Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. Medical Research Council study on chemotherapy in advanced ovarian cancer. Medical Research Council's Working Party on ovarian cancer. Standard interleukin-2 (IL-2) and interferon-alpha immunotherapy versus an IL-2 and 4-epirubicin immuno-chemotherapeutic association in metastatic renal cell carcinoma. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine. [Comparative parameters of myelotoxicity in patients treated with simultaneous chemotherapy and radiotherapy or only radiotherapy]. A randomized study of low-dose interleukin-2 subcutaneous immunotherapy versus interleukin-2 plus interferon-alpha as first line therapy for metastatic renal cell carcinoma. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group.
In a single-center, multiple-referral source study, 38 patients with progressive IgA nephropathy and controlled hypertension were randomized to treatment with prednisolone and cytotoxic agents, to therapy with low-dose cyclophosphamide then azathioprine, and to control groups. The follow-up period lasted 2 to 6 yr. Renal survival, as assessed by Kaplan-Meier analysis annually to 5 yr, showed significant preservation of function from 3 yr in the treatment group and 82, 82, 72, and 72% for 2, 3, 4, and 5 yr, respectively, compared with 68, 47, 26, and 6% in controls. Rate of loss of renal function, evaluated objectively by least-squares analyses of reciprocal serum creatinine, was reduced-and in one-third of the patients, arrested-during immunosuppressive treatment. Proteinuria, present in all patients at the time of entry into the trial, was reduced by treatment from 12 mo, compared with pretreatment levels or controls; erythrocyturia was reduced from 6 mo. Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry. Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease. No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry. Mean arterial pressures did not differ significantly between treatment and control groups. There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy. Morbidity attributable to treatment or to renal failure occurred in both groups; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure. Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents; results are consistent with modulation of systemic immune response or nephritic injury, thus explaining improved outcome, and indicate that this therapy has an acceptably low risk of side effects. A total of 264 eligible patients with advanced ovarian cancer were randomised to single or triple agent cytotoxic therapy; 261 were available for analysis. The treatments were continuous oral cyclophosphamide (arm S), and a combination of oral cyclophosphamide, hexamethylmelamine and methotrexate on a pulsed basis (arm T). Mortality attributed to cancer was slightly lower on arm T (p = 0.06), but this was offset by the greater toxicity of this regimen, and overall survival and activity index were similar on the two arms. There was thus little evidence of greater clinical benefit on the triple agent regimen. Tumour mass removed at operation, extent of remaining tumour and age all showed significant correlation with prognosis. Survival was longer in patients whose disease responded to either therapeutic regimen. Recombinant human interleukin-2 (IL-2) has a well-documented anti-tumor activity against RCC and has demonstrated a synergistic anti-tumor activity between doxorubicin and IL-2, thus providing better survival. This study investigated the toxicity and efficacy of the association between doxorubicin and IL-2, and interferon-alpha, and the immuno-chemotherapeutic association with IL-2 and 4-Epirubicin.
                Patients with histologic evidence of metastatic or advanced RCC were randomized to receive either IL-2 + IFN-alpha (Arm A) or IL-2 + 4-Epi (Arm B). Arm A patients received IFN-alpha subcutaneously at doses of 3 million UI on days 1, 3 and 5 for 6 weeks. Arm B patients received 4-EPI at doses of 25 mg/m2 on days 1, 8, 15, 22, 29 and 36. Treatment cycles were repeated at 10 week intervals.
                Of 38 evaluable patients, we observed 2 complete responses, 2 partial responses, 1 minimal response, 1 mixed response, 21 stationary disease and 11 disease progressions. There was no significant difference in overall survival between the two groups. However in arm B, the median overall survival for responding patients was better than that of patients who experienced a disease progression. Performance status was the only predictive prognostic factor.
                Our analysis confirms the low response rate associated with IL-2 treatments but seems to indicate a role of anthracycline in improving the survival of responding patients with an acceptable toxicity. The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia. A prospective randomized clinical trial was performed in 339 postmenopausal patients with advanced breast cancer. Two single modality treatment sequences, doxorubicin plus cyclophosphamide (AC) followed on failure by tamoxifen (TAM), and TAM followed by AC, were compared with combined modality chemo-endocrine therapy (TAM plus AC). The response rate to initial TAM (22.1%) was inferior to that for AC (45.1%), and for TAM plus AC (51.3%). However, patients randomized to the sequence TAM followed by AC showed a 42.5% overall tumor response to sequential protocol therapy, similar to the 46.9% for those randomized to AC followed by TAM. Furthermore, survival in all three arms was almost identical. Adverse prognostic factors for survival were liver metastases, short disease-free interval, poor performance status, and prior adjuvant chemotherapy. In no subgroup was significantly better survival associated with initial cytotoxic therapy. Endocrine therapy followed on failure by cytotoxics is appropriate for postmenopausal patients with advanced breast cancer. Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen. The Modern oncological treatment usually consists of the different kind of the therapies. Improvement of survival and local control of disease could be possible with combined treatments: surgery, radiotherapy, chemotherapy, etc. However if these treatments are given concomitantly one can expect higher toxicity.
                Comparation of parameters of miclotoxicity: red blood cell count, white blood cell count, platelets and hemoglobin in patients with advanced cervical carcinoma treated with concomitant chemo-radiotherapy versus radiotherapy alone.
                From 1997-1999, we performed prospective, by randomised, study, and 80 patients were divided in two groups: Group A--40 patients treated with concomitant chemo-radiotherapy versus, Group B--40 patients treated with radiotherapy alone. Red blood cell count, white blood cell count, platelets and hemoglobin were evaluated before enrollement, during the theraphy, after 3 and 6 months, according to CTC toxicity criteria.
                We perform statistical analysis using H2 test, and we found no significant difference in mild nad severe toxicity in red blood cell count, white blood cell count, platelets and hemoglobin among groups. IL-2 given subcutaneously in combination with interferon-alpha 2b (IFN) appears to induce a response rate comparable to that obtained with IL-2 intravenous injection in patients with metastatic renal cell carcinoma (RCC) but with lower toxicity. The role of IFN when combined with IL-2 has however still to be defined. The present study was performed to draw some preliminary conclusions about the effect of IFN in combination with IL-2 in metastatic RCC.
                The study included 30 consecutive patients with metastatic RCC who were randomized to treatment with IL-2 subcutaneous therapy (3 million IU twice/daily for 5 days/week for 6 weeks) or with IL-2 plus IFN (5 million U/m2 subcutaneously thrice weekly). In patients without progressive disease, a second cycle was repeated after a 28-day rest period.
                No significant difference in partial response rate was found between patients treated with IL-2 alone and those given IL-2 plus IFN (5/15 vs 4/15). Similarly, no difference was seen in the percentage of stable disease (7/15 vs 7/15). Toxicity was higher in patients who received IL-2 plus IFN. Lymphocyte and eosinophil mean increase was higher in patients treated with IL-2 alone than in those treated with IL-2 plus IFN, without however any significant difference.
                The present results, which require confirmation in a larger series, indicate that combination with IFN does not increase the efficacy of IL-2 subcutaneous immunotherapy in metastatic RCC but only the toxicity of treatment. Most studies of adjuvant chemotherapy, radiotherapy, or immunotherapy in non-small-cell lung cancer patients with complete surgical resection of disease have shown negative results. However, two studies of stage II and III disease by our Lung Cancer Study Group suggested an advantage to adjuvant therapy with cyclophosphamide, doxorubicin, and cisplatin (CAP).
                Since neither of those studies had an untreated control, the Lung Cancer Study Group undertook a trial that included a control group and also offered the potential benefit of adjuvant therapy with CAP to patients with T1, N1 or T2, N0 (stage I) non-small-cell lung cancer.
                After complete resection, eligible patients with stage I disease were classified by known prognostic factors and randomly assigned to receive or not to receive four courses of CAP at 3-week intervals beginning on day 30 after surgery. The CAP regimen consisted of 400 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, and 60 mg/m2 cisplatin. Stratification by prognostic factors was as follows: histology (squamous versus nonsquamous), white blood cell count before surgery (> or = 9100/mm3 versus < 9100/mm3), and Karnofsky performance status before surgery (< or = 90% versus 100%).
                Of the 269 patients entered in the study, 101 had recurrence and 127 have died. Mean time since randomization is 6.4 years; mean follow-up is 3.8 years. There were no differences in time to recurrence or overall survival (not stratified by histology) between the two groups, even when analyses were adjusted for prognostic variables. There was one treatment-related death on the CAP arm due to infection during neutropenia. Only 53% of the eligible patients received all four courses of CAP, and only 57% of such patients received all four cycles on time. In 74% of the patients, the site of initial recurrence was distant.
                The most likely explanations for the lack of efficacy of CAP are poor compliance to the protocol and relative inactivity of the regimen, compared with the activity of drug combinations used in more recent studies. On the basis of this trial, adjuvant therapy with CAP should not be recommended for patients with resected stage I lung cancer.
                Further trials to test adjuvant therapy are indicated, but investigators should use better antiemetics to improve patient compliance as well as more active chemotherapy regimens.
The current body of evidence supporting the use of immunosuppressive agents and cytotoxic therapies is limited. Side-effects associated with some of the therapies were severe.