M. A. Richards

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.

The relationship between c-erbB-2 expression, S-phase fraction and prognosis in breast cancer

The relationship between c-erbB-2 gene expression (assessed immunohistochemically), S-phase fraction (SPF) and prognosis has been analysed in 172 women with primary breast cancer. c-erbB-2 staining was independent of age, tumour size, number of nodes involved, tumour grade and DNA ploidy, but was more common in oestrogen receptor (ER) negative tumours (P = 0.02) and progesterone receptor (PgR) negative tumours (P = 0.03). A weak correlation between c-erbB-2 staining and SPF was observed (r = 0.18). Amongst women with node negative disease, SPF was significantly related to relapse free survival (RFS, P = 0.04) while c-erbB-2 staining was not (P = 0.2). In contrast, both SPF (P = 0.002) and c-erbB-2 staining (P = 0.016) provided significant prognostic information on RFS for women with node positive disease. Multivariate analysis showed that c-erbB-2 staining and SPF gave independent information on RFS for women with node positive disease.

The effects of chemotherapy on morphology, cellular proliferation, apoptosis and oncoprotein expression in primary breast carcinoma

The use of chemotherapy as a form of primary treatment for breast cancer is increasing and, as a result, more resection specimens contain tumours which have been exposed to cytotoxic drugs. We have studied the effects of chemotherapy on the tumour morphology and various biological features of breast carcinoma in a group of 35 patients. These were a group who responded to treatment in a clinical study of the use of primary chemotherapy designed to reduce tumour bulk prior to surgery. Characteristic morphological changes, temporally related to the administration of cytotoxic agents, are seen. The malignant cells become enlarged with vacuolated cytoplasm and vesicular nuclei containing prominent nuclei; occasionally the nuclei were angular and hyperchromatic. These features are interpreted as degenerative in nature. In 15 cases sufficient material was present in the pretreatment biopsies to compare the grade of the tumours before and after chemotherapy: changes were found in six tumours. Cytotoxic drugs do not induce a consistent pattern of change in the proliferation and apoptotic indices of individual tumours, but there is a tendency to reduce proliferative activity over all the tumours as a group. It was also found that chemotherapy is capable of modifying the expression of the oncoproteins c-erbB-2 and p53 in a minority of cases of breast cancer, usually resulting in an acquisition of immunoreactive oncoprotein. It is important to be aware of these effects when studying breast carcinomas removed after chemotherapy.

Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry.

Adjuvant systemic therapy for women with node-negative breast cancer is most easily justified for those patients at highest risk of relapse. We have examined the impact of tumor size, histologic grade, estrogen receptor (ER) status, tumor ploidy, and S-phase fraction (SPF) on relapse-free survival (RFS) for 169 patients with node-negative breast cancer in order to identify groups of patients at high and low risk of relapse. Patients with small tumors (less than or equal to 1.0 cm) had a significantly better RFS than those with larger tumors (P = .005), with 96% remaining relapse-free at 5 years. Patients with tumors less than or equal to 1.0 cm were thus excluded from analysis when attempting to define a group with a poor prognosis. Within the group of patients with tumors greater than 1.0 cm, tumor ploidy (P = .63), ER status (P = .3), or progesterone receptor (PgR) status (P = .24) did not predict for RFS. Patients with grade 1 or 2 infiltrating ductal tumors had a significantly better prognosis than those with grade 3 tumors (P = .04). The prognostic factor that gave the widest separation between subgroups, however, was SPF. Patients whose tumors were greater than 1.0 cm with an SPF less than or equal to 10% had a 5-year RFS of 78% compared with a 5-year RFS of 52% for those with an SPF greater than 10% (P = .006). We have combined tumor size and SPF to identify three prognostic groups: (1) tumor less than or equal to 1.0 cm, 5-year RFS 96%; (2) tumor greater than 1.0 cm plus SPF less than or equal to 10%, 5-year RFS 78%; 3) tumor greater than 1.0 cm plus SPF greater than 10%, 5-year RFS 52%. These prognostic groupings may help identify patients most suitable for adjuvant therapy.

Spinal cord compression in breast cancer: a review of 70 cases

Spinal cord compression (SCC) is a relatively uncommon but frequently disabling complication of metastatic breast cancer. We have conducted this retrospective study of 70 patients with SCC secondary to breast cancer with the aims of determining risk factors for its development and predictors of outcome. Median age at diagnosis of breast cancer was 51 years with median time to SCC 42 months. All patients had radiological evidence of bone metastases at the time of SCC, and only five were not known to have bone metastases prior to SCC. The most frequent symptom of SCC was motor weakness (96%) followed by pain (94%), sensory disturbance (79%) and sphincter disturbance (61%). Ninety-one percent of patients had at least one symptom for more than a week. Radiotherapy (RT) was given as primary treatment in 43 cases, whilst 21 had decompressive surgery and seven of these went onto have postoperative radiotherapy. Six patients were deemed too unwell for either modality. Following treatment, 96% of those who were ambulant before therapy maintained the ability to walk. In those unable to walk, 45% regained ambulation, with RT and surgery being equally effective. Median survival following SCC was 4 months, with no significant difference between those treated by RT or surgery. The most important predictor of survival was ability to walk after treatment, followed by time from diagnosis of breast cancer to SCC. We conclude that the majority of patients have warning symptoms of SCC and that nearly all will have evidence of spinal bone metastases before compression occurs. The results suggest that earlier diagnosis and intervention could improve outcome. There was no evidence of benefit from surgery over radiotherapy as primary treatment, survival in both treatment groups being poor.

Chemotherapy of advanced breast cancer: outcome and prognostic factors.

The outcome for 758 consecutive patients who had received one or more chemotherapy regimens for recurrent or metastatic breast cancer is presented. The response rate following first line treatment was 34%. Median duration of response was 7.8 months, median time to progression was 3.7 months and median survival was 7.9 months. The only factor predicting for response, of factors recorded at presentation and at initiation of chemotherapy, was the use of anthracycline based regimens, though this may reflect the patient selection policy. Initial disease free interval, presence of liver metastases and use of anthracyclines were significantly related to time to progression. Several factors related to survival following first chemotherapy, but anthracycline usage showed only a very weak correlation. One third of patients (249/758) received two or more chemotherapy regimens. The response rate (16%) and median time to progression (2.3 months) were significantly worse than for first line treatment. The outcome after third line chemotherapy was very similar to that observed following second line treatment. Achievement of an objective response with first line chemotherapy predicted for second response, but with insufficient power to be of use in selecting patients for subsequent chemotherapy. Time to progression following first line chemotherapy did not influence that after second line treatment.

The prognostic significance of DNA flow cytometry in breast cancer: results from 881 patients treated in a single centre

In this single-centre study of 881 patients, S-phase fraction (SPF) was shown to be a significant prognostic marker in terms of overall survival (OS), relapse-free survival (RFS) and survival after relapse (SAR). Further, SPF had independent prognostic significance when considering a range of other clinicopathological variables, namely tumour grade and stage, nodal status, patient age, tumour size, menstrual status and treatment details. For OS and RFS, SPF was the second strongest predictor of the clinical course of the disease after nodal status, and for SAR it was the strongest prognostic marker. SPF correlated positively with histological grade but was the stronger predictor of survival. The distribution of SPF values was markedly different for the two ploidy classes of tumour, with DNA aneuploid tumours having a significantly higher average SPF. However, SPF retained its independent prognostic ability when DNA diploid and aneuploid tumours were analysed separately, DNA ploidy itself also proved to be an independent prognostic marker but the survival difference between the two ploidy classes was much less than that seen for different levels of SPF. Tumours with several DNA aneuploid populations (multiploid tumours) tended to have a worse prognosis than other aneuploid tumours but this trend did not reach statistical significance. In this and other studies from this centre, SPF has proved to be a robust predictor of clinical outcome in carcinoma of the breast.

Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests

The influence of liver biochemistry tests on epirubicin pharmacokinetics has been investigated in 52 women with advanced breast cancer, 27 of whom had radiologically proven liver metastases. Patients received epirubicin 12.5-120 mg m-2 given as an i.v. bolus. Epirubicin levels were measured by HPLC following the first cycle of treatment. Epirubicin elimination, expressed as clearance (dose/AUC), in the 22 patients with normal AST and bilirubin was compared with that of 30 patients with a raised AST +/- raised bilirubin. Epirubicin clearance was significantly reduced in the patients with a raised AST, whether their serum bilirubin was normal (22 patients) or elevated (eight patients). In the 30 patients with a raised AST +/- raised bilirubin, epirubicin clearance correlated strongly with the level of AST (r = -0.72) but not with serum bilirubin, alkaline phosphatase, albumin or creatinine. Using a multiple regression analysis, AST was the only one of these biochemical variables predictive of epirubicin clearance (r2 = 0.47, P = 0.0006). We conclude that a raised serum AST is a more sensitive and reliable measure of abnormal epirubicin pharmacokinetics than increased bilirubin. These findings have implications for anthracycline treatment in patients with abnormal liver biochemistry.

Chlorambucil and interferon for low grade non-Hodgkin's lymphoma

Despite responsiveness to both chemotherapy and radiation therapy, most patients with low grade non-Hodgkins lymphoma (NHL) die as a consequence of the disease. Chlorambucil (CB) alone yields responses in approximately seventy-five percent of patients with a median duration of first remission of one to two years. However, although subsequent remissions can often be achieved, the characteristic continuous relapse pattern results in a median survival of between five and ten years (Jones et al., 1973; Young et al., 1977; Lister et al., 1978; Rudders et al., 1979; Hoppe et al., 1981; Anderson et al., 1982; Gallagher et al., 1986). It has been demonstrated that administration of leucocyte or recombinant DNA interferon causes regression of disease in approximately forty per cent of patients with low grade lymphoma (Merigan et al., 1978; Louie et al., 1981; Ozer et al., 1983; Horning et al., 1985; Wagstaff et al., 1986). Combinations of interferon with conventional cytotoxic agents have been investigated in murine models of leukaemia and lymphoma (Chirigos & Peason, 1973; Gresser et al., 1978; Slater et al., 1981; Tozawa et al., 1982; Mowshowitz et al., 1982); longer survival was observed in animals receiving the combination than in those receiving either drug alone. On the basis of these observations it was decided to investigate the concurrent administration of CB and interferon (IFN-a2) in previously treated patients with low grade NHL. Twenty-three patients (median age 52 years, range 28-70) with recurrent, low grade NHL (11 follicular, 6 centrocytic, 4 lymphoplasmacytoid, I peripheral T cell) and 1 patient with chronic lymphocytic leukaemia received CB and IFN-ac2 as shown in Figure 1. All, except one patient with follicular lymphoma had bone marrow infiltration at the time of treatment.