Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with Stage 1 nonseminoma treated with adjuvant chemotherapy.

OBJECTIVES: To study survival and late events after adjuvant chemotherapy in Stage 1 nonseminoma. METHODS: From 1978 to 1986, all patients had surveillance. From 1986, adjuvant chemotherapy (initially a 3-day regimen of etoposide, bleomycin, and cisplatin, but, more recently, bleomycin, Oncovin, and cisplatin) was offered to patients at a high risk of relapse (greater than 30%). RESULTS: A total of 382 patients with Stage 1 nonseminoma treated between 1978 and 2000 were reviewed. Of the 234 patients treated by surveillance, 71 (30%) had relapses (5 after 2 years), 6 died (2.6%) of germ cell cancer, and 3 developed second primary testicular cancer. Of the 148 men treated with adjuvant chemotherapy, 6 (4%) had relapses and 2 (1.4%) died of chemoresistant cancer. After one course of etoposide, bleomycin, and cisplatin, 3 (6.5%) of 46 developed a relapse; after two courses, 1 (3.6%) of 28 did so; and after bleomycin, Oncovin, and cisplatin every 10 days x2, 2 (2.7%) of 74 patients did so. Of the high-risk patients who were offered adjuvant treatment, 24% declined. As a consequence, the relapse rate of the surveillance patients only fell from 36% to 27% after the introduction of adjuvant therapy, although for the total cohort treated in the adjuvant era, the relapse rate was 16%. CONCLUSIONS: Adjuvant chemotherapy is more effective than retroperitoneal lymph node dissection for reducing the relapse risk in high-risk Stage 1 nonseminoma. However, given the uncertainty about the incidence of postchemotherapy late events, surveillance and retroperitoneal lymph node dissection remain justified alternatives. With positron emission tomography and laparoscopy showing increasing promise in these cases, quality-of-life studies and greater patient involvement in treatment selection are needed.

Sixty percent salvage rate for germ-cell tumours using sequential m-BOP, surgery and ifosfamide-based chemotherapy.

BACKGROUND: In germ-cell tumours (GCT), there is continuing controversy over the relative merits of dose dense therapy (increased frequency over a given time) versus vertical intensification (increased dose per fraction). The value of using a cisplatin-based dose dense approach in the salvage setting has not been documented and in addition the role of methotrexate remains uncertain. This paper reviews results from our investigations of these issues. PATIENTS AND METHODS: Between 1987 and 1996, 65 patients with relapsing or refractory germ-cell tumour received weekly m-BOP (methotrexate, bleomycin, vincristine and cisplatin) as salvage therapy. Residual masses were excised if possible and patients progressing after this received cisplatin and ifosfamide based chemotheraphy with or without high dose chemotherapy (HDCT) consolidation. RESULTS: With a median follow-up of 33 months, 34% are progression free following m-BOP, 11% who had surgery for residual masses which showed viable cancers are progression free. A further 15% who progressed following m-BOP with or without surgery were rendered progression free by third-line therapy. CONCLUSIONS: The use of m-BOP as second line therapy with deferment of cisplatin and ifosfamide based treatment to third line therapy with consolidation of third line responses with HDCT, leads to an overall progression-free survival of 60%. It does not appear that M-BOP prejudiced the response to third line therapy suggesting a lack of cross resistance. The potentially lower risk of leukaemia and infertility from m-BOP requires further evaluation.

Pilot studies of 2 and 1 course carboplatin as adjuvant for stage I seminoma: should it be tested in a randomized trial against radiotherapy?

PURPOSE: Underpinned by increased confidence in cure of metastatic seminoma by chemotherapy during the past 12 years, three management strategies for Stage I seminoma have been evaluated by six collaborating centers within the Anglian Germ Cell Tumor Group. This paper evaluates the efficacy of surveillance, prophylactic radiotherapy and adjuvant chemotherapy, and discusses these differing management approaches. METHODS AND MATERIALS: Patients were recruited into the study between 1982 and 1992. There was no randomization between treatment groups. Seventy-nine patients received prophylactic radiotherapy (median follow-up = 51 months), 67 patients had surveillance alone (median follow-up = 61 months) and 78 patients were treated with adjuvant single agent platinum (median follow-up = 44 months). Fifty-three of these patients received two courses of platinum (median follow-up = 51 months) and 25 patients received one course (median follow-up = 29 months, range 22-72 months). RESULTS: There were 18 (27%) recurrences on surveillance, five (6%) after radiotherapy, one (1%) after two courses of adjuvant single agent platinum and none after one course of carboplatin. There was one death from testis cancer after radiotherapy and none after adjuvant chemotherapy treatments. Two patients died with drug resistant disease after relapse on surveillance. There was one death from a myocardial infarction after prophylactic radiotherapy and one death from suicide in the surveillance group. A retrospective quality of life questionnaire reviewing the incidence of early and late toxicity revealed no major differences though they suggest that those treated with one course adjuvant carboplatin had somewhat less sickness and an earlier return to work. CONCLUSION: Single agent carboplatin appears well tolerated and is an effective adjuvant treatment for Stage I seminoma. A multicenter randomized trial of the different treatment modalities is required to further evaluate its use.

A phase II study of epirubicin in advanced transitional cell bladder cancer. The Yorkshire Urological Cancer Research Group.

A multicentre Phase II study of epirubicin has been performed in patients with measurable or evaluable recurrent or metastatic transitional cell bladder cancer. Epirubicin was given intravenously every 3 weeks at a dose of 100 mg/m2. An objective response rate of 28% was observed (one complete and nine partial remissions) in an evaluable group of 36 patients, (confidence interval 15%-45%). Subjective improvements in the condition of patients were seen in responding and 'no change' patients. An interesting observation was the good response seen in patients with recurrent bladder disease who had previously received radial radiotherapy. Toxicity was considered to be acceptable and manageable, the most frequent being alopecia, and nausea and vomiting. Haematological toxicity was slight. One patient developed skin pigmentation, a not previously recognized complication of epirubicin treatment. Three cases of possible cardiotoxicity were seen in the 43 patients evaluable for toxicity. Epirubicin in thus an active agent in transitional cell carcinoma of the bladder, with a role as a single agent for palliation. It may also be useful in combination regimens for more aggressive treatment.

A comparison of doxorubicin, epirubicin and mitozantrone as single agents in advanced breast carcinoma.

Between July 1985 and December 1987, 87 patients with advanced breast carcinoma were randomized to receive single agent doxorubicin (70 mg/m2), epirubicin (70 mg/m2) or mitozantrone (14 mg/m2) at 3-weekly intervals. The patients had received no previous chemotherapy for their advanced disease but 91% had received prior hormonal therapy. The response rates were 36% with doxorubicin, 32% with epirubicin and 26% with mitozantrone, but these differences did not reach statistical significance. The median survival of all patients was 8.3 months. There was no significant difference in response rates or survival according to menopausal status. The toxicities of the three agents are compared. Nausea, vomiting and alopecia were more severe in patients treated with doxorubicin or epirubicin than those treated with mitozantrone. Myelosuppression and infective episodes occurred more frequently with mitozantrone. Two cardiac complications were reported. This study shows that the toxicity and low efficacy of all three agents limit their use as single agents in advanced breast carcinoma. The role of single agent chemotherapy and the relative toxicities of these drugs are discussed.

Problems in the management of testicular seminoma associated with a horseshoe kidney.

Four patients with seminoma of the testis and coexisting horseshoe kidney are presented. Three patients had stage one disease, which would conventionally be managed by abdominal nodal irradiation. However, because of the risk of radiation nephritis, a surveillance policy was adopted with regular computed tomography (CT). Two of these three patients have relapsed and are disease free after chemotherapy. The fourth patient had Stage IIC disease which initially responded to combined radiotherapy and chemotherapy. This patient's disease relapsed and he died despite further treatment. Because of the altered retroperitoneal anatomy, CT interpretation must be made with special care.

A randomized trial of intracavitary bleomycin and Corynebacterium parvum in the control of malignant pleural effusions.

Fifty-eight patients with malignant pleural effusions were entered into a prospectively randomized clinical trial comparing the efficacy of a local instillation of bleomycin or corynebacterium parvum (C. parvum) in controlling fluid reaccumulation after simple needle aspiration (thoracentesis). The response was assessed at 30 days by chest X-ray and clinical examination. There were 44 evaluable patients; 18 of 25 (72%) of those receiving bleomycin and 9/19 (47%) of those who had C. parvum gained a complete or partial response. This difference in response rate was not statistically significant (p = 0.13). The majority of patients had an effusion from a primary breast carcinoma and the response in this group was almost statistically significant (p = 0.06) with 74% of bleomycin patients and 43% of C. parvum patients responding. Fever following instillation was more common with C. parvum (53% of patients compared with 24% after bleomycin, p = 0.02), whereas nausea was more common after bleomycin (28% vs. 10.5%, p = 0.16). Local chest pain after aspiration occurred in 52% of the bleomycin group and 47% of the C. parvum subjects. There was no significant difference between the groups in age, sex, tumour type, presenting symptoms, volume of aspirate, systemic therapy or number of previous aspirations. Both of these agents appeared to be active in the control of malignant pleural effusions although the response rate was higher with bleomycin and overall, both have acceptable levels of toxicity.

Intracavitary therapy with bleomycin for the treatment of malignant pleural effusions.

This paper briefly reviews the incidence of malignant pleural effusions (MPE) and the measures that have been used to treat this condition. The role of intracavitary bleomycin in controlling MPE, the doses used, and morbidity associated with its use are reviewed in depth with reference to multicenter studies that the author has coordinated as well as the published literature. The short- and long-term results reported when bleomycin was used alone or as compared with other agents are discussed. The author concludes that intracavitary bleomycin is an effective agent comparable to, if not more effective than, most agents used to prevent the recurrence of MPE after simple drainage procedures: it is safe and convenient to use; toxicity is low with minimal side effects and no myelosuppression. It can be safely administered to immunocomprised patients and those undergoing systemic chemotherapy.

Successful treatment of malignant carcinoid tumour with intravenous cis-platinum.

A case of carcinoid tumour responding to i.v. Cis-Platinum is described. These results suggest that this agent may be effective in treating this condition and further evaluation in a larger number of patients should be performed.

A randomized, prospective, comparative, multicentre trial of a single combination versus alternating combinations of antitumour drugs in advanced breast cancer.

A prospective, multicentre trial was conducted in 262 patients with advanced breast cancer randomized to receive every 3 weeks either: (i) a single five-drug combination of adriamycin (50 mg), vincristine (1.5 mg) and 5-fluorouracil (750 mg) given intravenously; with methotrexate (50 mg) intramuscularly and chlorambucil (10 mg) orally all at time zero, followed by three further doses of chlorambucil (10 mg) at 6-h intervals, or (ii) one course of two alternating three-drug combinations consisting of regimen A--vincristine (1.5 mg), adriamycin (70 mg) and methotrexate (50 mg) and regimen B--5-fluorouracil (750 mg) and vindesine (5 mg) intravenously with cyclophosphamide (50 mg) orally at time zero, followed by three further doses of cyclophosphamide (50 mg) at 6-h intervals. Results show that overall response rates to chemotherapy were comparable in the two arms of this study being 63% (83 of 131 patients) for the single combination and 64% (84 of 131 patients) for the alternating combinations. Response rates according to menopausal status indicate no significant difference for the two arms of this study. However overall, combining all patients treated with either the single or the alternating combinations, post-menopausal patients had a significantly lower response rate (57%) compared with pre-menopausal patients (76%), P less than 0.05. Overall serious side-effects were minimal and were similar in both treatment groups. Response durations and overall survival data, which are essentially similar for the two treatment groups, proved disappointing with a median response duration of only approx. 6 months and overall median survival only slightly in excess of 1 year. Alternative treatment approaches are needed to maintain the remissions initially achieved in metastatic breast cancer.

Adjuvant chemotherapy in the treatment of breast cancer: results of a multicentre study.

248 patients with locally radically treated early breast cancer (196 node-positive) were randomized post-operatively between 6 courses of a 'CMF like' chemotherapy and no further treatment. Results (with a minimum of 5 years follow-up on every patient) favour chemotherapy with a significant increase in the median time to recurrence from 31 to 50 months for all patients (P = 0.04) and from 26 to 49 months for node-positive patients (P = 0.023). No significant effect on survival is seen although there is a trend towards longer survival in the treated group. The regimen used was relatively non-toxic when compared to the traditional CMF with 34% of patients experiencing mild nausea and vomiting immediately post-injection and only 11% complaining of more severe nausea and vomiting. Because of this lower toxicity the treatment was found to be amenable to administration in both regional hospitals and specialized centres.

An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin.

Fifty-four consecutive patients with malignant effusions either pleural or peritoneal were treated by a simple aspiration followed by the administration of bleomycin to prevent a recurrence. All patients were followed up until reaccumulation of the effusion or death, with assessments being made of the patient's response at 30 days, 60 days, 90 days, 6 months, 1 year and then annually. There were 42 evaluable patients at 30 days, when the overall response rate for pleural effusions was 80.5% (21/26) and 62.5% (10/16) for peritoneal effusions. Patients who developed an effusion from primary breast neoplasms responded better than other groups, with an overall rate of 81% and 80% for pleural and peritoneal effusions respectively. Thirty percent (13) of the patients whose effusions was controlled by bleomycin required a further aspiration due to a recurrent effusions 9% (4) within the first 90 days and the remainder 21% (9) between 3 and 45 months after initial treatment. Altogether 19% (8/42) of the evaluable patients were effusion free at 1 year and 12% (5/42) clear at 3 years, but only two patients were still alive at four years. Side effects were minimal as 92% (50/54) patients treated experienced no adverse effects and there was no evidence of myelosuppression. The dose of bleomycin instilled varied between 60 mg and 180 mg, with 60 mg being given to 58% of patients and 90 mg to 30%, but there was no evidence to suggest that doses higher than 60 mg were more effective. The author concludes that the instillation of bleomycin following the simple aspiration of a malignant effusion is a safe, effective treatment which can benefit patients with this distressing complication of their malignant disease.

Intracavitary bleomycin in the management of malignant effusions: a multicenter study.

The efficacy of intracavitary bleomycin in preventing the recurrence of malignant effusions following aspiration was assessed in a multicenter study. Of 200 patients treated, 158 were evaluated for response at 30 days. The overall response rate was 58%, with pleural effusions responding better (62%) than peritoneal effusions (47%). Pleural effusions resulting from primary breast tumors showed the best response (72%). No side effects were seen in 79.5% of the 200 patients. Pain and transient fever were reported in 21% of the patients after intraperitoneal instillation but in only 5% of those receiving intrapleural instillations. Nausea was experienced by 5.5% of the patients. There was no evidence of myelosuppression in any patient nor of enhancement of myelosuppression in the 57 patients receiving concurrent cytotoxic therapy. There was one possible treatment-related death in an elderly man given 120 mg of bleomycin intrapleurally. This leads us to recommend that the maximum dose should be 60 mg, especially as the response rate was not improved by doses greater than 60 mg. We conclude that bleomycin should be the agent of choice when the instillation of a cytotoxic agent following the drainage of a malignant effusion is indicated, since it is effective in preventing recurrence of the effusion, is generally free from systemic effects, and can be given to myelosuppressed patients or those already undergoing systemic cytotoxic therapy.

Polyestradiol phosphate: a preliminary evaluation of its effect on breast carcinoma.

The effect of polyestradiol phosphate (Estradurin), a long-acting estrogen preparation given im, was assessed in 24 elderly postmenopausal patients with stage II or III primary or recurrent breast carcinoma. Although the drug has been available for many years, there has been no report in the literature of its use in treating breast carcinoma. The results of this study show that a total of 17 of 24 (70.8%) patients had evidence of tumor regression lasting a minimum of 3 months, while in 14 (58.3%) patients regression was maintained for greater than or equal to 6 months. Seven patients had complete (100%) tumor regression. Side effects were almost nonexistent and the agent has been shown to be effective, with good patient acceptability and guaranteed administration. It could be considered as an alternative to oral estrogen therapy where patient compliance is poor and gastrointestinal side effects are severe enough that patients often request a change of treatment.