Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer. A phase III study.

PURPOSE: To compare the efficacy and toxicity of epirubicin to that of the combination of epirubicin and cisplatin in patients with advanced breast cancer. PATIENTS AND METHODS: A total of 155 patients were randomized to receive either epirubicin (70 mg/m2) days 1 and 8 every 4 weeks or epirubicin (60 mg/m2) days 1 and 8 plus cisplatin (100 mg/m2) day 1 every 4 weeks. Epirubicin was continued until disease progression or to a cumulative dose of 1000 mg/m2. Cisplatin was discontinued after six cycles. In 45 premenopausal women an oophorectomy was performed. None of the evaluable patients had received chemotherapy for metastatic disease. RESULTS: Among evaluable patients (74 in the epirubicin group and 65 in the epirubicin plus cisplatin group) there were 19% vs 29% complete responses, and 42% vs 37% partial responses, with no significant difference. In the epirubicin plus cisplatin group the response rate was significantly higher in previously untreated patients as compared with patients who had received adjuvant chemotherapy (74% vs 55%, P = 0.002). Median times to disease progression were 8.4 months in the epirubicin group and 15.3 months in the epirubicin plus cisplatin group (P = 0.045). Median survival times were 15.1 and 21.5 months, respectively (P = 0.41). In the epirubicin plus cisplatin group leukopenia and thrombocytopenia were significantly more frequent, 29% of the patients developed mild to moderate peripheral neurotoxicity, 34% reported tinnitus and hearing changes, 6 patients developed nephrotoxicity (one died due to nephrotic syndrome), and 3 patients developed leukaemia (two died of this cause). Congestive heart failure occurred in six patients in the epirubicin group and three patients in the epirubicin plus cisplatin group. CONCLUSION: Cisplatin plus epirubicin is an active, although highly toxic regimen when used as first-line therapy in advanced breast cancer. The time to disease progression was significantly longer in the cisplatin plus epirubicin group (increased by 82%). Due to toxicity, the combination regimen cannot be recommended. However, the study indicated a very high activity of cisplatin in advanced breast cancer. Studies of first-line therapy in advanced breast cancer including cisplatin or other platin derivatives in combination with, for example, the taxanes are suggested.

Long-term survival and development of secondary malignancies in patients with acute myeloid leukemia treated with aclarubicin or daunorubicin plus cytosine arabinoside followed by intensive consolidation chemotherapy in a Danish national phase III trial. Danish Society of Haematology Study Group on AML.

In 1991 we reported the results from a prospective randomised phase 3 trial comparing 7 days continuous infusion of cytosine arabinoside (ara-C) combined with either daunorubicin (DNR) or aclarubicin (ACR) as direct i.v. injection for 3 days as induction chemotherapy (CT) for patients with de novo acute myeloid leukemia (AML) followed by early intensive consolidation CT with two alternating cycles of high-dose ara-C and two cycles of amsacrine plus etoposide, and finally 3 days of daunomycin plus 7 days of ara-C as administered for induction of remission. A total of 174 patients with de novo AML in the age group 17-65 years were included. The patients have now been followed till death or for at least 7 years, and an evaluation of the long-term survival and the risk of developing secondary neoplasms has been made. The overall survival rate 5-years after diagnosis was 23%, and after 10 years 19%. No difference was found between the two treatment regimens in overall survival or disease-free survival (DFS). For the subgroup of 99 patients who achieved complete remission after one or two induction courses, 5- and 10-year survival rates were 35% and 31% respectively, with the highest survival rates in the age group 17-39 years (57% at 5 years) as compared with 27% in patients aged 40-60 years (P= 0.007). Seven secondary neoplasms were diagnosed simultaneously with or after the diagnosis of AML indicating a standardized incidence ratio (SIR) of 3.41, (95% CI: 1.60-7.26). In three cases the secondary neoplasms were diagnosed simultaneously with the AML diagnosis and were for that reason completely unrelated to the chemotherapy administered for AML, as the psammomatous meningeoma diagnosed after only 8 months. The remaining three neoplasms which developed subsequently did not significantly exceed the expected number, with a SIR = 1.46 (0.47-4.57). Thus, no increased risk of solid tumors causally related to the intensive chemotherapy for de novo AML was observed. However, a generally increased risk of solid tumors in patients diagnosed simultaneously with the AML diagnosis seems likely. Over 20% of the patients were alive and in complete remission 5 years after the AML diagnosis, and they have a high probability of surviving the next 5-year period.

[Treatment of primary breast cancer. Consequences of mammographic screening in the municipality of Copenhagen]. / Behandling af primaer cancer mammae. Konsekvenser of mammografiscreening i Københavns Kommune.

In order to analyse changes in the pattern of primary treatment of breast cancer after introduction of mammography screening in the Copenhagen municipal area every second year, retrospective analyses of data from the Danish Breast Cancer Cooperative Group were performed. Newly diagnosed patients with breast cancer of the age of 50-69 years from the Copenhagen municipal area (1040 patients) were compared to a similar group of patients from the rest of Denmark (7353 patients). Parameters such as tumour size, lymph node status, grade of anaplasia, frequency of breast preserving surgery and adjuvant treatment were analysed. Introduction of mammography screening resulted in almost a doubling of newly diagnosed patients with invasive breast cancer during the prevalence phase, and a significant increase in the number of patients with tumour size < or = 1 cm without metastases to the axillary nodes. The frequency of breast preserving surgery increased from 5 to 45% in the municipality of Copenhagen compared to 6 to 19% in the rest of the country. Ratio between low-risk versus high-risk patients increased from 1.0 before screening to 2.7 in the following prevalence phase and 2.5 in the first year of the subsequent incidence phase, while the ratio in the rest of Denmark was the same throughout the whole study period. It can be concluded that the introduction of mammography screening resulted in significant changes in the treatment pattern of patients with primary breast cancer.

Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients.

Fifty-one patients with histologically confirmed epithelial stage III or IV ovarian cancer were entered into a study in which gemcitabine 800 mg/m2 was given as a 30 min intravenous infusion in a cycle once a week for 3 weeks followed by a week of rest. Patients were aged 58 years (range 23-70 years) with WHO performance status 0-2, and had received up to two different chemotherapy regimens. Thirty-eight patients had received only one prior platinum-containing chemotherapy regimen whereas 9 had received a first-line regimen on more than one occasion. A further 3 patients had received two different regimens. Of 42 patients evaluable for response, 8 (19%; 95% CI: 9%-34%) were partial responders. Seven of the 8 responders were resistant to first-line platinum-based therapy. Median duration of response was 8.1 months (range 4.4-12.5 months). Median progression-free survival was 2.8 months (range 0.2-12.5 months). Haematological toxicity with gemcitabine was modest, with grade 3 leukopenia (11 patients) and grades 3 and 4 thrombocytopenia (6 patients). Grade 3 non-haematological toxicity included nausea/vomiting (6 patients) and elevated AST/ALT (1 patient), while dose-limiting non-haematologic toxicity consisted of flu-like symptoms (2 patients), peripheral oedema (1 patient) and lethargy (1 patient). The activity and modest haematological and non-haematological toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of patients with ovarian cancer and in combination chemotherapy regimens, primarily in combination with platinum.

Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients.

BACKGROUND: Platinum-containing combination chemotherapy has resulted in improved survival rates in patients with advanced ovarian carcinoma, but the majority of the patients still die of their disease. It is therefore important to develop new non-cross-resistant drugs. Gemcitabine (2',2'-difluorodeoxycytidine) has shown a broad spectrum of antineoplastic activity in tumor cell cultures in vitro and in animal tumor models. Clinical activity also has been reported in a variety of solid tumor types. PURPOSE: Our purpose was to assess the clinical activity of gemcitabine in previously treated ovarian cancer patients and to further characterize the toxicity of the compound. METHODS: Gemcitabine (800 mg/m2) was given intravenously once a week for 3 consecutive weeks, followed by 1 week of rest. A maximum of two different prior treatment regimens was allowed. Response was assessed by pelvic examination and/or ultrasound and computed tomography scans every other course. RESULTS: Fifty patients were eligible; 35 (70%) had bulky disease (tumor greater than 5 cm in diameter). All patients had received prior platinum-containing combination chemotherapy. Forty-two patients were assessable for response. Eight (19%) of the 42 patients (95% confidence interval = 9%-34%) achieved a partial response, with a median response duration of 8.1 months (range, 4.4-12.5 months). All responders started treatment with gemcitabine within 6 months of prior treatment, and seven of the eight responders were resistant to first-line platinum-containing combination chemotherapy. Overall median time to progression was 2.8 months (range, 0.2 12.5 months), and overall median survival was 6.2 months (range, 0.2-26.0 months). Forty-eight patients were assessable for toxicity. Leukocytopenia and thrombocytopenia were the main toxic effects that caused dose omissions (27% and 14%, respectively) and dose reductions (37% and 21%, respectively). A transient mild flu-like syndrome occurred in 28% of the patients, and treatment-related peripheral edema developed in 22%. Grade 1 hematuria (53% of patients), grade 1-2 proteinuria (79% of patients), and liver toxicity that was mostly grade 1-2 (59% of patients) were also observed. CONCLUSIONS: Gemcitabine is a well-tolerated new drug with activity in platinum-resistant ovarian cancer patients. IMPLICATIONS: Confirmatory trials are needed, and the activity of gemcitabine in previously untreated patients should be assessed.

Inter-relationships between single carbon units' metabolism and resting energy expenditure in weight-losing patients with small cell lung cancer. Effects of methionine supply and chemotherapy.

The one-carbon unit metabolism was investigated in 8 weight-losing patients with small cell carcinoma of the lung (SCLC). At diagnosis, 6 of the 8 patients had elevated formiminoglutamic acid (FIGLU) excretion after a histidine load, suggesting a lack of one-carbon units. In accordance, a significant decrease of FIGLU excretion was observed in the patients after oral administration of DL-methionine for 4 days. The elevated FIGLU excretion was positively correlated to weight loss prior to diagnosis and negatively correlated to serum albumin at time of diagnosis. After 3 months of combination chemotherapy, FIGLU excretion was reduced in all patients except 1, who had progressive disease. Despite the elevated FIGLU excretions, all patients had normal blood folate levels. The resting energy expenditure (REE) was recorded in 7 patients, and a significant, positive correlation was observed between pretreatment FIGLU excretion and REE, although the REE measured in this group of patients was within the normal range. These data demonstrate an increased demand of "active" one-carbon units in energy consumption in a group of weight-losing cancer patients. The one-carbon unit deficit was reconditioned by oral administration of the one-carbon unit donor DL-methionine.

Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: a prospective, randomized study.

PURPOSE: This study examined the effect of frequent nutritional counseling on oral intake, body weight, response rate, survival, and quality of life in patients with cancer of the lung (small-cell), ovary, or breast undergoing cyclic chemotherapy. PATIENTS AND METHODS: Of 105 assessable patients, 57 were randomized to receive nutritional counseling, and 48 to receive no nutritional counseling and consumption of an ad lib oral intake. The intervention group was counseled to achieve a daily energy and protein intake according to recommended dietary allowances. Counseling was standardized and performed by a trained dietitian, and took place twice monthly during a 5-month period from start of chemotherapy. RESULTS: Dietary counseling increased daily energy intake by approximately 1 MJ and protein intake by 10 g over the entire study period. There was no change in the control group. Counseling led to an insignificant increase in body weight, but triceps skinfold measurement increased significantly after 5 months. Response rate and overall survival did not differ between the groups. Quality of life measured by the Quality-of-Life index (QL-index) increased significantly in both groups, but did not differ between groups. CONCLUSION: No clinical benefit could be demonstrated despite long-term and continuous improved food intake in cancer patients with solid tumors undergoing aggressive chemotherapy.

Second-look laparotomy in the management of patients after radical surgery for ovarian cancer.

BACKGROUND: Radically excised ovarian cancers present an unsolved problem with regard to the value of routine second-look operation. This study presents the outcome of second-look operations in an effort to help elucidate this problem. PATIENTS AND METHODS: Twenty-eight patients who underwent radical surgery for ovarian cancer stage IC-IIIA were given adjuvant chemotherapy with cyclophosphamide 500 mg/m2 i.v., adriamycin 40 mg/m2 i.v. and 5-fluorouracil 500 mg/m2 i.v., all administered on days 1 and 8 every 4 weeks until achievement of a cumulative adriamycin dose of 400 mg/m2. It was planned that second-look laparotomy would be performed 10-12 months after the primary operation. RESULTS: Four of 28 patients (14.3%) had positive findings at second-look laparotomy. Two of these 4 patients had only microscopic disease, and after second-line chemotherapy including cisplatin one of them is clinically free of tumor 50 months after the primary operation. Two of 28 patients had clinical recurrences before the planned second-look operation. Four of the 22 patients (18.2%) with negative second-look operations developed recurrent disease within a median time of 12 months later. The 5-year survival rate for all 28 patients was 67%. CONCLUSION: Although a small group of patients may benefit from a strategy that includes delayed second-look operation, we conclude that this should not be a routine procedure in the management of patients who undergo radical surgery for ovarian cancer.

Ceftriaxone versus latamoxef in febrile neutropenic patients: empirical monotherapy in patients with solid tumours.

121 patients with 132 febrile episodes were randomised to ceftriaxone or latamoxef monotherapy in order to compare antibiotic efficacy in neutropenic patients treated with cytotoxic chemotherapy for solid tumours. In 80 evaluable episodes no significant differences were observed between the two groups with respect to efficacy and fatal failure rates. Of episodes treated with ceftriaxone, 67% showed a favourable clinical response vs. 61% in the latamoxef group. The clinical response rates in episodes with documented bacterial infections were 67 and 56% in the two treatment groups. In 18% of the episodes with documented initial infections the patients died of presumably uncontrolled infection. The convenient once daily dosage schedule combined with fewer severe adverse reactions favours the use of ceftriaxone instead of latamoxef. Although a relative high degree of response was seen, empirical antibiotic monotherapy apparently does not offer a sufficient antibacterial cover in infections in this type of patient with defective host immunity.

Teniposide in advanced breast cancer. A phase II trial in patients with no prior chemotherapy.

The objective response rates were determined using teniposide as first-line chemotherapy for patients with recurrent breast cancer. Twenty-seven evaluable patients with advanced disease received teniposide 70 mg/m2 i.v. days 1-5 every 3 weeks. A total of 211 courses were given. Responses included one complete (4%) and 9 partial responses (33%) with a median duration of response of 9 months (range 2-31 months). The main toxicity was myelosuppression. The results show that teniposide has at least modest activity in patients with advanced breast cancer treated previously with endocrine therapy.

Combination therapy with carboplatin/cisplatin/ifosfamide/etoposide in ovarian cancer.

In 1987 a phase II study of combined high-dose platinum (carboplatin 300/mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3 q4wk) was carried out in 42 previously untreated ovarian cancer patients with residual disease. Since then, another phase II study of combined high-dose platinum and ifosfamide (1,500 mg/m2 days 1 to 3) has been carried out in 37 patients, while a third study of combined high-dose platinum and etoposide (70 mg/m2 intravenously days 1 to 5) is ongoing. Pathologic complete response (CR) and partial response (PR) rates in the first two studies were 62% in 37 evaluable patients, and 58% in 36 patients, 22% and 42% of whom were CRs, respectively. The preliminary results from the third study were: CR plus PR, 56%; CR, 24%. Hematologic toxicity was the dose-limiting factor in all three studies. Myelosuppression became substantial, but manageable, if another drug was added to the platinum combination. The percentage of patients experiencing World Health Organization grades 3 and 4 toxicity during treatment were: white blood cells 44%, 92%, and 79%; platelets 81%, 100%, and 95%, respectively, in studies I, II, and III. Nonhematologic toxicity was modest in all studies. Dose-limiting neurotoxicity occurred in 7%, 6%, and 5%; nephrotoxicity in 22%, 6%, and 11% of the patients. The percentage of patients receiving the stipulated doses of all study drugs in the sixth cycle was 31 in the first study compared with none in the second study. Combined high-dose platinum given either alone or in combination with ifosfamide or etoposide is highly active in ovarian carcinoma. However, further follow-up and a randomized trial are needed to establish the superiority of any one regimen.

Increased myelosuppression during cytostatic treatment and pleural effusion in patients with small cell lung cancer.

30 patients with small cell lung cancer (SCLC) and malignant pleural effusion were compared with 30 matched patients with SCLC but without pleural effusion. In the 30 with pleural effusion, white blood cell and platelet counts fell significantly after initial chemotherapy, necessitating dose reduction. Of the patients with pleural effusion, 16 developed severe (WHO grade IV) leukopenia, 7 had severe thrombocytopenia, and 2 patients died of infection. Accordingly, exhaustive aspiration of radiologically verified pleural effusion before starting chemotherapy in patients with SCLC is recommended.

Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial. The Danish Society of Hematology Study Group on AML, Denmark.

A regimen of aclarubicin (ACR) of 75 mg/m2 daily for 3 days plus a continuous intravenous infusion of cytosine arabinoside (ara-C) of 100 mg/m2 per day for 7 days was compared with daunorubicin (DNR) 45 mg/m2/day for 3 days plus ara-C for 7 days as first-line chemotherapy of de novo acute myeloid leukemia (AML) in a randomized, nationwide Danish study. A total of 180 patients aged between 17 and 65 years were entered onto the protocol. Patients who achieved complete remission (CR) were given five courses of intensive consolidation therapy consisting of two courses of high dose ara-C, two courses of amsacrine plus etoposide, and one course of DNR plus ara-C. Of 174 evaluable patients, 99 achieved CR. The rate of CR was significantly higher on ACR plus ara-C than on DNR plus ara-C [66% versus 50% (p = 0.043)] and decreased significantly with increasing age. The hematological toxicity was identical for the two regimens. A total of 83 patients entered consolidation therapy. At 4 years, 37% of patients with CR following ACR were still in remission compared with 33% following DNR (p = 0.48), and the total survival at 4 years was 29% versus 20% (p = 0.26). The duration of remission and total survival both decreased with increasing age. ACR plus ara-C seem at least as good or better than DNR plus ara-C as first-line chemotherapy of AML.

Combined high-dose carboplatin and cisplatin, and ifosfamide in previously untreated ovarian cancer patients with residual disease.

Carboplatin 200 mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3, ifosfamide 1,500 mg/m2 days 1 to 3, and mesna 900 mg/m2 days 1 to 3 every 4 weeks for six cycles were given to 37 previously untreated ovarian cancer patients with residual disease after the primary laparotomy. The median observation time was 17+ months (range, 9+ to 24+ months). Of all the patients, 81% had primary residual disease larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 36 assessable patients was 58%, PCR was 42%. Of the PCR patients, 53% had primary residual tumor larger than 5 cm. The substantial hematologic toxicity was manageable, but also the main reason for dose modifications. During treatment, 92% and 100% of the patients developed WBC and platelet nadir values corresponding to World Health Organization (WHO) grades 3 to 4. Dose-limiting encephalopathy, nephro- and neurotoxicity each occurred in 6% of the patients. The high PCR rate warrants further investigations of combined high-dose platinum and ifosfamide.

Phase II study of teniposide in advanced breast cancer.

In a phase II study, 19 patients with previously treated, advanced breast cancer received 50 mg/m2 teniposide (VM-26) i.v. on days 1-5 every 3 weeks. One partial response (PR) (5%) was observed. Toxicity consisting of leukopenia and thrombocytopenia was frequent and severe. VM-26 has minimal therapeutic activity when given at this dose and on this schedule to patients with heavily pretreated metastatic breast cancer.

High-dose platinum consisting of combined carboplatin and cisplatin in previously untreated ovarian cancer patients with residual disease.

A phase II trial of carboplatin, 300 mg/m2 day 1, and cisplatin, 50 mg/m2 days 2 and 3 every 4 weeks for six cycles, was performed in 42 previously untreated patients with residual disease after primary laparotomy. Overall, 79% of patients had primary residual tumor larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 37 evaluable patients was 62%, and in PCRs was 22%. Of the responding patients, 78% had primary residual tumor larger than 2 cm. The toxicity was cumulative but manageable, with thrombocytopenia being the main reason for dose reduction. Dose-limiting nephrotoxicity and neurotoxicity occurred in 22% and 7% of the patients, respectively. Combined high-dose platinum as a "single agent" appears to be as active as combination chemotherapy containing cisplatin, and the treatment is feasible. Further clinical trials of this combination alone or combined with other drugs are warranted.

Phase III study of intermittent 5-drug regimen (VBCMP) versus intermittent 3-drug regimen (VMP) versus intermittent melphalan and prednisone (MP) in myelomatosis.

A prospective randomized trial in 96 patients with previously untreated myelomatosis was performed comparing 3 regimens of chemotherapy: (i) Intermittent vincristine, BCNU, cyclophosphamide, melphalan, and prednisone (VBCMP) to (ii) intermittent vincristine, melphalan and prednisone (VMP) to (iii) intermittent melphalan and prednisone (MP). Induction response rates and survival were similar in all 3 regimens. An improvement in relapse-free survival was observed by adding vincristine to MP, but this did not achieve statistical difference (p = 0.10). Patients given VBCMP fared slightly worse than those given VMP. The haematologic toxicity was similar in all 3 regimens, but the tolerability of VBCMP was lower. Although showing no statistical differences between the 3 treatment regimens, the results support the view that a combination of MP 'standard' induction therapy in MM with frequently administered vincristine has a trend towards postponing treatment failure due to development of resistance to melphalan.

Classification and prognostic variables in myelomatosis.

It is difficult to compare the results of treatment obtained in different trials in myelomatosis because different sets of diagnostic criteria are used, and because the criteria by which patients are deemed eligible for entry vary. Thus the composition of different series of patients varies considerably. Furthermore, the outcome of treatment is recorded in different ways. Uniformity in the diagnostic categories entered would reduce the variance in survival between different trials: for example, trials in myelomatosis should exclude patients with monoclonal gammopathy of uncertain significance, non-progressive or indolent myeloma, extramedullary plasmacytoma, and plasma-cell leukaemia. The subdivision into simple prognostic groupings such as those proposed by the Medical Research Council is helpful in interpreting the survival patterns in different trials in which the proportions of patients in different prognostic groups are likely to vary. These groupings and other staging systems do not correlate with responsiveness to treatment. Rapid responders fare worse than slow responders, and this might provide a basis for a second randomisation to test whether a change in treatment could benefit the rapid responders.