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OBJECTIVE: This study aimed to assess the effectiveness of psychodynamic interventions in cancer care. METHODS: Between 2006 and 2009, each consecutive outpatient of the Oncology Center of the University Hospital of Lausanne was invited to participate in a trial evaluating the effects of psychological support. Accepting patients were randomly assigned to an immediate intervention or a delayed intervention [4-month waiting list]. Patients who declined support were asked to participate in an observational group [OG]. Socio-demographic and medical data, anxiety, and depression [HADS], psychological distress [SCL-90], alexithymia [TAS] and quality of life [EORTC] were recorded at baseline, and at 1, 4, 8, and 12-months follow-up. RESULTS: Of the 1973 approached patients, 1057 were excluded, 530 refused, and 386 were included with 196 of them participating in the OG. Of the patients in the intervention group [IG] [N = 190], 94 were randomized to the immediate intervention and 96 to the delayed intervention group (dIG). IG patients were younger, predominantly female, and had more psychological symptoms compared with those in the OG. Although patients of the IG and OG showed significant improvement in quality of life from baseline to 12-months follow-up, other outcomes [anxiety, depression, psychological distress, and alexithymia] remained unchanged. CONCLUSIONS: The intervention was not effective with regards to psychometric outcome. The results have to be interpreted in light of the study design [untargeted intervention], the low levels of psychiatric symptoms, dropout of symptomatic patients, and the high prevalence of alexithymia. more...

Decrire l’alexithymie chez des patients nouvellement diagnostiques de cancer. Les donnees sociodemographiques, medicales et psychometriques (HADS, SCL-90, EORTC-QLQ-C30 et TAS-20) ont ete enregistrees chez des patients recemment ( 56) a ete observe avec une correlation negative avec les symptomes psychiatriques, qui par ailleurs ne depassaient pas les seuils d’anxiete et de depression mesures avec le HADS, et une correlation positive avec la qualite de vie. La haute prevalence de l’alexithymie, consideree comme une protection, questionne la necessite et le type d’eventuelles interventions psycho-oncologiques. more...

Background: CYP2D6 is genetically highly polymorphic and several studies support that patients classified as poor-or intermediate-metabolizers achieve less or no benefit from tamoxifen treatment probably because they have lower levels of endoxifen. Genotyping is currently the major method used in studies and in clinical practice. However the ability of genotyping to predict plasma levels of endoxifen is uncertain for an individual patient. We assessed prospectively CYP2D6 activity by genotyping, phenotyping and the measurement of tamoxifen and its metabolites. Methods: Patients were genotyped for CYP2D6 (*1, *3, *4, *5, *6 and *XN) polymorphism. The CYP2D6 phenotype was determined by the dextromethorphan test. Plasma was collected at 2 time points after at least 4 months of treatment with tamoxifen 20 mg daily: tamoxifen, 4-hydroxytamoxifen, N-demethyltamoxifen and endoxifen were measured with high performance liquid chromatography coupled to triple stage tandem mass spectrometry. Linear regression analyses were performed on log transformed concentrations of tamoxifen, its metabolites, and the ratios 4- hydroxytamoxifen/tamoxifen, endoxifen/N-demethyltamoxifen versus the different genotype groups (UM, EM, IM, PM) and the dextromethorphan/dextrorphan ratio. Results: The data of 26 patients are currently available. Geometric mean plasma concentrations (coefficient of variation %) of tamoxifen, N-desmethyltamoxifen, 4-OH-tamoxifen and endoxifen were 377 nmol/L (39%), 482 nmol/L (36%), 5.9 nmol/L (52%) and 60.7 nmol/L (94%), respectively. Genetic variation in CYP2D6 was significantly correlated with endoxifen, 4-hydroxytamoxifen and the ratios of 4-hydroxytamoxifen/tamoxifen and endoxifen/N-demethyltamoxifen: determination coefficients (R-squared) of 44% (P=0.0002), 30% (P=0.0038), 57% (P= Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-09. more...

This study aimed to assess the effectiveness of psychodynamic interventions in cancer care.Between 2006 and 2009, each consecutive outpatient of the Oncology Center of the University Hospital of Lausanne was invited to participate in a trial evaluating the effects of psychological support. Accepting patients were randomly assigned to an immediate intervention or a delayed intervention [4-month waiting list]. Patients who declined support were asked to participate in an observational group [OG]. Socio-demographic and medical data, anxiety, and depression [HADS], psychological distress [SCL-90], alexithymia [TAS] and quality of life [EORTC] were recorded at baseline, and at 1, 4, 8, and 12-months follow-up.Of the 1973 approached patients, 1057 were excluded, 530 refused, and 386 were included with 196 of them participating in the OG. Of the patients in the intervention group [IG] [N = 190], 94 were randomized to the immediate intervention and 96 to the delayed intervention group (dIG). IG patients were younger, predominantly female, and had more psychological symptoms compared with those in the OG. Although patients of the IG and OG showed significant improvement in quality of life from baseline to 12-months follow-up, other outcomes [anxiety, depression, psychological distress, and alexithymia] remained unchanged.The intervention was not effective with regards to psychometric outcome. The results have to be interpreted in light of the study design [untargeted intervention], the low levels of psychiatric symptoms, dropout of symptomatic patients, and the high prevalence of alexithymia. more...

Thirty patients with previously untreated and measurable or evaluable advanced soft tissue sarcoma entered this phase II study. Median age was 53 years (range: 24-71 years). Starting dose of Epirubicin was 100 mg/m2 IV bolus on day 1 combined with Ifosfamide, 2.5 g/m2, as a 6-hr IV infusion on day 1 and day 2 with uroprotection with Uromitexan, 1.6 g/m2, on day 1 and day 2. This schedule was repeated every 3 weeks. In case of minimal myelosuppression, the dose of Epirubicin was increased by 10 mg/m2 up to 130 mg/m2. Ifosfamide dosage was not increased. Mean cumulative dose of Epirubicin received was 477 +/- 272 mg/m2 (range: 200-1200 mg/m2). Of 27 evaluable patients (WHO criteria), 13 had a partial response (48%), 4 showed no change (15%), and 10 had progressive disease (37%). Median time to progression was 27 weeks. Of 27 patients evaluable for toxicity, hematological toxicity at day 21 was mild. Nonhematological toxicities consisted of nausea and vomiting in 82% of patients (WHO grade 3-4 = 19%), stomatitis in 44.5% (WHO grade 3 = 7.5%), and alopecia in 96% (WHO grade 2-3 = 89%). Appearance of cardiac dysfunction without heart failure during the treatment led to discontinuation of this chemotherapy in 3 patients. The results of this study show that the combination of Epirubicin and Ifosfamide is effective in advanced soft tissue sarcoma with an acceptable toxicity. However, we cannot conclude from this trial whether combination Epirubicin and Ifosfamide is superior to Epirubicin alone. more...

Anti-angiogenic therapies have recently enriched the therapeutic armentarium against the most common cancers. Among these, bevacizumab, a monoclonal antibody against vascular endothelial growth factor, is currently used most frequently. While the addition of bevacizumab to chemotherapy improves overall survival in first and second line treatment of metastatic colorectal cancer, its effect in metastatic breast cancer is limited to improvements in tumor response and progression-free-survival. In non-small-cell lung cancer, the positive results of a first American phase III study have not been confirmed by a second European study and are subject to controversies. A summary of the data concerning anti-angiogenic therapies in these three cancers is presented including safety information. more...

In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]), and survival (median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer. more...

Recent progress unveiling the cellular and molecular basis of the immune response allows nowadays the design of novel therapies for tumor immunotherapy. These recent approaches translate into response rates that often surpass what can be obtained by conventional chemotherapies or targeted therapies. Here we present the main current developments with an accent on the Lausanne experience in the treatment of melanoma. First, the new developments of peptide-based vaccination are presented. Second, approaches related to adoptive transfer are illustrated with a particular attention for the patient conditioning using lymphodepletion. Finally, the Lausanne project of rational lymphocyte TCR optimization is described. more...

Purpose: To validate the Helsinki University Central Hospital (HUCH) Working Formulation, the first substaging system designed to predict prognosis of metastatic uveal melanoma and to facilitate design, reporting and interpretation of controlled clinical trials. Methods: Data of 226 patients who died of disseminated uveal melanoma were collected from members of the European Ophthalmic Oncology Group (OOG). Karnofsky or WHO performance status, largest diameter of largest metastasis and serum alkaline phosphatase (AP) level at diagnosis of metastases, and time to death were requested. The working formulation is based on a multivariate model that identified these variables as independent predictors of survival, modeling time on chemotherapy as a confounding variable (Eskelin et al. Cancer 2003; 97: 65–75). Patients whose predicted survival was less than 6 months were assigned to stage IVc, between 6 and 12 months to stage IVb and over 12 months to stage IVa. Observed survival time was calculated for each stage. Results: The median AP level was 0.69 (range, 0.24-11) times upper normal limit, median largest metastasis was 3.5 cm (range, 0.8-19), and percentage of patients representing WHO performance index 0, 1-2 and 3 was 61%, 38% and 1%, respectively. Of the 226 patients, 100 (44%) were assigned to stage IVa, 97 (43%) to IVb and 29 (13%) to IVc. The median observed survival times were 18.3, 10.0 and 4.6 months, respectively. In Kaplan-Meier analysis, the stages reflected best to worst survival (P more...

To make a diagnostic of cancer in a young adult (15-30 years of age) has important physical, psychological and social implications. The most frequent cancers seen at this age are cancer of the thyroid, testicular germ cell tumours, 'melanoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, leukaemia, cerebral tumours and sarcomas. Even if the prognostic of most of these cancers is excellent, treatments are difficult and often associated with long-term side effects. A multidisciplinary approach of these patients is essential. A long-term follow-up by a general practicioner or an oncologist is indispensable. more...

About 40% of the cancer patients suffer from depressive disorders which are seldom identified and even more rarely treated. Depression leads to a reduction in quality of life, diminished medical treatment compliance, prolonged hospital stays, and a reduction of global functioning. Aim of the study: The aim of the study is to compare the effectiveness of a standard treatment based on the guidelines for the management of major depression in the medically ill [1] with a short psychodynamic psychotherapy in cancer patients with major depression (MD) and adjustment disorders (AD) with depressive symptoms in an oncology population [2]. Methods: Cancer patients fulfilling the DSM-IV criteria for a MD and AD are randomly assigned to two groups. The first group receives standard treatment (pharmacotherapy, regular consultations by an oncologist) and the second a short psychodynamic psychotherapy of 16 sessions. Evaluation of effectiveness consists of pre and post intervention results, as well as intermediary and follow-up outcomes. Results: A total of 30 patients were included in the study, to date. Preliminary results indicate an improvement of depressive symptoms after 8 and 16 weeks in both groups, with a difference, though not statistically significant, favouring the psychotherapy; limitations of the study have to be addressed. Literatur: 1. Voellinger, R., et al., Major depressive disorder in the general hospital: adaptation of clinical practice guidelines. Gen Hosp Psychiatry, 2003. 25(3): p. 185-93. 2. Stiefel. F., Stagno, D. Intervention psychotherapeutique aupres des patients cancereux souffrant d'une symptomatologie depressive ; une etude clinique randomisee. Fondation Kisane 2005-2006. more...

Meaning in life is an important source of adaptation to somatic diseases. Aim: To validate the SMiLE (Schedule for the Meaning in Life Evaluation), a qualitative and quantitative instrument evaluating the meaning in life perceived by patients suffering from advanced cancers. The first step of this project is to develop and evaluate psychotherapeutic interventions. Methods: Cancer out patients in a palliative phase of disease were approached and possibly included. The SMiLE is an instrument, which helps patients to identify a maximum of seven fields which produces or could produce meaning in life. The relative importance of each field is weightened by means of a visual scale. The overall meaning in life is scored by a visual analogue scale ranging from –3 to 3. Patients are then asked to rate their satisfaction for each field and to define its importance on VAS ranging from 0 to 5. Face validity, feasibility and acceptability is also evaluated by VAS. Reliability has been assessed by test/retest at a three days interval in a sample of medical students. External validity will be evaluated by means of a comparison with the under-scale MEANING of the questionnaire FACIT-Sp and a VAS measuring the perception of the total meaning given in life. With the index of Karnofsky, VAS of physical symptoms and the Edmonton Symptom Assessment Scale potential sources of confounding variables are identified. Generalisation, comparison with a healthy population and cross-cultural differences will be evaluated by means of research centres (Lausanne, Munich, Dublin). Results: After 1 year of study, 99 patients are included in the study. So far, results indicate satisfying face validity, feasibility and acceptability. Further results will be presented in march 2007 at Nurnberg congress. Conclusion: Preliminary results indicate that the SMiLE is an adequate instrument to identify and evaluate fields that produce or could produce meaning in life in patients with advanced cancer. more...

Advances in cancer biology have led to the development of screening tests that allow an early diagnosis. Cancer screening is not just the matter of a single individual patient, it is a matter of public health. Screening is commonly viewed as of no harm, when in fact harms are associated with the majority of cancer screening tests. A test should only be used when the potential of benefit clearly outweighs the risks for harm. The data in the literature are not always clear cut and in a lot of cases guidelines are somewhat controversial. What is known and what is unknown about screening tests is quite different from what is believed by the public. The aim of this work is to summarize the different methods and guidelines in cancer screening to help choosing the right test at the right time for the right person. more...

This study was performed to compare the sensitivity of ultrasonography, computerized tomography during arterial portography, delayed computerized tomography, and magnetic resonance imaging to detect focal liver lesions. Forty three patients with primary or secondary malignant liver lesions were studied prior to surgical intervention.The results of the imaging studies were compared with intraoperative examination of the liver, intraoperative ultrasonography and pathology results (29 patients). In the non-operated (14 patients) group, we compared the number of lesions detected by each technique.One hundred and forty six lesions were detected. There was 84% sensitivity with computerized tomography during arterial portography, 61.3% with delayed scan, 63.3% with magnetic resonance imaging and 51% with ultrasonography in operated patients. In patients who did not undergo surgery, magnetic resonance imaging was more sensitive in detecting lesions.In operated and non-operated patients series, CT during arterial portography had the highest sensitivity, but magnetic resonance imaging had the most consistent overall results. more...

The prevalence of anaemia in patients with cancer lies between 10 and 40%, depending on the type of tumor and chemotherapy. Anaemia has a significant impact on the quality of life, along with pain or disease progression. There are multiple causes but the physiopathology resembles that of inflammatory anaemia. The following mechanisms can be distinguished: a resistance of the erythroid precursor cells (BFU-e, CFU-e) to erythropoietin, an inappropriately decreased renal erythropoietin secretion for a given haemoglobin value and alterations of the iron metabolism leading to a functional iron deficiency. Recombinant human erythropoietin (r-hu-EPO) is safe and efficient in the treatment of anaemia of chronic renal failure and rheumatoid arthritis. In oncology different phase I and II studies have demonstrated an efficacy (increase of haemoglobin, decrease of transfusion requirements) in about 50% of all adult patients. A response to a subcutaneous r-hu-EPO treatment with a relatively high posology of 150 U/kg three times a week can be expected after one to two months. No single reliable parameter will predict a response to the r-hu-EPO treatment. Several phase III studies confirm that anaemia in cancer patients undergoing chemotherapy (notably with cisplatin) can be corrected in 40 to 60% of all cases and that the haemoglobin increase improves the quality of life. Finally, recent clinical trials suggest that an early r-hu-EPO treatment might prevent the occurrence of anaemia secondary to chemotherapy. Several parameters will have to be specified such as the precise definition of the groups at risk, the appropriate haemoglobin level to initiate a r-hu-EPO treatment, its optimal posology, as well as the role of the iron substitution and its route of administration. The impact of the r-hu-EPO treatment on the quality of life of cancer patients constitutes a priority for future studies, which will have define the exact role of r-hu-EPO in oncology management. more...

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m−2 by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1–9) per patient. The median cumulative dose was 449 mg m−2. Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1–50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4–52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h−1 m−2 and an area under the curve of 6.00 μg ml−1 h−1 was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance. © 1999 Cancer Research Campaign more...

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. The majority of CD34+ cells expressed CD13 and CD33. A significant proportion was cytoplasmic myeloperoxidase (cMPO) positive. CD34+ MPO+ cells increased significantly in late collections. MPO expression was related to cell size. Cells expressing CD13 also increased in late collections in parallel to CFU-GM count. Small subpopulations of CD34+ CD38+ were committed to B cells, T cells and erythroid cell lineages. A small population expressing the megakaryocytic antigen had a small size and were predominantly CD38-. A minor subpopulation expressed stem cells antigens. These were significantly higher in late collections (CD34+ Thy-1+ and CD34+ CD33-). After mobilization, patients received three cycles of intensive chemotherapy followed by reinfusion of mobilized progenitors (5.45 x 10(6)/kg CD34+ cells, range 3.4-11.88). The numbers of reinfused CD34 cells or the individual subsets did not influence recovery of leucocytes (9 d) or platelets (9 d). In conclusion, the numbers of stem cells and their subsets differed between collections and, in unpretreated patients receiving intensive chemotherapy, there was no delayed engraftment when sufficient numbers of stem cells were reinfused. The recovery period was short and not correlated to any stem cell subsets. more...

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover.Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days.The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years.The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival. more...

A wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorectal cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting survival benefit as opposed to FU alone (J Clin Oncol 1989; 7: 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both treatment arms.Patients with inoperable or metastatic colorectal cancer were randomized to receive monthly FU 400 mg/m2/day plus LV 20 mg/m2/day as intravenous push daily for five days, or FU alone.Three hundred nine of the 310 patients randomized were eligible and included in the analysis. The objective response rate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO2 toxicity, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), was more pronounced for FU-plus-LV, without fatal events.This is the largest published randomized trial to compare FU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survival benefit obtained from biomodulating monthly FU with low-dose LV. The toxic effects of FU-plus-LV were acceptable to most patients, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dose LV provides a simple and economical means by which to achieve adequate FU efficacy in the treatment of advanced colorectal cancer. more...

It has previously been reported that MAGE-1, -2, -3 and -4 genes are expressed in human cancers including cutaneous melanoma. MAGE-1 and MAGE-3 represent targets for specific immunotherapy because they encode peptide antigens which are recognised by cytotoxic T lymphocytes (CTL) when presented by HLA class I molecules, and pilot clinical trials with these peptides are currently in progress. It is likely that other members of the MAGE gene family may also encode antigens recognised by CTL. Uveal melanomas, like cutaneous melanomas, arise from melanocytes that are derived from the neural crest. To determine if uveal melanoma patients would be suitable for MAGE-peptide immunotherapy, the expression of MAGE-1, -2, -3 and -4 genes was assessed by reverse transcription followed by polymerase chain reaction (RT-PCR) amplification and ethidium bromide staining. Expression of MAGE genes was not detected in any of 27 primary tumours. Either MAGE-1 or MAGE-4 was expressed in only 2 of 26 metastatic samples, but expression of MAGE-2 or -3 was not detected. Our data suggest that, unlike cutaneous melanomas, uveal melanomas may not be suitable candidates for MAGE-peptide immunotherapy. more...

Summary Background The primary aim was to induce a high number of pCR in early (FIGO IC, IIB + C) – and advanced (FIGO ffl – IV) – stage ovarian cancer with a surgery plus 4 cycles of cisplatin and meiphalan (PAMP) regimen. The second objective was to prevent relapse with WAR in patients in remission after chemotherapy. Patients and methods 218 eligible patients were treated after staging laparotomy with cisplatin 80 mg/sqm iv. on day 1 and melphalan 12 mg/sqm i.v. on day 2 q 4 weeks. Response was verified by second-look laparotomy. WAR was carried out with the open field technique on a linear accele rator (daily dose: 1.3 Gy, total dose: 29.9 Gy) in patients with pathological or clinical CR or pathological PR with microscopical residual disease. Results 146/218 patients (67%, 95% CI: 61%–73%) responded to PAMIP: 56 (26%) achieved pCR, 24 (11%), cCR, 56 (26%) pPR and 10 (5%) cPR (c = clinical, p = pathological). Multivariate analyses revealed that in advanced stages (92 cases in remission), the achievement of pCR was the most important factor for longer time to failure (TIF) and survival. Only 5 1/118 (43%) patients in remission received WAR Early-stage patients < = 55 years were more likely to have WAR than patients older than 55 years (77% vs. 23%; p = 0.02). Advanced-stage patients with cCR were less likely to be irradiated than patients with pCR or pPR (10% vs. 51%; p = 0.003). Toxicity of PAMP was acceptable with 10% of WHO grade 4 hematologic toxicity. Acute hematological toxicity of WAR caused interruption (33%) or incompleteness (33%) of irradiation in the majority of patients. Conclusions PAMP is an effective treatment for advanced ovarian cancer with a 67% response rate after 4 cycles. For the majority of patients in remission, WAR as a consolidation treatment was hardly feasible. For these patients new treatment modalities to consolidate remission are needed. more...

During the last years, high-dose chemotherapy with autologous hematological rescue has been increasingly used not only in the treatment of patients with relapsing lymphoma but also in ovarian and breast carcinoma. In this manuscript we present results in patients with high-risk primary breast cancer, and in those with metastatic tumors. When high-dose chemotherapy is given in the adjuvant setting for women presenting withor = 10 metastatic axillary nodes, results are very promising since 72% of the patients are alive without evidence of disease more than 3 years after operation. In patients with inflammatory breast carcinoma, high-dose chemotherapy induces 80% of complete remissions. Considering patients with metastatic disease, high-dose, chemotherapy increases the complete remission rate and duration of response. In several studies, survival exceeding 5 years without relapse is seen in 10 to 15% of the patients. Toxic death rate globally is 10% and is decreasing progressively since the first studies. However, in order to really determine the value of high-dose chemotherapy with autologous hematological support, randomized trials will be needed, comparing this new approach to conventional treatment. Such studies are already going on in the USA and in Europe and results are awaited with great interest. more...

From 1988 to 1992 the Swiss Group for Clinical Cancer Research (SAKK) entered 113 patients with Hodgkin's disease into three stage adapted trials (HD-4-6) from the German Hodgkin Study Group (DHSG). In an interim analysis freedom from treatment failure (FFTF) and overall survival (OS) of the SAKK patients (SAKK-pt) were compared to the remaining study population (GHSH-pt) (median follow-up: 30 months for HD-4 and HD-5, 24 months for HD-6).HD-4: SAKK (n = 16), DHSG (n = 241), FFTF-SAKK: 100%, FFTF-DHSG: 85%, p: ns, OS-SAKK: 100%, OS-DHSG: 99%, p: ns, HD-5: SAKK (n = 66), DHSG (n = 639), FFTF-SAKK: 90%, FFTF-DHSG: 85%, p: ns, OS-SAKK: 93%, OS-DHSG: 95%, p: ns, HD-6; SAKK (n = 31), DHSG (n = 411): FFTF-SAKK: 62%, FFTF-DHSG: 68%, p: ns, OS-SAKK: 70%, OS-DHSG: 88%, p0.008. The results in the SAKK patients with advanced disease are unsatisfactory. Despite the fact that the treatment was given on time with full doses, 10/30 patients achieved no complete remission (CR). Only one patient relapsed after an initial CR. 6 patients had primary progressive disease. 6 patients died despite conventional salvage chemotherapy. High dose chemotherapy/autologous bone marrow transplantation (HDC/ABMT) was only given to 3 out of 8 potential candidates. Only 2/11 patients are still alive and disease-free after relapse or initial progression. Both had received HDC/ABMT as part of their salvage regimen. This interim analysis identifies a group of patients in which treatment strategies need to be optimized. more...

From 1984 to 1989, the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial comparing early versus late alternating chemotherapy in patients with small-cell lung cancer.406 eligible patients were entered into the trial. Regimen A consisted of PAV (cisPlatin, Adriamycin, VP 16-213, and Regimen B of CyMOC (Cyclophosphamide, Methotrexate, Oncovin, CCNU). Cycles were repeated as rapidly as possible. patients were randomized to receive either ABABAB (early alternating chemotherapy) or AAABBB (late alternating chemotherapy). After six cycles patients with limited disease in complete or partial remission and those with extensive disease in complete remission received irradiation to the primary (45 Gy) and the CNS (36 Gy).The overall remission rate was 87% with 31% complete remissions. The median survival of all 406 eligible patients was 346 days with 15% of the patients alive at two years. The overall remission rate, the rate of complete remission, the median survival and the rate of long-term survival were not significantly different in the two treatment arms. In limited disease the estimated percentages of survival at 2 years were 33% in the early and 24% in the late alternating chemotherapy arms. Patients with extensive disease survived significantly longer with late alternating chemotherapy than on the early alternation regimen (median survival 336 days versus 301 days, p = 0.01). In the latter patients the received dose intensities (RDI) of cisplatin, adriamycin and etoposide were significantly higher in the late-alternation arm. Patients treated with early alternating chemotherapy rated their tumor symptoms, functional states, fatigue/malaise and restriction of social activity significantly better, reflecting an improved subjective adjustment.Alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is a feasible and effective treatment for small-cell lung cancer, with acceptable toxicity. Whereas patients with early alternating chemotherapy achieve a better subjective adjustment, late alternating chemotherapy allows for a higher RDI of cisplatin, adriamycin and etoposide, which results in a significantly longer median survival of patients with extensive disease. more...

Background: Retrospective studies assessing the impact of tamoxifen (Tam) metabolism and its active metabolite, endoxifen, on the efficacy of the treatment produced conflicting results. The prospective CYPTAM-BRUT 2 trial is ongoing1. In the present study we assessed if the level of Tam metabolites could be improved by doubling tamoxifen dose in breast cancer patients (pts) with any CYP2D6 genotype, poor (PM), intermediate (IM) and also extensive metabolizer (EM). Patients and methods: This multicenter, prospective, open-label trial included pts treated with Tam for ≥ 4 months. CYP2D6 activity was determined centrally by genotyping and phenotyping (dextromethorphan test). Liquid chromatography-tandem-mass spectrometry was used to measure Tam, N-desmethyltamoxifen (N-DMT), 4-hydroxytamoxifen (4-HT) and endoxifen twice at baseline (Tam 20 mg qd), then at days 30, 90 and 120 after having increased the dose to 20 mg bid. Endoxifen increase and the differences between genotype/phenotype subgroups were analyzed by ANOVA. Results: 76 pts were analyzed. Steady-state concentrations for Tam and its metabolites were reached in 30 days after doubling the dose. A range of 1.6 to 1.8 fold increase was observed. Geometric mean plasma concentrations in ng/ml (CV%) were: at baseline and day 30 respectively 134 (48) and 246 (46) for tamoxifen (p < 0.0001); 246 (53) and 413 (48) for N-DMT (p < 0.0001); 2.3 (44) and 3.7 (51) for 4HT (p < 0.0001); 18.7 (89) and 31.1 (92) for endoxifen (p = 0.005). The level of endoxifen increased 1.4 to 1.7 folds in all genotype subgroups with geometric mean plasma concentrations in ng/ml (CV%): 6.9 (36) to 9.7 (24) in PMs (p = 0.7); 14.2 (69) to 20.7 (76) in IMs (p < 0.0001); and 22.6 (76) to 38.7 (85) in EMs (p < 0.0001). Similar results were obtained while considering phenotype subgroups. Genotypes and phenotypes explained less than 30% of the variability in endoxifen levels. The occurrence of hot flashes and night sweating were followed prospectively. Endoxifen levels did not predict an increase in HF/NS events' overall occurrence (OR = 1.01, CI95% 0.78–1.31 for HF and 1.01, CI95% 0.79–1.29 for NS). Twelve pts received CYP2D6 inhibitors. Nine pts did not complete the planned 4 months with tamoxifen 20 mg bid. The main reasons were mood disorders, hot flashes, headache and nausea. Self-reported treatment compliance assessed by monthly anonymous questionnaire was ≥ 95%, except 80–95% in 4 pts. Conclusions: This is the first trial reporting the impact of the increase of tamoxifen dose in all CYP2D6 genotypes, including EMs. Dose escalation of tamoxifen increased significantly the plasma level of endoxifen by similar ratio in all genotype subgroups. Because of a huge inter-individual variability genotyping and phenotyping are not adequate surrogate markers of endoxifen level. Very low endoxifen levels are observed even in pts classified as EM. Future trials aiming to improve the plasma level of endoxifen should consider direct measurement of the metabolite in plasma and adjust tamoxifen dose according to the initial level of the metabolite independently of the genotype. Reference 1. A. Dieudonné, Journal of Clinical Oncology, 2011; vol 29, No 15, suppl (May 20, 2011): TPS 140 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-05. more...

Several articles covering treatment of mammary carcinoma in situ and invading mammary cancer have been published recently. This article delivers a short description of the clinical picture and the treatment of a noninvasive tumor as well as of the mainly conservative primary treatment of invasive carcinoma in common use since 20 years. Systemic adjuvant treatment is discussed in the context of results from a meta-analysis publishes two years ago in 'Lancet'. Finally, various directives for the execution of an adjuvant treatment are given that are offered today outside of a study protocol. more...

1. A novel anticancer vinca alkaloid derivative (I) has been given as an i.v. bolus to cancer patients, using four different dosage regimens with dose levels ranging from 0.04 to 0.84 mg/m2 (equivalent to between 0.12 and 1.35 mg per dose), and the pharmacokinetics determined up to 72 h after dosing. In addition, secondary effects of leukopenia and neutropenia, were related to drug exposure using a sigmoid Emax model. 2. Plasma levels of I declined in a triphasic manner with a terminal half-life of approximately 50 h; most drug elimination (55%) being associated with the terminal phase. 3. Clearance of I was relatively low (245 +/- 160 ml/min) and remained constant with increasing doses. Initial distribution volume was low (approximately 71) but once distribution was complete, it was comparatively high (327 +/- 2121). 4. Both leukopenia and neutropenia were fitted successfully to a sigmoid Emax model showing that these effects were related to the total exposure to the drug. The Hill constant was less than 1, indicating a relatively shallow exposure/response curve and a predictable, graded increase in response with increasing I exposure, rather than a sudden quantal response. 5. Pharmacokinetically, I shows some similarities to other vinca alkaloids in its plasma level decline profile, although there are some notable differences which can be exploited clinically. In addition, the ability to model both leukopenia and neutropenia to the exposure to I, provides a valuable tool in the design of the most appropriate dosage regimen for the drug, as well as for dose adjustment taking into account inter-individual variations. more...

From 1984 through 1986, 205 patients with non-small cell lung cancer were entered into a group-wide trial of the Swiss Group for Clinical Cancer Research (SAKK). This trial evaluated the combination of mitomycin (8 mg/m2 intravenously [IV] on day 1), vindesine (3 mg/m2 IV on days 1 and 8), and cisplatin (60 mg/m2 IV on day 1) with forced diuresis, repeated every 4 weeks (MiViP regimen). One hundred eighty-three patients were evaluable. Six complete and 69 partial responses were documented for an overall response rate of 41% (95% confidence interval, 34% to 50%). In the multivariate analysis the strongest predictors for response were the participating institution and the number of initially involved organ sites. The estimated median time to progression for patients with a complete response, partial response, or stable disease was 155 days (estimated inter-quartile range, 99 to 258 days). In the multivariate analysis the time to progression was significantly associated with the number of involved organ sites (P = 0.041). The estimated median survival time for the 183 evaluable patients was 239 days (estimated inter-quartile range, 137 to 436 days). In univariate and multivariate analyses performance status, number of involved organ sites, pretreatment status with radiation therapy, and participating institution were all significantly associated with survival. The principal toxicities were myelosuppression and nausea and vomiting with 16% of the patients refusing further treatment after a median of four cycles of chemotherapy. In conclusion, the MiViP regimen was an active combination chemotherapy in patients with non-small cell lung cancer in a large trial performed by the SAKK. The prognostic value of the participating institution and the number of organ sites involved by metastatic deposits in non-small cell lung cancer needs further investigation. more...