Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study.

This communication represents the definitive report of a randomized phase III study comparing cisplatin and carboplatin, in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma. A total of 221 patients entered the study and were randomized into two arms. Of these, 114 patients (109 evaluable for activity) were randomized to arm A, receiving cisplatin 120 mg/m(2), mitomycin C 8 mg/m(2) and vindesine 3 mg/m(2) per cycle; 107 patients (101 evaluable for activity) were randomized to arm B receiving carboplatin 500 mg/m(2) with the same doses of mitomycin C and vindesine per cycle. Patients with progressive disease (PD) were excluded from the study after the 2nd cycle, and those with stable disease (SD), partial response (PR) and complete response (CR) received six cycles of chemotherapy (or less in case of early progression). Patients were stratified according to the clinical stage (IIIB vs. IV), performance status (0+1 vs. 2+3) and tumor histological grade (I+II vs. III). In the cisplatin arm two patients (1.9%) achieved a CR, 38 (34.9%) a PR, 45 (41.2%) a SD and 24 (22.0%) had PD; the overall response rate was 40/109 (36.8%). In the carboplatin arm five patients (5.0%) achieved a CR, 31 (30.7%) a PR, 40 (39.6%) a SD, and 25 (24.7%) had PD; the overall response rate was 36/101 (35.7%). No statistically significant difference in response rate was present between the two arms, and the response rate was not influenced by performance status, histological grade or clinical stage. The Kaplan-Meyers curves displayed a significant advantage both for time to progression (P=0.005) and overall survival (P=0.008) for patients in the carboplatin arm. The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV, and occurred irrespectively of tumor histological grade; response duration and survival of responders was identical in the two arms. Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm (P=0.012). Thus, substitution of cisplatin by carboplatin in the combination chemotherapy regimen, although more hematologically toxic (but less emetogenic) resulted in a similar response rate, but a significantly longer time to progression and overall survival.

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.

Content of epidermal growth factor receptor in metastatic breast cancer: its role in endocrine sensitivity prediction.

Epidermal growth factor receptor (EGF-R) is known as an indicator of endocrine independence of breast cancer. However, a small proportion of EGF-R expressing tumors was found to respond to endocrine treatments. On the other side, a cut-off point of EGF-R positivity is not yet defined. In the aim to find out whether there exists a cut-off value that sharply discriminate the endocrine sensitive and endocrine insensitive breast cancers, the quantitative EGF-R content was analyzed in a group of 42 female patients with metastatic disease, being routinely treated with chemo-, chemo-endocrine, or endocrine therapy alone. Steroid receptors (SR) and EGF-R were determined by biochemical methods in tissue samples of an unselected group of patients. Patients with metastatic disease, either at diagnosis, or developed after the treatment of operable or locally advanced breast cancer, were included in the present analysis. According to the treatments used, and their therapeutic response, all patients were divided in endocrine sensitive or resistant, and chemo-sensitive or resistant. The SR and EGF-R status and content was analyzed in relation to the sensitivity to both systemic treatments. The EGF-R content was significantly lower in responders to endocrine treatments, compared to non-responders, while there was no difference in EGF-R level, in relation to the sensitivity to chemotherapy. In addition, the EGF-R content was significantly higher in chemo-sensitive tumors, than in endocrine sensitive. On the contrary, ER content was significantly higher in endocrine sensitive, than in endocrine resistant, and in chemo sensitive patients, as well. Similar differences were found in PR content, but they were less pronounced. While the individual ER contents in endocrine sensitive and endocrine resistant tumors overlapped, the EGF-R ranges were different: no one endocrine sensitive tumor exceeded the EGF-R content of 26 fmol/mg, thus suggesting the EGF-R cut-off point of endocrine sensitivity. The clinical use of EGF-R, with the cut-off point of 26 fmol/mg, in addition to clinical criteria of endocrine sensitivity and SRs, would significantly improve the correct endocrine sensitivity prediction (from 52 to 78%). In conclusion, in a group of metastatic breast cancer patients, treated routinely by systemic therapies it was found, that the use of higher cut-off point for EGF-R positivity can improve the prediction of endocrine sensitivity. The prognostic relevance of this cut-off value remains to be analyzed.

Prognostic value of CA125 kinetics and half-life in advanced ovarian cancer.

This retrospective study was undertaken in order to assess the prognostic value of prechemotherapy serum CA125 level, CA125 kinetics, and CA125 half-life compared to the ten common clinicopathological variables in patients with advanced ovarian cancer (AOC). CA125 serum levels were determined before and during induction cisplatin polychemotherapy in 222 patients. A prechemotherapy CA125 level higher than 35 U/mL was found in 134 patients. Blood samples were further obtained before each course of chemotherapy (CT). CA125 half-life values were calculated in 112 patients with CA125 levels above 60 U/mL using van der Burg's exponential regression model. The prechemotherapy CA125 level had no prognostic value for survival. However, the median survival time of patients with CA125 levels below the upper normal limit of normality after two courses of CT was 101 months compared to a median survival of 21 months in patients without CA125 normalization (p=0.0000). Half-life calculation showed a significant correlation with survival. The median survival times of patients with T1/2 <20 days and T1/2 >20 days were 101+ and 18 months, respectively (p=0.0003). In a survival analysis using the Cox proportional hazard model, independent prognostic variables for survival included therapeutic response (p<0.0001), Karnofsky index (p<0.0001), residual disease (p<0.0001), tumor grade (p=0.0002), CA125 half-life (p=0.007), and CA125 kinetics (p=0.04). As a consequence, the possibility to predict treatment response by the CA125 half-life during chemotherapy and the time needed for normalization of CA125 levels can divide patients into good and poor prognostic groups early during chemotherapy.

Patient statement of satisfaction with antiemetic treatment is related to quality of life.

The aim of our study was to explore the possible relationship between patient satisfaction with antiemetic treatment and quality of life (QoL). The study sample consisted of 136 chemotherapy-naive patients with breast cancer, with Karnofsky index 90% to 100%, scheduled to receive their first cycle of, mainly adjuvant, 5-fluorouracil/doxorubicin/cyclophosphamide chemotherapy. Two antiemetic regimens were used for the prevention of acute emesis. No antiemetic prophylaxis was given for delayed emesis. QoL was assessed using the Rotterdam Symptom Checklist (RSCL). The RSCL was completed before chemotherapy (day 1) and on day 5. Statement of satisfaction was given on day 5. The change in RSCL scores between day 5 and day 1 was calculated and compared in three subgroups of patients: those very satisfied (n = 55), satisfied (n = 65), and unsatisfied with antiemetic treatment (n = 16). Patient statement of satisfaction was related to psychological distress (p = 0.002), physical symptom distress (p = 0.002), and activity level (p = 0.002). It was also related to the control of nausea (p < 0.01) and vomiting (p < 0.0001). We suggest that patient statement of satisfaction with antiemetic treatment could be an outcome measure for response assessment in antiemetic trials.

Expression of epidermal growth factor receptor in breast cancer, from early stages to advanced disease.

Epidermal growth factor receptor was determined in 106 newly diagnosed breast cancer patients, using the biochemical method. The group consisted of 58 patients in stage I-II, and 48 patients in stage III-IV. Although a significant inverse correlation was found between EGF-R status, and ER or PR status, quantitative content of EGF-R did not correlate either with quantitative ER, or PR levels. The ER/PR content was similar in all clinical stages, suggesting their stability during the clinical course of the disease. EGF-R content was significantly higher in stage IV, compared to stage I, while intermediate clinical stages and all substages did not differ according to the EGF-R content. EGF-R was confirmed as a weak prognostic factor within clinical stages. However, in a whole group, the overall survival was significantly better in patients whose tumors EGF-R content was lower than 26 fmol/mg, compared to those with higher ERF-R content. EGF-R content was highly predictive for the response to systemic endocrine treatment, in metastatic breast cancer patients. In locally advanced breast cancer a trend towards higher levels of EGF-R was found in inflammatory breast cancers, compared to non-inflammatory ones. Slightly higher levels were found in responders to local non-endocrine primary treatments (radiotherapy with or without chemotherapy), compared to non-responders, suggesting the possible predictive role of EGF-R for the response to such treatments. Our results emphasized the usefulness of quantitative receptor determination suggesting the relative stability of EGF-R content during the clinical course of breast cancer, its independence from ER, its significant predictive and weak prognostic values, and a possible correlation with the aggressiveness of the disease, and response to non-endocrine treatments.

Mitoxantrone, 5-fluorouracil and low-dose leucovorin in doxorubicin-resistant advanced breast cancer patients: a phase II study.

AIM: Twenty-two anthracycline-resistant advanced breast cancer patients were entered from June 1995 till November 1997 in a phase II study to assess the activity and tolerability of second-line chemotherapy consisting of mitoxantrone, 5-fluorouracil and low-dose leucovorin. STUDY DESIGN: Patients were eligible if they failed to respond to doxorubicin-containing chemotherapy, given as first-line chemotherapy for metastatic disease. Treatment consisted of mitoxantrone, 12 mg/m2 iv infusion on day 1, and leucovorin, 50 mg iv 1 hr before 5-fluorouracil, 350 mg/m2 iv infusion on days 1-3, every three weeks. RESULTS: Nineteen patients were eligible for response, 2 refused further therapy after 2 cycles, and 1 was excluded because grade 3 myelotoxicity developed during the first cycle. Partial remission of 15 months duration occurred in 1 patient, in 7/19 women disease remained stable with a median duration of 11 months (range, 5-24), and 11/19 patients experienced progressive disease. Median time to disease progression was 2 months (range, 0-17), and median survival was 8 months (range, 0-24). Toxicity was generally mild and acceptable. One patient was excluded because of grade 3 granulocytopenia and thrombocytopenia, and one due to cardiotoxicity assessed by the drop of left ventricular ejection fraction to more than 20% below the initial value. CONCLUSIONS: In spite of the very low objective response rate, almost one-fourth of our anthracycline-resistant patients achieved a disease stabilization of 27 weeks duration during mitoxantrone-based second-line chemotherapy. Hence, mitoxantrone in combination with 5-fluorouracil, especially continuous infusion, should be further investigated in this setting, particularly if new and expensive drugs, considered the most active, are not readily available.

Cathepsin D: association between TN-stage and steroid receptor status of breast carcinoma.

PURPOSE: To assess whether the expression of estrogen-induced protease, cathepsin D, might facilitate biological subgrouping of patients with breast carcinomas, and accordingly, its potential applicability in clinical oncology. PATIENTS AND METHODS: This study includes 70 patients with histologically confirmed breast carcinoma. Pathological findings were classified according to tumor size (T) and the presence or absence of metastases in regional lymph nodes (N). Steroid hormone receptor (SR) density as well as cathepsin D concentrations were assayed in the cytosol of breast carcinomas in accordance with the recommendation of the EORTC. RESULTS AND DISCUSSION: Statistically significant direct correlations were observed between cathepsin D expression and axillary node status as well as SR status. However, it is important to point out that in spite of these statistically significant findings, there were no biologically significant associations due to a wide range of individual cathepsin D values. Baseline levels of cathepsin D expression were found in patients with SR-negative status and node-negative tumors as well as in patients with SR-negative status and tumors of

pS2 in breast carcinoma: association with steroid hormone receptor status.

AIMS AND BACKGROUND: Knowledge of the steroid hormone receptors has proved to be of significant value in breast cancer. In the present study the possible importance of estrogen-regulated pS2 protein was investigated. Our direct purpose was to answer the question whether the expression of pS2 may be a marker of functional heterogeneity with respect to the steroid hormone receptor status. METHODS AND STUDY DESIGN: The study included 152 patients with primary, operable, histologically confirmed breast carcinomas. Histology specimens were reviewed and classified according to type, nodal status, tumor size and grade. Steroid hormone receptors were assayed by biochemical methods according to the procedures recommended by the EORTC. pS2 protein measurement was performed in breast carcinoma cytosols using an immunoradiometric assay. The results were analyzed by non-parametric statistical methods. RESULTS: A statistically significant inverse correlation between pS2 protein expression and histological tumor grade was found. The expression of pS2 protein was confirmed to be correlated with steroid hormone receptor status. However, it is important to point out that in spite of these statistically significant findings there were no significant biological associations due to overlapping individual pS2 protein values. The baseline level of expression of pS2 protein was obtained in histological grade III carcinomas with a negative steroid hormone receptor status. It was shown that the distribution of carcinomas according to the baseline level of pS2 protein expression was heterogeneous among estrogen receptor-positive carcinomas, and strikingly homogeneous among estrogen and progesterone-negative carcinoma. CONCLUSION: Our study suggested that PR and pS2 protein may identify distinct subsets of estrogen receptor-positive breast carcinomas.

Evaluation of the nutritional status and tumor characteristics in premenopausal and postmenopausal breast cancer patients.

Evaluation of the nutritional status, fat tissue distribution, and tumor characteristics was carried out in patients with primary breast cancer. The patients were classified into two groups according to their menopause: premenopausal and postmenopausal. Breast cancer prevalence was considerably higher in postmenopausal patients (61%). The patients' nutritional status was shown through the body mass index. Based on this indicator, the patients were characterized as nonobese and obese. In the premenopausal group, there was no significant difference between these categories, whereas the number of obese patients was significantly higher (80%) in the postmenopausal group. The analysis of tumor parameters as related to menopause and body size did not yield any significant differences. However, the estrogen receptor content was significantly higher in postmenopausal patients (p < 0.0001). Distribution of fat tissue of the android type was higher in obese postmenopausal women than in premenopausal ones (77%). The investigation showed that the breast cancer incidence odds are 3.5 times higher in obese postmenopausal than in premenopausal patients.

Randomized study of zorubicin versus zorubicin-cisplatin in undifferentiated carcinoma of the nasopharynx (UCNT)

BACKGROUND: The most active chemotherapy regimens in UCNT were those combining anthracyclines (doxorubicin or epirubicin) and cisplatin. Our previous pilot study on 37 patients treated with the zorubicin-cisplatin combination with a RR of 67% and literature data about other anthracyclines such as epirubicin achieving a response rate of over 50% were the basis of this randomized study comparing efficacy and toxicity of the combination vs. zorubicin as monotherapy. PATIENTS AND METHODS: A total of 80 patients entered the study. The diagnosis of UCNT was confirmed by two independent pathologists. All patients had their primary tumors in the nasopharynx. The patients were randomized in two groups: group A (zorubicin 325 mg/m2, day 1), and group B (zorubicin 250 mg/m2, day 1 and cisplatin 30 mg/m2, days 2-5). The inter-cycle interval was four weeks. The two groups were well balanced according to sex, age, stage Ho and TNM stage. RESULTS: Group A: 40 patients included, 34/40 evaluable for activity. Activity on evaluable patient basis: CR 4/34 (11.75%), PR 4/34, SD 14/34, PD 12/34, response rate 8/34 (23.5%); response rate on intent to treat basis 8/40 (20%). TOXICITY: granulocytopenia grade 3-4 6/40, thrombocytopenia grade 3-4 2/40, no febrile neutropenias, nausea/vomiting any grade 3/40, cardiac toxicity any grade (rhythm) 3/40 other toxicities minor or absent. Group B: 40 patients included, 36/40 evaluable for activity. Activity on evaluable patient basis: CR 10/36 (27.78%), PR 17/36, SD 3/36, PD 6/36, response rate 27/36 (75%); response rate on intent to treat basis 27/40 (67.5%). TOXICITY: granulocytopenia grade 3-4 10/40, thrombocytopenia grade 3-4 8/40, two febrile neutropenias, nausea/vomiting any grade 13/40, other toxicities mild or absent. Of the group of patients achieving a CR, four relapsed following 7, 11, 22 and 23 months, one was lost to follow-up, one died after six months from fulminant hepatitis B and eight are in complete remission lasting for 30+ to 66+ months. Following CR achievement none received any consolidation radiotherapy, and the projected five years of freedom from relapse for complete responders is about 60%. CONCLUSION: Zorubicin is an effective drug in UCNT and its combination with cisplatin has a significant activity and an acceptable toxicity.

Modulation of cisplatin antitumor activity by short infusional high-dose cytosine arabinoside in advanced pretreated head and neck carcinoma: a phase II study.

The aim of the present study, which included 24 pretreated patients (both with radiotherapy and/or cisplatin-containing chemotherapy) with histological grade I/II head and neck cancer, was to investigate whether the enhancing action of cytosine arabinoside on cisplatin antitumor activity might be evidenced without excessive hematological toxicity with the administration of short infusional high-dose cytosine arabinoside, applied before cisplatin. Cytosine arabinoside was administered on day 1 of the treatment cycle at 0h and 12h at the dosage of 500 mg/m2 (1 hour infusion), and cisplatin at 6h and 18h of the same day with a dose of 20 mg/m2. On days 2, 3 and 4, only cisplatin 30 mg/m2/24h was administered. 19 patients were evaluable for activity including 14 patients pretreated with cisplatin-containing chemotherapy. 2/19 achieved complete response (CR), 2/19 a partial response (PR), 8/19 had stable disease and 7/19 progressive disease. Objective responses (2 CR and 1 PR) were evidenced in 3/14 patients previously resistant to cisplatin at the same dosage as in the present regimen. WHO grade IV toxicity for granulocytes was recorded in only one patient.

Single 8 mg dose of oral ondansetron failed to prevent FAC chemotherapy-induced acute nausea and vomiting.

The aim of this open, nonrandomized, monocentric study was to evaluate the efficacy of a single daily dose of 8 mg oral ondansetron in the prophylaxis of acute nausea and vomiting in chemotherapy-naive breast cancer patients receiving their first cycle of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). Forty-five female patients were recruited, median age 42 years. The number of emetic episodes and the grade of nausea were recorded. 51% of patients achieved complete, and 9% major control of acute emesis. 33% of patients experienced no acute nausea, and in 18% nausea was mild. Complete protection from nausea and vomiting (complete prophylaxis) was obtained in 12/45 (27%) of patients. Treatment success (no vomiting with no more than mild nausea) was achieved in 18/45 (40%) of patients. We conclude that the efficacy of a single dose of 8 mg oral ondansetron in controlling acute nausea and vomiting induced by FAC chemotherapy is not high enough to justify its use as a sole antiemetic agent in outpatients.

Daily oral etoposide in metastatic breast cancer.

Etoposide, administered i.v. or orally, as a single agent, in 1- to 5-day courses, was found to be minimally effective in pretreated advanced breast cancer patients. Clinical data suggested an effectiveness of a chronic low-dose oral etoposide schedule, in refractory and those malignancies otherwise unresponsive to the drug. Therefore, the aim of our open-labeled, non-randomized, phase II clinical study was to investigate the efficacy and toxicity of chronic daily etoposide (50 mg/m2 daily, for 21 consecutive days, every 28 days) as a first-line chemotherapy for metastatic breast cancer. Twenty-one advanced breast cancer patients, with or without previous adjuvant CMF chemotherapy, were included. One complete (CR) and five partial remissions (PR) were obtained in 18 patients evaluable for response. Disease stabilization was obtained in 10 patients (55%), while two patients (11%) failed to respond. Grade 3-4 hematological toxicity developed in seven out of 21 patients evaluable for toxicity or in 15 out of 96 cycles. Nonhematological toxicity was moderate. Our results showed the efficacy and relative low toxicity of a chronic oral etoposide regimen in advanced breast cancer patients. Adjuvant CMF chemotherapy did not influence the therapeutic response. Previous irradiation of the breast tended to increase the etoposide hematological toxicity.

[Malignant mesothelioma--therapeutic response to various combinations of anthracyclines]. / Maligni mezoteliomi--terapijski odgovor na razlicite kombinacije antraciklina.

This report deals with results of chemotherapy with different antracycline combination in advanced malignant mesothelioma. Two patients were treated with CYVADIC combination including Adriamycin 40 mg/m2. There was no treatment response and both patients were evaluated as stable disease with median survival 5.5 months and median time to progression 4 months. Four patients were treated with Adriamycin 75 mg/m2 and Cisplatin 120 mg/m2. Two patients achieved a partial response with median survival 8 months and median time to progression 6.5 months. Combination treatment with Epirubicin 180 mg/m2 and Cisplatin 120 mg/m2 was applied to 5 patients, 4 being evaluable for activity. There was one partial response, median survival in this group was 5 months and median time to progression 3.5 months. The Adriamycin dose of 75 mg/m2 and the Epirubicin dose of 180 mg/m2, which were used in our patients are the highest escalated doses, not reported in literature data. Using the meta-analysis of both literature data and our study, which can be considered as a pilot study for dose escalation, there seems to be dose-effect relationship for antracyclin activity in malignant mesothelioma. The meta-analysis registers also slightly better treatment results (response rate 12.6% in 277 patients) with antracyclin containing regimens as compared to combination chemotherapy which does not include antracyclines (response rate 10.3% in 175 patients).

Treatment of tumour-induced hypercalcaemia in advanced breast cancer patients with three different doses of disodium pamidronate adapted to the initial level of calcaemia.

A group of 38 female patients with advanced breast cancer experiencing the first occurrence of tumour-induced hypercalcaemia (TIH), mostly with osteolytic progressive bone metastases, were included in a prospective calcaemia-adapted study using three different doses of pamidronate (30 mg, 45 mg and 60 mg). Serum calcium normalisation was achieved in 29/38 (76%) patients. Comparison of the response rate in three therapeutic groups confirmed the need for higher doses of pamidronate in moderate TIH. Our study also emphasised the importance of effective anticancer systemic therapy.