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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.

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.

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.

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.

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.

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

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.

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.

Between April 1981 and June 1985, 195 patients with ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) Stages IIB, IIC, III, and IV, entered a trial that consisted of surgery and chemotherapy with cisplatin (P) and melphalan (PAM) with or without hexamethylmelamine (HexaPAMP or PAMP regimens) every 4 weeks for 6 cycles. Because the intent was to study the outcome by treatment after evaluation of first-line chemotherapy, patients were evaluable only if the response was assessed by a second-look operation or if measurable disease progression was documented. One hundred fifty-eight patients (81%) were evaluable for response. Forty-five (28%) achieved pathologically confirmed complete remissions (pCR), and 24 of these patients received whole-abdominal radiation (WAR) for consolidation of response. Five patients with complete remission after WAR relapsed, as did nine of the 21 with complete remission who had not undergone WAR. The 3-year time to progression percentage (TTP +/- SE) from second-look operation was 70% +/- 7% for all patients who achieved pCR, 83% +/- 8% for those who received WAR, and 49% +/- 15% for those who did not receive WAR (this was not a randomized comparison). The 3-year TTP percentage for the 49 partial responders was 21% +/- 6%, identical for the 19 who had WAR and the 30 who had no radiation therapy. Additional or alternative methods for consolidation of pCR are needed since patients continue to relapse despite optimal initial response to therapy.

Paraneoplastic neurologic syndromes (PNS) are remote, nonmetastatic complications of systemic cancer. Clinically they are characterized by subacute, progressive neurologic deficits that usually result in profound disability and eventually death. PNS may be present as long as 2 to 4 years before diagnosis of the associated tumor, but it can develop after diagnosis or when the cancer is thought to be in remission. Serum and cere-brospinal fluid (CSF) from many patients with PNS contains antineuronal antibodies which recognise antigens within the tumor. This suggests that PNS are autoimmune disorders in which the immune response, elicited by the patient’s tumor, cross-reacts with specific neuronal proteins.