Alkylator resistance in human B lymphoid cell lines: (1). Melphalan accumulation, cytotoxicity, interstrand-DNA-crosslinks, cell cycle analysis, and glutathione content in the melphalan-sensitive B-lymphocytic cell line (WIL2) and in the melphalan-resistant B-CLL cell line (WSU-CLL).

Two human B lymphoid cell lines WIL2 (melphalan sensitive. ***IC50:8.57 +/- 1.08 mM) and WSU-CLL (melphalan resistant, ***IC50:223.18 +/- 6.45 mM) were used as models to study alkylator resistance in human lymphoid cells. Melphalan transport studies demonstrated decreased initial melphalan accumulation in WSU-CLL cells as compared to WIL2 cells. Lineweaver-Burk plots of the rate of initial melphalan uptake showed an approximately 3.5-fold decrease of Vmax in WSU-CLL cells as compared to WIL2 cells. Melphalan transport was inhibited by 2-amino-bicyclo[2,2,1] heptane-2-carboxylic acid(BCH) in both cell lines, indicating that the amino acid transport (System L, which is sodium independent and inhibited by BCH) is functional in these two cell lines. Only a minor degree of inhibition of melphalan transport was noted after sodium depletion (System ASC, which is sodium dependent and unaffected by BCH). Interstrand-DNA-cross-link formation showed a highly significant correlation with in-vitro cytotoxicity in both two cell lines. However, the melphalan concentration at which such interstrand DNA cross-linking occurred differed significantly when WIL2 cells and WSU-CLL cells were compared. The kinetics of interstrand-DNA-cross-link formation and removal following treatment with melphalan also differed significantly, with WSU-CLL cells, showing a much more rapid rate of removal of interstand DNA cross-links as compared to WIL2 cells. Cell cycle analysis showed that melphalan treatment resulted in the progressive arrest of the WSU cells in G1 and G2 phases. But WIL2 cells failed to enter G1 or G2 arrest after melphalan treatment, suggesting an increased rate of DNA repair occurring in melphalan-resistant WSU-CLL cells. There was no significant difference between the two cell lines in regard to either glutathione content or glutathione-S transferase activity. These findings indicate that multiple factors are associated with alkylator resistance in lymphoid cells including alteration of uptake, DNA repair and cell cycle progression. However no evidence for alteration in glutathione content and glutathione-S-transferase activity was found.

Alkylator resistance in human B lymphoid cell lines: (2). Increased levels of topoisomerase II expression and function in a melphalan-resistant B-CLL cell line.

Previous studies have demonstrated alkylating (melphalan) resistance in the B-CLL derived WSU-CLL cell line as compared to WIL2 B lymphocytic cells. Nuclear extracts from WSU-CLL cells demonstrate a highly significant increase in DNA topoisomerase II activity as compared to WIL2 cells. Western blot analysis showed the level of topoisomerase II proteins expressed in WSU-CLL cells to be increased as compared to WIL2 cells. WSU-CLL cells were 5.24-fold more sensitive than WIL2 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. No difference in topoisomerase I activity or of the level of topoisomerase I protein expression was observed comparing the two cell lines. The sensitivity to the cytotoxic effects of topoisomerase I inhibitor, camptothecin, did not differ in WSU-CLL and WIL2 cell lines. Pre-incubation with doxorubicin significantly increased melphalan induced interstrand-DNA-crosslink formation and cytotoxicity in WSU-CLL cells as compared to WIL2 cells. The affinity of topoisomerase II for WSU-CLL UV-irradiated-crosslinked DNA was increased 2.84-fold as compared to that of WSU-CLL native DNA. The affinity of topoisomerase II for both UV-irradiated (crosslinked) and for native DNA was significantly decreased after doxorubicin-pretreatment. Measurement of DNA polymerase beta and DNA polymerase beta revealed significant elevations in DNA polymerase beta (58.82 +/- 3.67 units/mg protein in WSU-CLL cells, as compared to 27.82 +/- 4.39 units/mg protein in WIL 2 cells; p < 0.01) but not DNA polymerase beta (0.82 +/- 0.11 units/mg protein in WSU-CLL cells, compared to 0.74 +/- 0.09 units/mg protein in WIL2, p > 0.05). However, exposure to aphidicolin (an inhibitor of DNA polymerase a) failed to increase melphalan induced cytotoxicity suggesting that although DNA polymerase a activity was increased in WSU-CLL cells the mechanisms of resistance does not involve this specific DNA repair pathway. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for crosslinked DNA in melphalan resistant cells appears to be the major factor responsible for alkylator resistance by changing DNA topology and thereby facilitating DNA repair.

Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients.

PURPOSE: The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer. METHODS: The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety. RESULTS: A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity. CONCLUSIONS: Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses.

c-erb-B2 expression and response to treatment in metastatic breast cancer.

The frequency of c-erb-B2 expression, clinical correlates and treatment outcome was investigated in 92 patients with metastatic breast cancer. Positive c-erb-B2 immunostaining was found in 24/92 (26%) of tumours. There was a statistically significant inverse correlation between c-erb-B2 expression and ER status. There was also a significant inverse correlation between c-erb-B2 expression and tumour free interval. c-erb-B2 expression had no influence on response to treatment with tamoxifen among patients co-expressing both c-erb-B2 and estrogen receptor (ER). Following chemotherapy (CAF) treatment there was a trend to a lower response rate among c-erb-B2+ as compared to c-erb-B2- patients. However, more c-erb-B2+ patients had received prior adjuvant chemotherapy, and when this factor was included in a multivariate analysis only prior adjuvant chemotherapy treatment predicted for response to CAF chemotherapy for metastatic disease. Time to treatment failure (TTF) was significantly shorter among cerb B2+ as compared to c-erb-B2- patients. The current study suggests that the c-erb-B2 expression is found at similar frequency in metastatic as in primary breast cancer. Although c-erb-B2 expression did not predict for response to either hormonal therapy or to chemotherapy for metastatic disease, patients with c-erb-B2+ metastatic lesions appear to have a more aggressive clinical course.

Phase III efficacy study of interleukin-3 after autologous bone marrow transplantation in patients with malignant lymphoma.

We evaluated the efficacy of recombinant human interleukin-3 (rhIL-3) in reducing the number of platelet transfusions and major infections after autologous bone marrow transplantation (ABMT) in patients with malignant lymphoma. 198 patients with non-Hodgkin's lymphoma (NHL, n = 111) and Hodgkin's disease (HD, n = 87) were randomized to receive rhIL-3 10 microgram/kg/d (n = 130) or placebo (n = 68) for a maximum of 28 d after ABMT. Several well-known conditioning regimens were used. From day 1 after ABMT patients were treated with placebo or rhIL-3 at a dose of 10 microgram/kg/d by continuous i.v. infusion for 7 d and then by s.c. administration for 21 d or until platelet (50 x 109/l) and neutrophil (0.5 x 109/l) recovery had occurred. Treatment was completed in 54% of the patients in the rhIL-3 group versus 75% in the placebo group (P < 0.004). Adverse events were the main reason for premature discontinuation in the IL-3 group (23% IL-3 v 5% placebo). The median number of platelet transfusions was not significantly different between the IL-3 group and the placebo group (8.0 IL-3 v 6.0 placebo, P = 0.09). Platelet engraftment (>/= 20 x 109/l) was not significantly faster in the IL-3 group (28 d in the IL-3 and 27 d in the placebo group, P = 0.06) and the incidence of haemorrhagic complications was similar in both groups. In patients receiving the full intended dose of rhIL-3, platelet engraftment to >/= 20 x 109/l was delayed (P = 0.007). The median time to neutrophil engraftment was 23 d in the IL-3 and 25 d for the placebo group (P = 0.39). There was no difference in the incidence of major infections. We conclude that treatment with IL-3 has no clinical benefit in patients receiving ABMT for malignant lymphoma.

Induction of alkylator (melphalan) resistance in HL60 cells is accompanied by increased levels of topoisomerase II expression and function.

Human leukemic HL60 cells were selected for resistance to alkylating agents by stepwise exposure to increasing concentrations of L-phenylalanine mustard (melphalan). The resulting resistant cell line (R-HL60) was 4-fold resistant (melphalan IC50 value, 27.84 +/- 4.2 microM) to melphalan compared with parental HL60 cells (melphalan IC50 value, 6.9 +/- 1.78 microM). Nuclear extracts from R-HL60 cells possess a approximately 4-fold increase in DNA topoisomerase II activity compared with parental HL60 cells. As determined using Western blot analysis, the level of topoisomerase IIalpha protein expressed in R-HL60 cells was approximately 3-fold that of parental HL60 cells. However, there were no differences observed in the level of topoisomerase IIbeta protein, in the topoisomerase I activity, or in the level of topoisomerase I protein expression comparing the two cell lines. R-HL60 cells were 5-fold more sensitive than parental HL60 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. The sensitivity to the cytotoxic effects of the topoisomerase I inhibitor camptothecin did not differ in R-HL60 and parental HL60 cell lines. Preincubation with doxorubicin significantly increased melphalan-induced interstrand DNA cross-link formation and cytotoxicity in R-HL60 cells compared with the parental HL60 cells. The affinity of topoisomerase II for UV-irradiated cross-linked HL60 DNA was increased by approximately 2.5-fold compared with that of HL60 native DNA. The affinity of topoisomerase II for both UV-irradiated (cross-linked) and native DNA was significantly decreased after doxorubicin pretreatment. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for cross-linked DNA in melphalan-resistant cells seems to contribute to alkylator resistance by changing DNA topology, thereby facilitating DNA repair.

Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group.

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups. CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.

High dose chemotherapy with haematopoietic rescue in breast cancer.

High dose chemotherapy (HDC) for breast cancer has been used for some 15 years. All studies demonstrate a high response rate with approximately 20% prolonged (> 3 years) disease free survival among patients who achieved complete remission (CR) following HDC. Debate about the value of HDC has centered around the issue of patient selection, including selection by chemotherapy response. Results of one randomised, published trial of HDC versus conventional dose treatment, however, demonstrate a better outcome for the HDC group with a higher CR rate and prolongation of survival. These results have been updated and continue to show a stable proportion of long term complete remitters. In the adjuvant setting one recent trial has demonstrated no benefit from HDC 'consolidation' in 'high-risk' patients. Results of a number of other studies are pending and will help to settle this issue. The article reviews issues including patient selection by prior chemotherapy response, other methods of selection, the chemotherapy regimens used and the timing of HDC. While additional and confirmatory studies are required HDC for breast cancer remains an effective treatment modality.

Fadrozole versus megestrol acetate: a double-blind randomised trial in advanced breast cancer.

Ninety-six patients were entered into a randomised, double-blind, double-dummy, clinical trial to assess the efficacy and safety of fadrozole as compared to megestrol acetate as second-line hormonal treatment for patients with advanced breast cancer. Analysis of results was on an intention-to-treat basis and included response rate, time to progression (TTP), time to treatment failure (TTF) and survival. Forty-six patients received fadrozole and 50 were randomised to megestrol acetate. Patients and pretreatment prognostic variables were balanced in the two arms of the trial. The objective response rates [3/46 (7%) for fadrozole and 3/50 (6%) for megestrol acetate], TTP, TTF and survival were similar in the two arms of the trial. Toxicity was also similar in the two arms of the trial and consisted mainly of oedema, hypertension and minor gastrointestinal symptoms. Fadrozole appears to be as active as megestrol acetate in second-line hormonal treatment of advanced breast cancer.

Docetaxel vs mitomycin plus vinblastine in anthracycline-resistant metastatic breast cancer.

This nonblinded, multicenter, randomized phase III study compares the median time to progression (primary endpoint), response rate, and quality of life, safety, and survival of docetaxel (Taxotere) vs mitomycin (Mutamycin) plus vinblastine (Velban) in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. Patients were randomized to receive an intravenous infusion of either 100 mg/m2 of docetaxel for 1 hour every 3 weeks, or 12 mg/m2 of mitomycin every 6 weeks plus 6 mg/m2 of vinblastine every 3 weeks. This preliminary analysis presents data on 200 patients among 392 patients recruited. Median time to progression was longer in the group treated with docetaxel compared with the mitomycin/vinblastine group (17 vs 9 weeks). The overall response rates were higher with docetaxel (28% vs 13%, respectively), and fewer patients in the docetaxel group had progressive disease as their best overall response (29% vs 48%). As expected, thrombocytopenia was more common in the mitomycin/vinblastine group, and neutropenia occurred more frequently in the docetaxel group. Severe fluid retention in the docetaxel group (8.7%) resulted in treatment discontinuation in 5 patients (5%). Severe thrombocytopenia (12%) and constipation (6%) led to treatment discontinuation in 7 and 3 patients, respectively, in the mitomycin/vinblastine group. Based on this preliminary analysis, docetaxel appears to be equally as safe as and more active than mitomycin/ vinblastine in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. These results are subject to cautious interpretation because this analysis was conducted on the first 200 patients who finished the study treatments, and these preliminary results may underestimate response and overstate treatment discontinuation rates. Thus, the final analysis on the entire patient population is necessary to confirm these preliminary findings.

Interleukin-4 prevents spontaneous in-vitro apoptosis in chronic lymphatic leukaemia but sensitizes B-CLL cells to melphalan cytotoxicity.

The effect of IL4 on cell viability, cell growth, apoptotic fraction, melphalan-induced cytotoxicity and the degree of interstrand DNA cross-linking after alkylating agent exposure was investigated in peripheral blood B-cell chronic lymphocytic leukaemia (B-CLL) cells obtained from 10 patients suffering from chronic lymphocytic leukaemia and in B lymphocytes from five normal individuals. The addition of IL4 to culture medium maintained in-vitro viability and decreased spontaneous in-vitro apoptosis in both B-CLL cells and normal peripheral blood B lymphocytes. IL4 did not, however, stimulate proliferation of either cell type. IL4 sensitized alkylator-resistant B-CLL cells to the cytotoxic effects of melphalan (L-phenylalanine mustard) but had no influence on melphalan-induced cytotoxicity against normal B lymphocytes. The enhanced cytotoxicity against B-CLL cells was accompanied by an increase in the amount of interstrand-DNA cross-linking in these cells following short-term exposure to melphalan.

Undifferentiated nasopharyngeal carcinoma: pattern of failure--experience at the Johannesburg Hospital (1989-1994).

The records of 18 African patients with recurrent undifferentiated nasopharyngeal carcinoma (UDNPC) were reviewed. The skeletal system was the most common site of distant metastases. The pattern of skeletal involvement conformed to the general pattern, with the spine and pelvis being the most common sites. We conclude that metastatic UDNPC seen in Southern Africa resembles its North African and Southeast Asian counterparts.

Weekly gemcitabine and monthly cisplatin for advanced non-small cell lung carcinoma.

Most chemotherapy for non-small cell lung cancer (NSCLC) currently includes combination chemotherapy based on cisplatin. Gemcitabine is a nucleoside analog with demonstrated activity against NSCLC, yet it has low toxicity. This phase II study was designed to examine the efficacy of a combination chemotherapy regimen consisting of gemcitabine followed by cisplatin. The patient population comprised 53 patients with pathologically confirmed locally advanced or metastatic NSCLC. Gemcitabine 1,000 mg/m2 was administered on days 1, 8, and 15 and cisplatin 100 mg/m2 was given on day 15. Chemotherapy was administered every 28 days. Of the 50 patients evaluable for response, there were two complete responses (4%) and 24 partial responses (48%). The median duration of response was 8.5 months, median survival was 13 months, and the 1-year survival rate was 61%. The regimen was generally well tolerated. World Health Organization grade 3 leukopenia occurred in 28.8% of patients, while grade 3 and 4 neutropenia occurred in 38.8% and 19.2% of patients, respectively. Grade 3 and 4 thrombocytopenia was seen in 13.3% and 7.7% of patients, and grade 3 and 4 anemia occurred in 11.5% and 1.9% of patients, respectively. Alopecia and oral toxicity was mild, although most patients experienced mild nausea and vomiting. Relatively few patients required dose modifications for any of the three weekly doses of chemotherapy. We conclude that the combination of gemcitabine and cisplatin is an effective regimen for NSCLC, resulting in high response and survival rates. Additional prospective randomized studies with other cisplatin-based combination chemotherapy regimens are warranted.

Prospective randomized placebo-controlled study of granulocyte-macrophage colony-stimulating factor without stem-cell transplantation after high-dose melphalan in patients with multiple myeloma.

PURPOSE: To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days. RESULTS: GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients. CONCLUSION: GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.

Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer.

PURPOSE: The aim of this study was to examine the efficacy of a regimen of initial gemcitabine followed by cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-three patients (36 men and 17 women; age range, 35 to 74 years) were enrolled. Patients had bidimensionally measurable disease. Gemcitabine (phase-specific agent) was administered on days 1, 8, and 15 at a dose of 1,000 mg/m2. Cisplatin (cycle-specific agent) was administered on day 15 (100 mg/m2). Chemotherapy was administered in 28-day cycles. RESULTS: Of 53 patients enrolled, 50 were assessable for response. The overall response rate was 52%. There were two complete responses (4%) and 24 partial responses (48%). The median survival duration was 13 months and the 1-year survival rate was 61%. The regimen was generally well tolerated. World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 38.8% and 19.2% of patients, respectively. Grade 3 and 4 thrombocytopenia occurred in 13.3% and 7.7% of patients, respectively. Most patients experienced mild nausea and vomiting. Few patients had hair loss and oral toxicity was mild. Relatively few patients required dose modifications for any of the three weekly doses of chemotherapy. For the first two cycles of chemotherapy, the dose-intensity per infusion was 947 mg/m2 for gemcitabine and 85 mg/m2 for cisplatin. CONCLUSION: This regimen of gemcitabine and cisplatin was effective, with high response and survival rates and few dosage modifications during its administration. Prospective randomized studies with other cisplatin-based combination chemotherapy regimens are indicated.

Association between human immunodeficiency virus type 1 infection and cancer in the black population of Johannesburg and Soweto, South Africa.

A case-control study of 913 black cancer patients (aged 15-50 years) was undertaken to measure the association between human immunodeficiency (HIV) infection and cancers believed to have an infective aetiology. Controls were patients with cancers believed not to be infective in origin. The prevalence of HIV in the controls of 7.3% (24 of 325) was similar to the background HIV seropositivity in this population. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, year of diagnosis, marital status and sex were calculated. There was a strong association between HIV infection and Kaposi's sarcoma (KS), with 27 of 33 cases being HIV seropositive, OR = 61.8 (95% CI 19.7-194.2) and an elevated association with non-Hodgkin's lymphoma (NHL), with 27 of 40 cases being HIV seropositive [OR = 4.8 (95% CI 1.5-14.8)]. The elevated odds ratio for KS associated with HIV infection accords with the observed increases in the incidence of KS in several sub-Saharan African countries where the prevalence of HIV is high. The odds ratio for NHL associated with HIV infection was lower than that reported in developed countries, and the reason for this is not clear. No other cancers, including cervical and liver cancers, showed significantly elevated odds ratios associated with HIV infection.

Salvage treatment after failure or relapse following initial chemotherapy for follicular non-Hodgkin's lymphoma.

In an attempt to further define prognostic factors in patients with follicular non-Hodgkin's lymphoma, two subgroups of patients receiving 2nd line therapy; (a) those who had failed to achieve CR with initial therapy and (b) those who had relapsed after achieving initial CR, were examined. Patients who failed to achieve initial remission were not totally refractory to retreatment. Seven of 34 (21%) who had failed to respond to initial treatment achieved CR following treatment with various 'salvage chemotherapy' approaches. There were, however, no significant pretreatment prognostic factors that were predictive for response. Among patients who relapsed after initial CR, 22 of 54 (41%) achieved a second CR following retreatment with conventional chemotherapy approaches. The only factors which were significant in predicting for second CR were sex (female) and age (< 60 years). In both subgroups, patients who achieved CR following 'salvage' therapy survived significantly longer than those who responded less favourably. These findings emphasise the fact that response to treatment is the major predictor of survival among patients with indolent non-Hodgkin's lymphomas.

The treatment of disseminated malignant melanoma with special reference to the role of interferons, vinca alkaloids and tamoxifen.

Malignant melanoma continues to increase in incidence. While early melanoma is highly curable by surgical means, the prognosis of patients with more advanced lesions and/or metastatic disease remains poor. Conventional chemotherapy with dacarbazine has a low frequency and short duration of response. Alternative drugs with single-agent activity include vinca alkaloids, nitrosoureas, procarbazine and platinum compounds. The addition of tamoxifen to chemotherapy, particularly cisplatin-based chemotherapy, appears to be beneficial. Recent studies suggest that combination chemotherapy may give better outcomes than single-agent treatment. Significant clinical activity has also been demonstrated with the use of interferons, particularly interferon alpha, and also with IL-2. Two recent studies suggest that the addition of interferon to chemotherapy may be beneficial. In addition, specific active immunotherapy with tumour vaccines has shown promise. The optimal methods of combining these treatment methods, such as chemotherapy and biological response modifiers/immunotherapy, however, remain to be defined.

High-dose chemotherapy with hematopoietic rescue in breast cancer: from theory to practice.

The development of more effective treatment strategies currently provides the only realistic hope of reducing breast cancer mortality. Among such treatments, high-dose chemotherapy (HDC) has been proposed to be a potentially curative strategy. Consideration of the factors involved in the successful treatment of human tumors suggests that HDC could be integrated into the treatment of breast cancer, but only if the treatment is adequately planned with regard to tumor kinetics and chemotherapy sensitivity and resistance patterns. Two randomized studies of the use of HDC in breast cancer have been published recently. In the first, HDC using a combination of cyclophosphamide, mitoxantrone, and etoposide as initial treatment was compared to a conventional dose regimen consisting of cyclophosphamide, mitoxantrone, and vincristine. The second study compared the effects of early or delayed HDC in patients who had an optimal response to conventional-dose induction chemotherapy. Both studies showed HDC to be more effective than conventional-dose treatment in delaying the time to progression, but only in the study in which HDC was used as the initial treatment was there an effect on survival. The differences between these two investigations can probably be explained on the basis of the different effects of the treatment regimens on tumor kinetics and the efficiency of HDC when used as salvage therapy in the delayed HDC group. Dose-intensive therapy has an established role in breast cancer. Attention now needs to focus on methods of optimizing this treatment strategy.