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.     

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.     

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.     

Duration of second remission of Hodgkin's disease in children. Results of treatment achieved by the Polish Leukemia and Malignant Lymphoma Therapy in Children Group]

Recurrence was noted in 18.5% of 194 children, in which chemotherapy with MVPP regimen produced complete I remission. In 6 out of 36 children with recurrent disease MVPP regimen was repeated, while the remaining children were treated with B-DOPA alone or combined with MOPP regimen. Local radiotherapy was used in 17 children. The second complete remission was achieved in 30 (83.7%) children. Thirteen out of 36 patients died because of the progress of the disease (11 children), and for complications (2 children). Percentage of persisting 5- and 10-year II remissions are 58.2% and 54.6%, respectively. A 5- and 10-year survival rates in children with recurrent disease are 80.5% and 60.5%, respectively. Our relatively favourable results we associate--first of all--with the chemotherapy intensity.     

A Comparison of Nitrogen Mustard and Vinblastine Sulfate in the Treatment of Patients with Hodgkin's Disease

In a crossover study the effectiveness of intermittent maintenance doses of nitrogen mustard was compared to that of vinblastine sulfate in the treatment of 61 patients with advanced Hodgkin''s disease. Forty-five of the patients had had previous radiation therapy. Nine of 29 patients who received nitrogen mustard as the first drug had a complete response and five had a partial response. The comparative results in 32 patients receiving vinblastine sulfate first were nine complete responses and 13 partial responses. The median duration of the complete responses to each drug was 43 weeks. The partial responses were of shorter duration. When the second drug was given in adequate doses, almost as many patients responded with a similar median duration of response.It is concluded that nitrogen mustard and vinblastine sulfate are equally effective single agents in the treatment of patients with advanced Hodgkin''s disease and that patient preference would favour vinblastine sulfate because of its negligible side effects.     

Improved combination chemotherapy in advanced gastric cancer.

Thirty-five patients with advanced-stage metastatic or unresectable gastric adenocarcinoma were given combination chemotherapy consisting of fluorouracil, doxorubicin, and 1,3-bis (2-chlorbethyl)-1-nitrosourea. Two patients achieved complete remission and 16 partial remission to give an overall response rate of 52%. Six further patients (17%) had stable disease, while in 11 (31%) the disease showed clear-cut progression despite treatment. The only pretreatment factors that suggested poor prognosis were poor initial patient performance and the stomach as the predominant site of disease. Patients responding to treatment had a significantly longer time to relapse (median 48 weeks) than patients with stable disease (median 16 weeks) and a significantly improved survival time (medians, 52 weeks with 30% of patients'' living at 88 weeks and 32 weeks with all dead at 64 weeks respectively). Comparing these results with those in other reports indicated that the three-drug combination chemotherapy consisting of fluorouracil, doxorubicin, and either a nitrosourea or mitomycin was superior to single and two-drug regimens and currently represents the optimum treatment for advanced-stage gastric cancer. Gastric adenocarcinoma should now be considered to be a gastrointestinal malignancy that is relatively susceptible to chemotherapy, and studies of these improved chemotherapeutic regimens as post-surgical adjuvants may lead to further improvements in prognosis.     

Proposed regimens for chemotherapy and radiotherapy to control preliminary failures of combined therapy in Hodgkin's disease

Both regimens concern children who underwent--depending on the stage of the disease--three different therapeutical regimens: B-DOPA and/or MVPP combined with radiotherapy. Depending on the results of this treatment, each out of four saving regimens includes two types of chemotherapy: B-DOPA/CAD, MVPP/CAD, MOP-P/ABV/CAD, and MVPP/B-DOPA in case of delayed recurrence. Each cycle of chemotherapy should be introduced with high frequency. Doses of irradiation being additional method and indicated in some patients are given.     

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.     

CELL KINETIC ALTERATIONS IN NORMAL AND NEOPLASTIC CELL POPULATIONS IN VITRO AND IN VIVO FOLLOWING VINCRISTINE*. A REPLY TO DR CAMPLEJOHN'S REVIEW ARTICLE†

It is shown that the lethal action of vincristine (VCR) is dose-dependent and may occur at interphase and mitosis. In general, the VCR dose used to destroy cells must be approximately ten times higher than that used to arrest cells in mitosis at metaphase. There is strong evidence that cells can survive metaphase arrest by a sublethal dose of VCR either completing cytokinesis normally after metabolism of the drug or becoming polyploid because of an impaired mitotic spindle apparatus. These cells are not doomed to die, at least in some cell systems. Furthermore, there is strong evidence in three animal tumour systems (transplantable and autochthonous tumours) that VCR is able to induce in vivo partial synchronization of proliferating tumour cells and/or recruitment of resting cells into the proliferating compartment. Failures to induce partial synchrony in cell populations by VCR may be attributed to resistance to VCR or cytolysis or slow proliferation of cells in badly vascularized tumours. Chemotherapy after synchronization seems to be effective as shown by non-randomized trials in bad-risk patients with solid tumours and acute leukaemias. In a randomized co-operative trial results of the two-drug synchronization protocol in patients with non-Hodgkin's lymphoma of high grade malignancy were statistically better than those of a four-drug protocol (COPP) established empirically. The two-drug protocol was equally effective as the four-drug protocol in Hodgkin's disease. Side-effects were less pronounced with the so-called synchronization scheme.     

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.     

Long-term follow-up after relapses in children with Hodgkin's disease

In the years 1969-1980, 68 children with Hodgkin's disease were subjected to a combined MVPP and radiotherapy. Remissions were obtained in 64 patients, and relapses occurred in 11 children. The treatment of relapse consisted in administration of B-DOPA alone or alternatively with MVPP combined with radiotherapy (in 7 out of 11 patients). The patients were recycled every 2-3 weeks which, with other modifications of chemotherapy, allowed for the completion of the six first cycles within the period of 4,5 to 7 months. A relapse caused death of one child, and two others demonstrated further relapses. At present eight children have been showing disease-free survival following a relapse for the period of 29+ to 152+ (median, 94.5 months). The authors concluded that in patients with relapses of Hodgkin's disease the decisive role rests upon aggressive chemotherapy (high frequency of cycles).     

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.     

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical outcome at one year.

A study was conducted to investigate a novel approach to the prophylaxis of schizophrenic relapse. The treatment strategy comprised brief intermittent courses of neuroleptic agents begun as soon as non-psychotic symptoms believed to be early signs of relapse appeared. Fifty four stable, remitted outpatients meeting the American Psychiatric Association''s DSM-III criteria for schizophrenia were randomised double blind to receive brief intermittent treatment with either active or placebo depot neuroleptic injections. Only three patients given placebo injections and two controls were admitted to hospital during one year of follow up. Eight (30%) of the patients given placebo injections and only 2 (7%) of the controls, however, had a recurrence of schizophrenic symptoms. Patients given placebo injections experienced fewer extrapyramidal side effects and showed a trend towards a reduction in tardive dyskinesia. Dysphoric and neurotic symptoms were identified before eight out of 11 relapses, and these symptoms were more frequent in patients given placebo depot injections. These results suggest a viable but not necessarily better alternative to continuous oral or depot treatment for less ill, chronic, stabilised schizophrenics based on the early treatment of putative prodromal symptoms of relapse.     

Bacille Calmette-Guérin as maintenance therapy for non-Hodgkin's lymphoma.

Following complete remission of non-Hodgkin''s lymphoma by chemotherapy, irradiation or both, 44 patients were studied to assess the value of bacille Calmette-Guérin (BCG) as maintenance therapy. Patients with stage LI, EI or EII disease were allocated at random to receive BCG or no further maintenance therapy, and those with stage LII, LIII, EIII or IV disease received BCG therapy or orally administered cyclophosphamide. BCG had no effect on the duration of remission or the overall survival from the time of randomization. However, after the first recurrence there was a significant improvement in survival in the patients who had received BCG maintenance therapy.     

Relapse rate and long-term management of plaque psoriasis after treatment with photochemotherapy and dithranol.

The relapse rate of plaque psoriasis after initial clearing with the "Ingram" dithranol regimen or photochemotherapy was comparable when no maintenance treatment was given. It was estimated that psoriasis recurs to half of its pretreatment extent after about six months in half the patients. Maintenance treatment with photochemotherapy once a week or once every three weeks was useful in reducing the relapse rate. This study failed to show any statistical difference in relapse rates between these two maintenance schedules. If this finding turns out to be true over longer periods of study the maintenance schedule entailing treatment once every three weeks with its lower cumulative dose of long-wave ultraviolet light will clearly be preferable. The psoriasis in most patients was under better overall control with maintenance treatment than with intermittant clearing courses given when the extent of the psoriasis had become unacceptable to them. There was, however, a group of roughly one-fifth of patients who remained in satisfactory remission for over 16 months after initial clearing. Regular maintenance treatment was unnecessary in them. Much more information is needed on response to treatment in subgroups of patients to permit recognition from the start of which patients are likely to have long remission and which are not.     

Preliminary clinical evaluation of systemic chemotherapy of invasive cancer of the bladder by the CMV protocol]

The authors discuss the results of preliminary clinical trials with chemotherapy with CMV (cisplatin, methotrexate, vinblastine) in the group of 17 patients with the infiltrating cancer of the bladder. Chemotherapy was used as an element of the radical treatment (in 7 patients, i.e. 41.2%) or as ++palliative treatment (in 10 patients, i.e. 58.8%). Objective response to the treatment was noted in 73.3% of the treated patients, including 13.3% of the complete recovery, and 60.0% of partial improvement. In the remaining 26.7% of patients (including all patients with distant metastases) no response to therapy was achieved. Complications of therapy are discussed. Systemic chemotherapy with CMV regimen proved efficient in the infiltrating cancer of the bladder.     

Treatment of acute lymphoblastic leukaemia: effect of variation in length of treatment on duration of remission. Report to the Medical Research Council by the Working Party on Leukaemia in Childhood.

Patients with acute lymphoblastic leukaemia (ALL) were allocated at random either to stop maintenance chemotherapy after six 12-week courses or continue with a further six. The main difference between the two groups was in the incidence of bone-marrow relapse within nine months after stopping treatment. Such relapses occurred less in older patients and those with higher leucocyte counts initially than in those who appeared to have the best prognosis--namely, those with typical low-count childhood ALL. No patient given prophylactic irradiation to cranium and spine combined with intrathecal methotrexate suffered meningeal relapses, whereas among those not given such prophylaxis the lack of benefit from continuing treatment was mainly attributable to meningeal relapses.     

Optimal therapy for adults with langerhans cell histiocytosis bone lesions

Background

There is little data on treatment of Langerhans cell histiocytosis (LCH) in adults. Available data is on small numbers of patients with short follow-up times and no comparison of results from different treatment regimens. We analyzed the responses of adult LCH patients with bone lesions to three primary chemotherapy treatments to define the optimal one.

Methods and Findings

Fifty-eight adult patients with bone lesions, either as a solitary site or as a component of multisystem disease, were analyzed for disease location and response to surgery, curettage, steroids, radiation, vinblastine/prednisone, 2-Chlorodeoxyadenosine (2-CdA), or cytosine arabinoside (ARA-C). The mean age of patients was 32 years, with equal gender distribution. Twenty-nine patients had 1 lesion; 16, 2 lesions; 5, 3 lesions; and 8 had 4 or more. Most bone lesions were in the skull, spine, or jaw. Chemotherapy, surgery, curettage, or radiation, but not steroids alone, achieved improvement or resolution of lesions in a majority of patients. Comparison of the three chemotherapy regimens revealed 84% of patients treated with vinblastine/prednisone either did not respond or relapsed within a year, whereas 59% of patients treated with 2-CdA and 21% treated with ARA-C failed. Toxicity was worse with the vinblastine/prednisone group as 75% had grade 3–4 neuropathy. Grade 3–4 cytopenias occurred in 37% of the 2-CdA -treated patients and 20% of the ARA-C-treated patients. The major limitation of this study is it is retrospective and not a clinical trial.

Conclusions

ARA-C is an effective and minimally toxic treatment for LCH bone lesions in adults. In contrast, vinblastine/prednisone results in poor overall responses and excessive toxicity.     

Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Summary Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achivement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

Management of Adult Acute Myelogenous Leukaemia

Consecutive adult patients admitted to St. Bartholomew''s Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well.A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials.