Lucien Perey

Treatment of bone metastases from breast cancer and myeloma with pamidronate

28 patients with progressing painful bone metastases (18 breast cancer, 9 myeloma and 1 low grade lymphoma) received pamidronate 60 mg by 24 h continuous infusion for at least 2 courses (range 2-12). In patients urinary calcium and hydroxyproline excretion significantly decreased in relation to diminution of bone resorption. 9 of 18 breast cancer patients and 8 of 9 evaluable patients with myeloma had symptomatic improvement. Sclerotic areas of previously lytic lesions appeared in 8 breast cancer patients and in 1 myeloma patient. Transient fever developed in 1 patient and local phlebitis in 2. Among the 28 patients, 15 did not receive any anticancer treatment or have any change of the anticancer therapy during pamidronate administration. Of 7 with breast cancer, 4 had an improvement of symptoms and 4 sclerosis on radiographs. Impressive control of symptoms was the major feature of 8 myeloma patients, but only 1 had radiographic sclerosis.

Anastrozole (‘Arimidex’) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: Results of the double-blind cross-over SAKK trial 21/95 - a sub-study of the TARGET (Tamoxifen or ‘Arimidex’ Randomized Group Efficacy and Tolerability) trial

It is desirable to identify the most effective sequence of endocrine therapies for the treatment of postmenopausal women with advanced, hormone-responsive breast cancer. In a retrospective analysis of two large, randomized, comparative Phase III trials in this patient population, the Tamoxifen or ‘Arimidex’ Randomized Group Efficacy and Tolerability (TARGET) trial and the North American trial, we ascertained that tumors responding to anastrozole as first-line therapy may subsequently respond to tamoxifen as second-line therapy. In a double-blind cross-over trial, the SAKK 21/95 sub-trial (including patients from the Swiss centres in the TARGET trial), we further investigated the clinical impact of anastrozole followed by tamoxifen compared with that of tamoxifen followed by anastrozole. Patients with locally advanced or metastatic breast cancer who had continued on randomized treatment until objective disease progression and were still considered suitable for endocrine therapy, could continue on blinded therapy crossing-over to the alternative treatment. They were assessed for time to progression (TTP) from treatment randomization, TTP after crossing-over treatments, time from randomization to progression after crossing-over treatments and overall survival. Median TTP from randomization for patients receiving first-line treatment with anastrozole (n= 31) and tamoxifen (n= 29) was 11.3 and 8.3 months, respectively, p= 0.75. Median TTP from treatment cross-over was 6.7 months for tamoxifen after progression on anastrozole (n= 19) and 5.7 months for anastrozole after progression on tamoxifen (n= 18), while median time from randomization to second progression was 28.2 and 19.5 months, respectively. Overall survival from randomization for the anastrozole-tamoxifen sequence and the tamoxifen-anastrozole sequence was 69.7 versus 59.3 months, respectively, p= 0.10. The relative risk of death was higher for the tamoxifen followed by anastrozole sequence (1.63; 95% confidence interval [CI] 0.89–2.98). Tamoxifen is an effective second-line therapy after anastrozole. Our data, together with the better tolerability profile of anastrozole compared with tamoxifen, support the use of anastrozole as first-line therapy for advanced breast cancer in postmenopausal women with hormone receptor-positive tumors. Treatment with tamoxifen may still be useful upon subsequent progression.

Association between immunity and prognostic factors in early stage breast cancer patients before adjuvant treatment.

AbstractObjective: The association of known prognostic factors with immune cell counts and β2-microglobulin and soluble IL-2 receptor (sIL-2r) serum levels as markers of activation of the immune system was investigated in breastcancer. Methods: Two hundred thirty five operated stage I and II breast cancer patients to receive adjuvant treatment in IBSCG trials were assessed in a cross-sectional study immediately before the first treatment. Leukocytes, lymphocytes and lymphocyte subset counts, β2-microglobulin and sIL-2r serum levels were assessed as immunological parameters. Prognostic factors were tumor load, receptor status, patient characteristics, and contextual factors of the immune assessment (such as time of the day, time since surgery, type of surgery, concomitant medication, co-morbidity). Results: In an operated early stage breast cancer patient population, tumor load was not associated with immune cell counts, β2-microglobulin, or sIL-2r before adjuvant treatment. There was a pattern of association of prognostically favorable factors such as estrogen receptor (ER) positive tumor and older age with higher NK cell counts or with β2-microglobulin or sIL-2r. In addition, immune cell counts and the markers of activation of the immune system were affected by several contextual factors, such as diurnal variability, time since surgery, type of surgery, and the intake of concomitant medication. Conclusions: The association of NK cell counts and β2-microglobulin or sIL-2r serum levels with prognostically favorable factors such as ER positive tumor and older age supports the assumption that the immune system plays a role in the course of early breast cancer. The exact nature of this role requires furtherstudy.

Treatment of Tumor-Induced Osteolysis by APD

Bisphosphonates, associated with rehydration, became the treatment of choice of malignant hypercalcemia when it became apparent that these compounds normalized plasma calcium in most cases within a few days and with almost no side effects, and that their effect was prolonged. Dichloromethylene bisphosphonate and aminobisphosphonate, especially APD, were shown to inhibit bone resorption with no noticeable inhibition of bone formation, and were highly effective in the long-term treatment of Pagets disease. APD was used in almost 300 patients with malignant hypercalcemia published in the literature and has been used in the medical clinic at Lausanne for several years. When given to 14 patients with malignant hypercalcemia at the dose of 25 mg/day until plasma calcium became normal for two consecutive days, APD had to be given for 4-11 days, severe hypercalcemia needing longer treatment than mild hypercalcemia (Adami et al. 1982). When given for a fixed period of 6 days, again plasma calcium normalized in all patients, whether APD was given i.v. (30 mg/day, ten patients) or orally (1200 mg/day, ten patients) (Adami et al. 1985). Further shortening of the treatment to one single infusion given over 24 h did not decrease the efficacy, as long as high enough doses were given (Blomqvist 1986). For severe hypercalcemia of above 3.5 mmol/liter 60-90 mg had to be given, while 30-45 mg was sufficient in milder cases (Body 1984). Otherwise, mild, transient, and asymptomatic hypocalcemia could occur. Normalization of plasma calcium went along with clinical improvement, sometimes even with correction of coma. Renal function was improved, even when the initial plasma creatinine levels were up to twice normal. Hypercalcemia could reoccur, but the duration of the effect of APD (1 week to several months) depended among other things on the dose administered. The decrease in plasma calcium was accompanied by a decrease in urinary calcium and hydroxyproline, both showing inhibition of bone resorption. In the case of recurrency, the treatment could be repeated with almost unaltered efficacy, except in end-stage cancer disease. When given to 13 normocalcemic patients with bone metastases from breast cancer, hydroxyproline and urinary calcium again decreased. Bone pains and radiologic signs of metastatic bone resorption also showed significant improvement, although these latter effects could also be explained by the antitumoral treatment, in this uncontrolled open trial.(ABSTRACT TRUNCATED AT 400 WORDS)

High tumour contamination of leukaphereses in patients with small cell carcinoma of the lung: a comparison of immunocytochemistry and RT-PCR

In small-cell lung carcinoma (SCLC) tumour cell contamination of leukaphereses is unknown. The present study was performed to define appropriate markers for reverse transcriptase polymerase chain reaction (RT-PCR), then to assess the contamination rate of leukaphereses and corresponding bone marrow samples. Immunocytochemistry (ICC) and RT-PCR methods were also compared. Among the 33 patients included, analyses were performed in 16 who had multiple leukaphereses and 17 who had only bone marrow. Leukapheresis products and bone marrow were analysed by ICC using several specific monoclonal antibodies against neural-cell adhesion molecule (N-CAM), epithelial glycoprotein (EGP-40) and cytokeratins (CK). Samples were also analyzed by RT-PCR for expression for N-CAM, synaptophysin, neuron-specific enolase, chromogranin, cytokeratin-18/-19, CEA, EGP-40, apomucin type 1 (MUC-1) and human endothelial cell-specific molecule (ESM-1). Using ICC staining, contaminating tumour cells were detected in 34% of leukaphereses (27% in patients with limited disease and 43% in those with extensive disease). N-CAM was the most reliable marker for detection of contamination. For RT-PCR, CK-19 and CEA were the only appropriate markers. Positive signal rate in leukaphereses increased to 78% (89% for patients with limited disease and 67% for extensive disease). In bone marrow, both techniques were in agreement whereas in leukaphereses, RT-PCR was better than ICC. A high rate of tumour cell contamination was demonstrated not only in bone marrow but also in leukaphereses from SCLC patients. The most appropriate technique was RT-PCR mainly in patients with limited disease.

Extensive phenotypic analysis of CD34 subsets in successive collections of mobilized peripheral blood progenitors

The transplantation of mobilized progenitor cells after high‐dose chemotherapy shortens haemopoietic engraftment. CD34 cell subsets were examined in 20 consecutive mobilized progenitor cell collections obtained from patients with solid tumours that had not been previously treated. The analysis of CD34 cells was based on the expression of intracellular antigens, surface antigens including CD38, and cell size using multi‐dimensional flow cytometry. We also correlated the numbers of stem cell subsets reinfused to haemopoietic recovery.

Is Cisplatin Required for the Treatment of Non-Small-Cell Lung Cancer? Experience and Preliminary Results of a Phase I/II Trial with Topotecan and Vinorelbine

Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade, paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, and topotecan have been introduced into the clinic. These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5–1.0 mg/m2/day × 5) and i.v. vinorelbine (20–30 mg/m2/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75–1.0 mg/m2/day and i.v. vinorelbine of 25 mg/m2/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m2) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC.

Intensification of chemotherapy for the treatment of solid tumours: feasibility of a 3-fold increase in dose intensity with peripheral blood progenitor cells and granulocyte colony-stimulating factor

Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy.

Interaction of tamoxifen with concurrent cytotoxic adjuvant treatment affects lymphocytes and lymphocyte subsets counts in breast cancer patients

Abstract The effects and interaction of endocrine and cytotoxic adjuvant treatment on measures of cellular immunity were assessed in 41 stage I–II breast cancer patients from International Breast Cancer Study Group trials. Counts of lymphocytes and lymphocyte subsets [(T, T4, T8, B, natural killer (NK) and activated T (AT) cells] were assessed by flow cytometry immediately before adjuvant therapy at baseline and on day 1 of the 3rd cycle. Twenty-two patients received cyclophosphamide, methotrexate and 5-fluorouracil (CMF), 7 CMF and tamoxifen (TAM), and 12 TAM alone. On day 1 of the 3rd cycle the counts of total lymphocytes (P=0.003 ) and all lymphocyte subsets (P<0.05) except AT cells were significantly lower than baseline in the CMF treatment group. There was no significant change in the CMF+TAM or in the TAM treatment group. The combination of CMF and TAM resulted in less pronounced decrease in lymphocyte and subset counts from baseline to day 1 of the 3rd cycle. It seems possible that there is an interaction between TAM with CMF that affects lymphocyte and lymphocyte subset counts during cytotoxic treatment.

Does subjective burden of early breast cancer and its treatment affect immune measures during adjuvant therapy

Psychosocial factors have been described as affecting cellular immune measures in healthy subjects. In patients with early breast cancer we explored bi-directional psycho-immune effects to determine whether subjective burden has an impact on immune measures, and vice versa.Patients (n= 239) operated for early breast cancer and randomized into International Breast Cancer Study Group (IBCSG) adjuvant clinical trials were assessed immediately before the beginning of adjuvant treatment (baseline) and 3 and 6 months thereafter, at the beginning of the corresponding treatment cycle. Cellular immune measures (leukocytes, lymphocytes, lymphocyte subset counts), markers of activation of the cellular immune system (β2-microglobulin, soluble interleukin–2 receptor serum levels), and self-report subjective burden (global indicators of physical well-being, mood, coping effort) were assessed concurrently. The relationship between subjective burden and gradients of immune measures was investigated with regression analyses controlling for adjuvant treatment. There was a pattern of small negative associations between all variables assessing subjective burden before the beginning of adjuvant therapy with the gradients of the markers of activation of the cellular immune system and NK cell counts. In particular, better mood predicted a decline in the course of β2-microglobulin and IL-2r at months 3 and 6. The gradient of β2-microglobulin was associated with mood and coping effort at month 3. However, the effect sizes were very small. In conclusion, in this explorative investigation, there was an indication for subjective burden affecting and being affected by markers of activation of the cellular immune system during the first 3 and 6months of adjuvant therapy. The question of clinical significance remains unanswered. These associations have to be investigated with refined assessment tools and schedules.