J. S. Malpas

Follicular lymphoma: prognostic factors for response and survival.

One hundred forty-eight patients with newly diagnosed follicular lymphoma were treated over a 12-year period. Twenty-two patients received radiotherapy for stage I and II disease, followed by adjuvant chemotherapy in 14 patients. One hundred thirteen were treated at presentation with short courses of chemotherapy, most often with single-agent chlorambucil for bulky stage II and stages III and IV disease. Thirteen patients were managed expectantly until there was evidence of disease progression. The median survival was 9 years. Patients treated with radiotherapy for stage I and II disease had an 83% relapse-free survival, but those with bulky stage II or stages III and IV disease treated with chemotherapy pursued a remitting and relapsing course with a 70% response rate at initial and subsequent retreatments, but a median duration of remission of 4 years in stage III and 1 year in stage IV disease (P = .041). Patients were observed in relapse and retreatment was administered as appropriate, once every 33 months on average. Poor prognosis patients could be identified by a combination of the presentation characteristics: B symptoms, hepatosplenomegaly, anemia, and abnormal liver function. These factors predicted a poor response to treatment and correlated with a short survival. Histologic subgroups were not associated with differences in survival, but transformation to a diffuse high-grade lymphoma was observed in 23 of the 72 patients (32%) at risk, with a median follow-up of 6 years and 6 months, and was associated with a very poor prognosis. The present treatment strategy has proved successful for most patients with localized disease and those older patients with indolent small volume disseminated follicular lymphoma. New approaches are being investigated for the younger poor prognosis patients.

Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials.

PURPOSE A meta-analysis was performed to compare survival after treatment with melphalan and prednisolone (M + P) with that after combination chemotherapy (CCT) in patients with multiple myeloma. METHODS Meta-analysis was performed on 18 published trials comprising 3,814 patients comparing M + P with CCT. Two-year survival percentages with observed and expected deaths at 2 years were calculated for each trial, and the overview methodology was applied to these figures. RESULTS Overall results from the 18 trials suggest that there is no difference in efficacy between the two treatments. This finding, however, masks a highly significant correlation between 2-year survival rates for M + P-treated patients in individual studies and the difference between the M + P and CCT 2-year survival rates for that study (r = .69; P = .0008). In separate overviews, those studies with a high M + P 2-year survival rate showed a survival difference in favor of M + P (P = .02), whereas those with a low rate suggested a difference in favor of CCT (P V .07). Comparison of the 2-year survival rates in the M + P treatment arms of each of the studies with available data showed an inverse correlation between survival and the proportion of patients with either poor performance status (P less than .001) or immunoglobulin A (IgA) M band (P = .02). CONCLUSIONS These results imply that M + P is superior for patients with an intrinsically good prognosis and inferior for those patients with a poor prognosis. If reliable prognostic factors can be established for this disease, they could be used to select therapy for individual patients.

Failure to preserve fertility in patients with Hodgkin's disease

SummaryThe hypothesis that the “down-regulated” gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkins disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 μg) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At followup assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserlin was ineffective in conserving fertility.

Multiple myeloma treated with high dose intravenous melphalan

High dose melphalan (HDM, 140 mg/m2 i.v.) has been evaluated in 58 patients under 63 years with multiple myeloma. Among previously untreated patients 11/41 (27%) entered a complete remission (CR: no measurable myeloma protein and a normal bone marrow) and 21 (51%) entered a partial remission (more than 50% reduction in myeloma protein and improvement in all other features). Median duration of remission is 19 months. Two patients who had responded to previous conventional treatment entered CR after HDM. Among 15 patients who had failed on previous chemotherapy the response rate was 66% including two CRs. However, in this group all patients have relapsed within 1 year. Profound myelosuppression, moderate nausea, vomiting, mucositis and diarrhoea with reversible alopecia occurred in all patients. There were 10 deaths within 2 months of treatment mainly due to sepsis and haemorrhage.

High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma.

PURPOSE We report the results of intensive chemotherapy with high-dose melphalan (HDM) following conventional-dose cytoreductive chemotherapy in previously untreated patients with myeloma. PATIENTS AND METHODS From 1986 to 1991, 53 previously untreated patients with myeloma received HDM 200 mg/m2 plus methylprednisolone 1.5 g daily (MP) for 5 days with autologous bone marrow transplantation (ABMT) after cytoreductive chemotherapy. RESULTS At the time of HDM administration, responses to induction therapy were complete remission (CR) in nine patients, partial remission (PR) in 38, and no response (NR) in six. Following HDM, all but one patient responded, with 40 patients achieving a CR (75%). There was one treatment-related death following HDM. The median time to reach a WBC count more than 1,000/microL and platelet count more than 25,000/microL was 19 days (range, 13 to 30) and 24 days (range, 15 to 55), respectively. The median duration of response has not been reached at 20 months, and it is significantly longer for patients in CR than for those in PR (P < .025). Currently, with a median follow-up duration of 31 months (range, 6 to 58), 12 patients are dead and 40 are alive, and the estimated probability of survival at 54 months is 63%. Multivariate analysis found hemoglobin (Hb) more than 10 g/dL (P = .012), and stage A disease (P = .001) at diagnosis to be favorable indicators for survival. CONCLUSION Myeloma patients who are able to receive HDM plus ABMT following conventional chemotherapy achieve a high proportion of CRs, which may be associated with prolonged survival.

A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma : long-term follow-up results

High‐dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high‐dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 × 106 units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high‐dose chemotherapy (melphalan 140–200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression‐free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow‐up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu‐like symptoms and malaise which were usually self‐limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multi‐centre studies in the setting of minimal residual disease following autologous transplantation.

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

Sixty-six untreated patients with advanced non-Hodgkins 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.

Solitary plasmacytoma. I: Extramedullary soft tissue plasmacytoma

The details of 16 patients with extramedullary plasmacytoma are presented. All but one presented with localized disease, and all were treated successfully by radiotherapy. Only one patient developed local recurrence and only one has developed disseminated disease. Radiotherapy is recommended as the primary treatment of choice for these localized radiosensitive tumors. It is suggested that the good prognosis of plasmacytomas of the head and neck, in contrast to plasmacytomas arising at other sites, is related to the observation that a high proportion of these tumors are localized at the time of diagnosis and that very large primary tumors are uncommon.

MVPP chemotherapy regimen for advanced Hodgkin's disease

During January 1968 to December 1972, 133 patients with advanced Hodgkins 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.

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkins 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 Hodgkins disease is strongly recommended.