Clinical Experience with Vincaleukoblastine Sulfate in the Treatment of 11 Patients with Hodgkin's Disease

Eleven patients with established Hodgkin''s disease were treated with vinblastine sulfate. Each patient received from 0.15 to 0.20 mg./kg. of body weight intravenously in 10 divided doses over a five-hour period as initial therapy. All had received one or more of the more established forms of treatment before being given vinblastine. The response to treatment with vinblastine was excellent in three patients, good in one, and poor in three; there was no response in four. The longest remission was 15 months. Two of the patients were father and son. The side effects of treatment in this series included alopecia, leukopenia, and septicemia.     

Infectious syphilis in Canada in 1986.

Thirteen men with a median age of 37 (range 28 to 46) years who had extensive Kaposi''s sarcoma associated with acquired immune deficiency syndrome (AIDS) were treated with combination chemotherapy and alpha-interferon. Four patients had stage III disease and nine had stage IV disease (one with pulmonary and eight with gastrointestinal involvement). Treatment consisted of monthly courses of actinomycin D, 1 mg/m2, and vinblastine sulfate, 6 mg/m2, given intravenously on day 1, bleomycin, 10 mg/m2 given intravenously on days 1 and 8, and human lymphoblastoid (alpha-) interferon, 10 million U/m2 given subcutaneously three times a week for six doses starting on day 14. Forty-one treatment cycles (median 3, range 1 to 12) were administered. The median granulocyte and platelet counts on day 14 before the start of interferon therapy were 600 X 10(9)/L and 134 X 10(9)/L respectively; the counts did not fall further during interferon therapy. There was no difference in T-cell subsets, 2'',5''-oligoadenylate synthetase level or results of blastogenesis studies after interferon therapy. Four patients required admission to hospital for neutropenia-associated fever. A complete response (of 24 weeks'' duration) was seen in one patient and a partial response (of 14 to 44 weeks'' duration) in four. One patient had a mixed response, with regression of skin involvement but progression of pulmonary disease. The median length of survival was 48 (range 4 to 143) weeks. Eleven patients died of progressive Kaposi''s sarcoma, one of lymphoma and one of Pneumocystis carinii pneumonia. The results suggest that this form of therapy is not appropriate for patients with Kaposi''s sarcoma associated with AIDS.     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

Bleomycin in the Reticuloses

Bleomycin alone was used in the treatment of 54 patients with Hodgkin''s disease in its later stages, 17 with generalized lymphosarcoma, 22 with reticulum cell sarcoma, and 7 with mycosis fungoides. The patients had had radiotherapy and full courses of conventional chemotherapy. Bleomycin was given in doses of 30 mg weekly to an average total dosage of 200 mg, though up to 800 mg could be given because of its marrow-sparing properties. Sixteen (29%) of the patients with Hodgkin''s disease remitted, most of them achieving only a partial remission, and similar results were obtained in the other three reticuloses. Bleomycin would seem to have some beneficial action in the late stages of Hodgkin''s disease, though it is less effective than some drug regimens recently introduced. Nevertheless it may be useful when there is diminished bone marrow reserve. It would be a suitable drug to use in combination therapy of these four reticuloses.     

TRISETHYLENE-IMINO-S-TRIAZINE (TRIETHYLENE MELAMINE OR TEM) IN THE TREATMENT OF NEOPLASTIC DISEASES

Trisethylene-imino-s-triazine (triethylene melamine or TEM) produced minimal effects in inhibiting transplantable lymphoma and mammary adenocarcinoma in mice. In strain A mice, injection of the compound induced pulmonary tumors.TEM was tried on 32 patients with neoplastic disease, including nine patients with Hodgkin''s disease and five with lymphosarcoma and lymphatic leukemia. The therapeutic and toxic effects were similar to those observed with nitrogen mustard (HN2). Satisfactory remissions of up to three months were observed in Hodgkin''s disease and lymphosarcoma following parenteral administration of TEM. It is the authors'' impression that the remissions obtained with TEM were not as complete and did not last as long as those obtained with HN2.TEM is effective by the oral route as well as parenterally, and produces much less emetic reaction than HN2. On the other hand, the chemotherapeutic range is narrower than that of HN2. Patients who do not respond to HN2 show no response to TEM.TEM is a drug of some clinical usefulness in the same conditions and with the same general limitations and toxic effects as HN2. The ease of administration of TEM increases its hazards, and close clinical and hematologic observations are essential on patients receiving the agent.     

Randomised trial of two-drug and four-drug maintenance chemotherapy in advanced or recurrent Hodgkin's disease. Medical Research Council's working party on lymphomas.

Between 1970 and 1975, 108 patients who presented with advanced or recurrent Hodgkin''s disease and were free of disease after six courses of chemotherapy with mustine, vinblastine, procarbazine, and prednisone (MVPP) were allocated at random to one of two regiments of maintenance treatment: either intermittent treatment with vinblastine and procarbazine or intermittent treatment with MVPP. After a median follow-up period of nearly five years there was no significant difference between the two groups in either the rate of relapse or death rate. Six of the 55 patients given the two-drug regimen died compared with 10 of the 53 given the four-drug regimen. The four-drug required hospital attendance and was less agreeable than the two-drug regimen. The efficacy of maintenance chemotherapy with the two-drug regimen was no less than that with the four-drug regimen, but the two-drug regimen had several practical advantages.     

Vincristine in the Treatment of Neoplastic Disease

Seventy-eight patients with advanced malignant disease were treated with vincristine, an alkaloid derived from Vinca rosea Linn. Fifty-nine of these survived one month from the beginning of treatment and could be evaluated. Twenty made a good response, with return to activity and more than 75% regression of tumour deposits. Seven made a fair response with resumption of partial activity and at least a 25% regression of tumour deposits. Favourable results were seen in patients with Hodgkin''s disease, reticulum cell sarcoma, lymphosarcoma, carcinoma of the breast, acute leukemia and choriocarcinoma. The duration of remission was usually brief but in five instances exceeded six months. Toxic reactions include a high incidence of alopecia and neurologic complications. The bone marrow depression is constant and predictable.     

Survival after intratumoral interleukin-2 treatment of 72 melanoma patients and response upon the first chemotherapy during follow-up

Systemic high-dose interleukin-2 (IL-2) treatment achieves long-term survival in a subset of advanced patients with melanoma. As we reported previously, intratumoral IL-2 induced complete local responses in more than 60% of melanoma patients. This study aimed to analyze the long-term outcome of 72 patients treated in two prior trials. Melanoma patients (49 stage III, 23 stage IV) with injectable metastases received intratumoral IL-2 injections thrice weekly at individually escalated doses (median duration, 6.5 weeks; median total IL-2 dose, 72 MIU; median number of injected metastases, 10). The observed 2-year overall survival rates were 95.5% for stage III patients with cutaneous metastases only (stage IIIB), 72% for those with combined cutaneous and lymph node involvement (stage IIIC), 66.7% for stage IV patients with disease limited to distant soft-tissue metastases (stage IV M1a), and 9.1% for those with visceral metastases (stage IV M1b and stage IV M1c). Thirty patients who reported recurrence of unresectable distant metastases subsequently received chemotherapy in the further course of disease and showed an overall response rate of 36.7% (16.7% complete responses, 20% partial responses). A high total dose of IL-2 and a dacarbazine/temozolomide-based chemotherapy regimen were variables correlated with a clinical response. In conclusion, patients with cutaneous metastasis without lymph node involvement in stage III and with soft-tissue metastasis without visceral involvement in stage IV showed unexpected favorable survival rates after intratumoral treatment with IL-2. Furthermore, the intratumoral IL-2 treatment seemed to be associated with increased complete and partial responses in subsequent chemotherapies.     

Does vinblastine add to the potency of alpha interferon in the treatment of renal cell carcinoma?

The combination of alpha interferon and vinblastine has been reported to yield a response rate of 30-40% in previously untreated patients with metastatic renal cell carcinoma. This combination was given to nine patients with advanced metastatic renal carcinoma after they failed or relapsed on alpha-interferon alone, to attempt to evaluate the role of vinblastine in this combination. Neither complete nor partial response was observed. Two patients had disease stabilization for two and seven months. Our preliminary results suggest that vinblastine did not add to the efficacy of interferon in this group of patients.     

Second malignancies in Hodgkin's disease: a complication of certain forms of treatment.

A total of 764 patients with Hodgkin''s disease treated with radiotherapy (RT) or chemotherapy or both were reviewed 3-186 months (median 43 months) after initial treatment to assess the incidence of second malignancies. Incidence of solid tumours and acute non-lymphoblastic leukaemia (ANLL) were calculated by a life-table method and percentages of patients affected derived from life-table plots. Within 10 years after initial treatment the overall incidence of second solid tumours was 7.3%, and over a comparable period 2.4% of patients developed ANLL. Solid tumours occurred only in patients given RT with or without adjuvant chemotherapy, and ANLL occurred only after treatment with MOPP (mustine, vincristine, procarbazine, and prednisolone) or modified MOPP regimens. Neither solid tumours nor ANLL occurred in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The highest incidence of leukaemia (5.4%) occurred after treatment with extensive RT plus (5.4%) occurred after treatment with extensive RT plus MOPP; hence the benefits of this approach in Hodgkin''s disease must be weighed against its carcinogenic potential.     

Commentary: assessing the effects of environmental pollution when people know that they have been exposed.

OBJECTIVE: To examine the effectiveness of routine clinic review in detecting relapse after treatment for Hodgkin''s disease. DESIGN: Review of hospital records. SETTING: Regional centre for cancer treatment and research. SUBJECTS: 210 patients with Hodgkin''s disease recruited to a chemotherapy trial protocol between 1984 and the end of 1990 who had achieved a complete or partial remission after treatment. MAIN OUTCOME MEASURES: The number of clinic visits made by patients over the period of observation, the number of relapses occurring during that time, and the route by which relapse was detected. RESULTS: The 210 patients generated 2512 outpatient reviews, and 37 relapses were detected. Thirty relapses (81%) were diagnosed in patients who described symptoms, which in 15 cases had resulted in an earlier appointment being arranged. In only four cases (11%; 95% confidence interval 4% to 25%) was relapse detected as a result of routine physical examination on investigation of a patient who did not have symptoms. CONCLUSIONS: Relapse of Hodgkin''s disease after treatment is usually detected as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients. It is therefore proposed that the frequency of routine follow up visits should be reduced and greater emphasis placed on patient education. This should underline the importance of symptoms and encourage patients to arrange an earlier appointment if these develop.     

Comparison of combined and single-agent chemotherapy in non-Hodgkin's lymphoma of favourable histological type.

Sixty-six untreated patients with advanced non-Hodgkin''s lymphoma of favourable histological type were allocated alternately to initial treatment with cyclophosphamide, vincristine, and prednisolone or with chlorambucil. The complete remission rate was higher in the group receiving combination chemotherapy, but the overall response rate was the same for both groups. The mean duration of complete remission was the same as that of good partial remission, and was the same for both treatments. The duration of remission was influenced by histological type and extent of disease at presentation, but not age. Those who responded to the initial treatment (whether with complete or with good partial remission) survived significantly longer than did non-responders. It is concluded that neither treatment is satisfactory and that new treatment programmes are needed for patients with a favourable prognosis, especially young patients with extensive disease.     

MVPP chemotherapy regimen for advanced Hodgkin's disease

During January 1968 to December 1972, 133 patients with advanced Hodgkin''s disease (HD) were admitted to hospital for combination chemotherapy with mustine, vinblastine, procarbazine, and prednisolone (MVPP regimen). Remission rates were 76% among 49 untreated patients and 90% among 42 patients who had relapsed after radiotherapy. The corresponding five-year survival rates were 65% and 86% respectively. Provided the observed yearly mortality (6%) remains unchanged 75% of patients who had previously received no treatment or irradiation and achieved remission are expected to continue in first remission after five years. Forty-two patients had received prior chemotherapy. They had lower remission and five-year survival rates (40% and 33% respectively), and fewer than half of those achieving remission were still in first remission after five years. There were several reasons for the poor prognosis in this group, including advanced-stage disease (stage IVB), age over 40, and achievement of remission.Chemotherapy was administered on an outpatient basis. Haematological toxicity and immediate drug-related side effects were similar to those of other regimens but there was no appreciable neurotoxicity. Most deaths were due to either HD itself or complications of advanced disease. Five malignancies other than HD occurred in patients who had received both single-agent chemotherapy and radiotherapy before MVPP chemotherapy. Two patients developed osteonecrosis of the femoral heads.Combination chemotherapy has a profound effect on the prognosis of advanced HD. The MVPP regimen yields results comparable to those of other regimens but with perhaps less toxicity.     

Slow infusions of vinblastine in the treatment of adult idiopathic thrombocytopenic purpura: a report on 43 cases

Forty-three adult patients with idiopathic thrombocytopenic purpura (ITP) were treated by slow intravenous infusions of vinblastine. Nineteen had ITP of recent onset (i.e. of less than 6 months duration) and had contraindication to steroids (3 patients), refractoriness to steroids (6 patients) or to steroids and high dose intravenous immunoglobulins (IVIg, 10 patients). Of the 19 patients, 10 achieved complete response (CR), 2 achieved partial response (PR), 2 had minor response (MR) and the remaining 5 patients had no response (NR). Six of the complete responders remained in CR after 12 to 48 months, whereas all other responders relapsed within 3 months, in spite of maintenance therapy. Twenty-four patients had chronic ITP (i.e. of 6 months duration or more) and had showed no or only transient response to steroids and/or splenectomy, and in many of them, to other therapeutic approaches. Four achieved CR, 4 PR, 6 MR and 10 NR. All but 3 responses were shorter than 3 months, in spite of maintenance therapy. Most responses to slow infusions of vinblastine began after the first infusion. Main side effects included leukopenia in 9 patients (but with absolute neutropenia in only one) and peripheral neuropathy in 2 patients. Interval from diagnosis was the only prognostic factor of response to treatment. We conclude that slow infusions of vinblastine may be a useful approach in ITP of recent onset, when contraindication or refractoriness to steroids and/or IVIg exists. In our experience, this treatment has limited benefit in chronic ITP. In addition, it remains to be demonstrated that slow infusions of vinca alkaloids have any superiority over intravenous bolus injections of the same drugs.     

NEWER THERAPY FOR LEUKEMIA,POLYCYTHEMIA, AND LYMPHOMA

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin''s disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

Cancer of the Bladder in Patients Treated with Chlornaphazine

Two patients treated for Hodgkin''s disease with chlornaphazine developed cancer of the bladder five and six years after treatment with the drug had been stopped.     

Psychological problems associated with diagnosis and treatment of lymphomas. I: Retrospective study.

Patients treated for Hodgkin''s disease and non-Hodgkin''s lymphoma have a better prognosis than other patients with cancer so may have a lower prevalence of psychological and social morbidity. Trained interviewers used standardised methods to assess 90 patients at a mean of 32 months after the diagnosis of Hodgkin''s disease or non-Hodgkin''s lymphoma. Chemotherapy and radiotherapy had commonly caused adverse effects including hair loss, vomiting, nausea, and loss of appetite. Although most patients were free of disease and not receiving treatment at follow up, some still suffered from a lack of energy (31 patients), loss of libido (19), irritability (22), and tiredness (19); 30 patients complained of continued impairment of thinking or disturbance of short term memory. After diagnosis 21 patients had suffered from an anxiety state or depressive illness, or both, while 27 had experienced borderline anxiety or depression, or both. Mood disturbance was positively correlated with adverse effects of treatment, particularly those affecting the gastrointestinal tract. Social adjustment was less affected, but failure to return to work, or a long delay in returning to work, and a persistent lack of interest in leisure activities gave cause for concern. These findings of substantial psychiatric and social morbidity in patients with Hodgkin''s disease and non-Hodgkin''s lymphoma prompted a prospective study of these patients to determine their nature and duration.     

Prednisone in MOPP chemotherapy for Hodgkin's disease.

High remission rates have been produced by MOPP (mustine, vincristine, procarbazine, and prednisone) chemotherapy in patients with advanced Hodgkin''s disease, but the prednisone component has caused adverse effects in patients who have undergone radiotherapy. The remission rates and length of remission were reviewed in 211 patients with Hodgkin''s disease who received chemotherapy either with or without prednisone. In contrast to the findings of a British study, there were no significant differences in remission rates or length of remission between patients who had received prednisone and patients who had not. There were differences between the British prospective study and this retrospective one, but it is difficult to know what accounted for the substantial differences in the findings.     

Decreased tuftsin concentrations in patients who have undergone splenectomy.

Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin''s disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin''s disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin''s disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin''s disease should perhaps be reconsidered.     

Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation.

OBJECTIVE--To analyse the risk of second primary cancers during long term follow up of patients with Hodgkin''s disease. DESIGN--Cohort study. SETTING--The British National Lymphoma Investigation (a collaborative group of over 60 participating centres in Britain treating lymphomas). PATIENTS--2846 patients first treated for Hodgkin''s disease during 1970-87, for whom follow up was complete in 99.8%. MAIN OUTCOME MEASURES--Second primary cancers; uniform pathology reviews confirmed the diagnosis of Hodgkin''s disease and of second primary non-Hodgkin''s lymphomas. RESULTS--113 second primary cancers occurred. Relative risk of cancer other than Hodgkin''s disease was 2.7 (95% confidence interval 2.3 to 3.3) compared with the general population, with significant risk of leukaemia (16.0(9.1 to 26.0)); non-Hodgkin''s lymphoma (16.8(9.8 to 26.9)); and cancers of the colon (3.2 (1.4 to 6.2)), lung (3.8 (2.6 to 5.4)), bone (15.1 (1.8 to 54.7)), and thyroid (9.4 (1.1 to 33.9)). Absolute excess risk associated with treatment was greater for solid tumours than for leukaemia and lymphomas. Relative risk of leukaemia increased soon after treatment, reaching a peak after five to nine years. It was increased substantially after chemotherapy (27.9 (12.7 to 52.9)), combined treatment with radiotherapy and chemotherapy (21.5 (7.9 to 46.8)), and relative to number of courses of chemotherapy but was not significantly increased after radiotherapy (2.5 (0.1 to 14.1)). Relative risk of non-Hodgkin''s lymphoma increased in the first five years after treatment and remained high but showed no clear relation with type or extent of treatment. Relative risk of solid tumours was less raised initially but increased throughout follow up and for lung cancer 10 years or more after entry was 8.3 (4.0 to 15.3). The risk of solid tumours increased after treatments including radiotherapy and after chemotherapy alone. The risk after chemotherapy increased significantly with time since first treatment. CONCLUSION--The risk of solid cancer, not of leukaemia, is the major long term hazard of treatment for Hodgkin''s disease, and this seemed to apply after chemotherapy as well as after radiotherapy. These risks of second cancers are important in choice of treatment and in follow up of patients, but they are small compared with the great improvements in survival which have been brought about by modern therapeutic methods for Hodgkin''s disease.