratory vital capacity (VC), the transfer factor of the lungs for carbon monoxide (TLCO), the diffusing capacity of the alveolo-capillary membrane (Dm), the pulmonary capillary blood volume (Vc) and the transfer factor of the lungs for carbon monoxide per unit alveolar volume (KCO) were determined before and at 3 week intervals during chemotherapy. Both groups, similar in terms of factors that may influence pulmonary function, showed during therapy a significant decrease in TLCO compared with the pretreatment value. Only at the end of the therapy was a significant difference in TLCO between both groups observed. Dm diminished also significantly in both groups during treatment, but differences between both groups were not seen. VC and Vc decreased in patients receiving BEP but remained constant during treatment with EP. It can be concluded that the Dm, KCO, and the widely used TLCO are not suitable parameters to monitor specifically pulmonary toxicity induced by bleomycin as part of a multidrug regimen. However, VC and Vc appear to be proper lung function assessments which reflect specifically alterations induced by bleomycin.
To compare the efficacy of four cycles of paclitaxel–bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).
Patients and Methods
Patients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m2 in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual.
Accrual was from November 1998 to April 2009. A total of 169patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a good prognosis of GCC (eight patients administered BEP; six patients administered T-BEP) or a poor prognosis of GCC (one patient administered BEP; four patients administered T-BEP). PFS at 3 years (intent to treat) was 79.4% in the T-BEP group versus 71.1% in the BEP group (hazard ratio [HR], 0.73; CI, 0.47 to 1.13; P [log-rank test] = 0.153). PFS at 3 years in all eligible patients was 82.7% versus 70.1%, respectively (HR, 0.60; CI: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different.
T-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.
Adjuvant treatment for intramedullary tumours is based on radiotherapy. The place of chemotherapy in this setting has yet to be determined. Between May 1992 and January 1998, eight children with unresectable or recurrent intramedullary glioma were treated with the BB SFOP protocol (a 16-month chemotherapy regimen with carboplatin, procarbazine, vincristine, cyclophosphamide, etoposide and cisplatin). Six children had progressive disease following incomplete surgery and two had a post-operative relapse. Three patients had leptomeningeal dissemination at the outset of chemotherapy. Seven of the eight children responded clinically and radiologically, while one remained stable. At the end of the BB SFOP protocol four children were in radiological complete remission. After a median follow-up of 3 years from the beginning of chemotherapy, all the children but one (who died from another cause) are alive. Five patients remain progression-free, without radiotherapy, 59, 55, 40, 35 and 16 months after the beginning of chemotherapy. The efficacy of this chemotherapy in patients with intramedullary glial tumours calls for further trials in this setting, especially in young children and patients with metastases. © 1999 Cancer Research Campaign
chemotherapy; child; intramedullary tumour; spinal cord tumour; glioma; astrocytoma
We investigated the efficacy and toxicity of induction chemotherapy with cisplatin and etoposide with either bleomycin or ifosfamide in patients with intermediate-prognosis testicular non-seminoma. A total of 84 eligible patients were randomized to receive four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of bleomycin, etoposide, cisplatin (BEP). Intermediate prognosis was defined as any of the following: lymph node metastases 5-10 cm in diameter, lung metastases more than four in number or > 3 cm, HCG 5000-50,000 IU l(-1), AFP > 1000 IU l(-1). The complete response (CR) rates to VIP and BEP were similar, 74% and 79% respectively (P = 0.62). Including the cases in whom viable cancer was completely resected with post-chemotherapy debulking surgery, the percentages of patients who achieved a no-evidence-of-disease status were 80% on VIP and 82% on BEP (P = 0.99). In addition, there were no differences in relapse rate, disease-free and overall survival after a median follow-up of 7.7 years. The 5-year progression-free survival was 85% (95% CI 74-96%) in the VIP arm and 83% (95% CI 71-96%) in the BEP arm, hazard ratio (VIP/BEP) 0.83 (95% CI 0.30-2.28). The VIP regimen was more toxic with regard to bone marrow function; the frequency of leucocytes below 2000 microl(-1) throughout four cycles was 89% on VIP and 37% on BEP (P < 0.001). Our study does not indicate that ifosfamide is superior to bleomycin in combination with cisplatin and etoposide. The sample size in this study is small as the study was prematurely discontinued when data became available from a competing study that showed no improved effectiveness of VIP compared with BEP. Taken together with these data, bleomycin should not be replaced by conventional-dose ifosfamide.
A 26-year-old girl was referred to us in December 2008 with progressive pelvic mass while on chemotherapy. In May 2008, she presented with large adnexal mass and high alpha-fetoprotein (AFP, 265.7 ng/mL; normal range, 0 to 10). She underwent laparoscopic right salpingo-oophorectomy with staging. Since histology was immature teratoma grade I, FIGO stage 1 she was kept on surveillance. In September 2008, she developed recurrent pelvic mass with AFP levels of 2,400 ng/mL. Three courses of chemotherapy (bleomycin-etoposide-cisplatin) were given. Post-chemotherapy AFP normalized but tumor size increased. CT-scan (abdomen-pelvis) showed a large pelvic mass with calcification specks; infiltrating the sigmoid colon and abdominal wall. With provisional diagnosis of growing teratoma syndrome she had exploratory laparotomy with excision of pelvic mass along with sigmoid colon, excision of right pelvic and subcutaneous deposits, omentectomy and sigmoid anastomosis. Left ovary, left tube and uterus appeared normal and were preserved. Histology of all masses showed mature teratoma, no immature elements. At six months follow up she is disease free and has resumed menstruation. Growing teratoma syndrome is a clinico-pathological presentation during/post-chemotherapy in malignant ovarian germ cell tumor where mature teratoma grows and requires complete surgical excision. Our case highlights the safety and adequacy concerns of laparoscopic management of malignant ovarian tumor. Literature review suggests good prospects of resumption of menses, child bearing and five year survival in case of growing teratoma syndrome.
Salpingo-oophorectomy; Growing teratoma syndrome; Immature teratoma; Malignant ovarian germ cell tumor; Chemotherapy; Laparoscopy
The survival in cases with relapsed Wilms tumor is dismal. Recently, however the introduction of new therapeutic agents and experimental strategies has improved the survival. We analysed the survival of patients with relapsed Wilms tumor according to the treatment period. During the early period 1983-1993, patients who had received two drugs were treated with doxorubicin and the others were treated with cisplatin and etoposide, whereas during the late period 1994-2004, patients were treated with combinations of cyclophosphamide/etoposide and carboplatin/etoposide. During the early period, 8 of 57 experienced relapse, and 8 of 41 relapsed during the late period. Only 2 patients treated during the early period survived in complete response (CR), whereas during the late period, 5 patients remained alive in CR, and 3 of those received high-dose chemotherapy (HDC) with autologous peripheral stem cell rescue (SCR). The estimated 5 yr event-free survival rate was 37.5% in the entire study group, 50% for patients in the late period, and 25% for patients in the early period (p=0.38). The survival in patients with relapsed Wilms tumor dramatically improved during the late period and HDC with SCR was one of the effective salvage strategies.
Wilms Tumor; Nephroblastoma; Recurrence; Salvage Therapy; Stem Cells
Poor outcome in Stage 4 neuroblastoma may be improved with increased dose intensity of therapy. We investigated the feasibility of sequential collection and infusion of peripheral blood stem cells (PBSC) as hematopoietic support for non-myeloablative dose intensive induction chemotherapy given every 21-28 days.
Twenty-two children with Stage 4 neuroblastoma (≥ 1yr of age) received 2 cycles of high dose cyclophosphamide (4 gm/m2), doxorubicin (75mg/m2) and vincristine (2mg/m2) followed by 3 cycles of interpatient dose escalating carboplatin (dose level 0 = 800 mg/m2; dose level 1 = 1000 mg/m2), high dose cyclophosphamide (4 gm/m2) and etoposide (600 mg/m2). PBSC were harvested following cycle 2, 3, and 4 in Cohort 1 and infused after each subsequent cycle. In Cohort 2, PBSC were harvested after cycle 2 and split into 3 aliquots for infusion. Dose limiting toxicity (DLT) and ability to administer cycles within 28 days was assessed.
Sufficient PBSC (≥ 2 × 106 CD34 cells/kg per infusion) were collected from 17/21 eligible patients with minimal toxicity and no detectable neuroblastoma cells by immunocytology. Carboplatin at 1000 mg/m2 resulted in DLT of delayed platelet recovery > 28 days in 4/8 patients. Despite de-escalation to 800 mg/m2, platelet DLT occurred in 4/7 Cohort 1 and 3/7 Cohort 2 patients.
As defined in this protocol, doses of carboplatin were not tolerable with the PBSC dose administered. However, it was feasible to collect sufficient PBSC from small neuroblastoma patients to use as hematopoietic support with minimal risk of tumor contamination and toxicity.
neuroblastoma; peripheral blood stem cell support; dose intensity; carboplatin
This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m−2 day 1, followed on days 1–5 by ifosfamide 1 g m−2 intravenously (i.v.) and cisplatin 20 mg2 i.v.) at 3-weekly intervals. The primary outcome measure was response to TIP. In all, 51 patients were registered, of whom 43 were eligible for response assessment. Eight achieved complete remission (CR) and 18 a partial remission with negative markers (PR−ve); favourable response rate (FRR=CR+PR−ve) 60%, 95% CI (44–75%); survival at 1 year was 70% (56–84%) and failure-free survival 36% (22–50%). In the group of 26 patients meeting the ‘good-risk' criteria described by the Memorial Hospital, the FRR was 73% (52–88%) compared with 41% (18–67%) for the 17 ‘poor-risk' patients. These results are inferior to those previously reported for TIP in a single-centre study when it was given more intensively, at higher dose and with growth factor support. Nonetheless, TIP as described here can cure a substantial proportion of patients.
cisplatin; ifosfamide; metastatic germ cell cancer; paclitaxel; salvage chemotherapy