Maintaining professional activity during breast cancer treatment.

The question of returning to work and pursuing professional activity during cancer treatment is an increasingly important consideration. The present work focuses on factors affecting the feasibility of maintaining professional activity during treatment for breast cancer, for women who wished to do so. Written questionnaires were collected from 216 patients between March and November 2012. Since the onset of their treatment, 31.4% of the women (68/216) had not been on sick-leave. The main factors associated with the pursuit of professional activity were: considering the availability of their physician to answer questions as unimportant [OR = 18.83 (3.60-98.53); P ≤ 0.05]; considering the diagnosis of cancer as likely to have a weak impact on career perspectives [OR = 4.07 (2.49-6.64); P ≤ 0.05]; not having any children in the household [OR = 3.87 (2.38-6.28); P ≤ 0.05]; being in a managerial position [OR = 3.13 (1.88-5.21); P ≤ 0.05]. Negative predictive factors were: physician mentioning adverse effects of the treatment [OR = 0.31 (0.16-0.58); P ≤ 0.05], and patient rating workload as high [OR = 0.26 (0.15-0.46); P ≤ 0.05]. As a result of advances in therapeutic strategies, more patients will expect healthcare professionals, as well as employers and occupational health societies, to prioritise issues pertaining to the maintenance of professional activities during cancer treatment.

Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study.

BACKGROUND: Trastuzumab (T) combined with chemotherapy has been recently shown to improve outcome in HER2-positive breast cancer (BC). The aim of this study was to evaluate the toxic effects of concurrent radiation therapy (RT) and T administration in the adjuvant setting. PATIENTS AND METHODS: Data of 146 patients with stages II-III HER2-positive BC were recorded. Median age was 46 years. In all, 32 (23%) and 114 (77%) patients received a weekly and a 3-week T schedule, respectively. A median dose of 50 Gy was delivered after surgery. Internal mammary chain (IMC) was irradiated in 103 (71%) patients. RESULTS: Grade >2 dermatitis and esophagitis were noted in 51% and 12%, respectively. According to the Common Toxicity Criteria v3.0 scale and HERA (HERceptin Adjuvant) trial criteria, respectively, 10% and 6% of the patients had a grade >/=2 of left ventricular ejection fraction (LVEF) decrease after RT. Multivariate analyses revealed two independent prognostic factors: weekly T administration (for LVEF decrease) and menopausal status (for dermatitis). Higher level of T cumulative dose (>1600 mg) was only borderline of statistical significance for acute esophagitis toxicity. CONCLUSION: We showed that weekly concurrent T and RT are feasible in daily clinical practice with, however, a decrease of LVEF. Cardiac volume sparing and patient selections for IMC irradiation are highly recommended. Longer follow-up is warranted to evaluate late toxic effects.

Serum caspase-1 levels in metastatic melanoma patients: relationship with tumour burden and non-response to biochemotherapy.

Interleukin-1beta converting enzymes (ICEs/caspases) are involved in programmed cell death (apoptosis). This study sought to quantify the caspase-1 level in metastatic malignant melanoma patients and to try to establish a correlation between the level of caspase-1 and different parameters related to this pathology. In addition, we evaluated the possible relationship between the clinical response to biochemotherapy and the caspase-1 level. The serum caspase-1 level was determined in 81 metastatic malignant melanoma patients and 50 normal volunteers using enzyme-linked immunosorbent assay (ELISA). Patients received cisplatin, recombinant interleukin-2 (Proleukin) and alpha-interferon (Roferon A) in two induction cycles, and assessment of clinical response was performed according to World Health Organization (WHO) criteria. The median caspase-1 level in melanoma patients was significantly higher (P = 0.0035) than in control samples. Interestingly, a positive correlation between caspase-1 level and the tumour burden was shown (rs = 0.629, P = 0.009). When the clinical response was taken into consideration, the level of caspase-1 was significantly higher in biochemorefractory patients compared with responding ones (P = 0.04). After treatment, the caspase-1 level remained very high in biochemorefractory patients, while in responding ones no change was observed. Furthermore, a positive correlation between the clinical response and the caspase-1 level was established (rs = 0.404, P = 0.024). In conclusion, we observed an elevated caspase-1 level in metastatic malignant melanoma patients. In addition, the correlations obtained between the caspase-1 level and both the tumour burden and the clinical response to the treatment support the concept that disrupted apoptosis pathways might be involved in the progressive disease of advanced melanoma and/or may confer resistance to treatment.

A before-after study using OncoDoc, a guideline-based decision support-system on breast cancer management: impact upon physician prescribing behaviour.

Guideline-based decision support systems have been developed to influence the prescribing behaviour of clinicians, but they have not yet shown to increase physician compliance with best practices in routine. OncoDoc is a non-automated system that allows flexibility in guideline interpretation to obtain best patient-specific recommendations at the point of care. OncoDoc is applied to breast cancer management. We have experimented the system at the Institut Gustave Roussy with a before-after study in which treatment decisions for breast cancer patients were measured before and after using the system in order to evaluate its impact upon physicians' prescribing behaviour. After 4 months, 127 decisions were recorded. Physicians compliance with OncoDoc was significantly improved (p < 10(-4) ) to reach 85.03% after using the system. Comparison of initial and final decisions showed that physicians modified their prescription in 31% of the cases. Clinical trial accrual rate increased of 50%, though not statistically significant because estimated on small figures.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.

Phase I-II study of irinotecan in combination with mitomycin C in patients with advanced gastrointestinal cancer.

This phase I-II study was conducted to determine the maximum tolerated dose and optimal schedule of a combination of irinotecan (CPT 11) and mitomycin C (MMC) in a population of previously treated patients with gastrointestinal malignancies. Four cohorts of patients were recruited with MMC given at 8 mg/m2 for the first 3 levels together with irinotecan at 300 mg/m2, 325 mg/m2, and 350 mg/m2; the fourth dose level was given with MMC at 10 mg/m2 and irinotecan at 325 mg/m2. All treatment was repeated at 21-day intervals. The dose-limiting toxicity was hematologic (thrombocytopenia at level 4), and the recommended doses for subsequent phase II studies are MMC 8 mg/m2 with irinotecan 325 mg/m2. Evidence of efficacy was seen at all dose levels examined and justifies further exploration of this combination in a less heavily pretreated patient population.

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer.

Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. Irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). Oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.

ONCODOC: a successful experiment of computer-supported guideline development and implementation in the treatment of breast cancer.

Originally published as textual documents, clinical practice guidelines have poorly penetrated medical practice because their editorial properties do not allow the reader to easily solve, at the point of care, a given medical problem. However, despite the proliferation of implemented clinical practice guidelines as decision support systems providing an easy access to patient-centered information, there is still little evidence of high physician compliance to guidelines recommendations. Apart from physicians' psychological reluctance, the incompleteness of guideline knowledge and the impreciseness of the terms used, another reason may be that, although suited to average patients, clinical practice guideline recommendations are not a substitute for the physician-controlled clinical judgement that should be applied to each actual individual patient. Therefore, computer-based approaches based on the automation of context-free operationalization of guideline knowledge, although providing uniform optimal strategies to problem-focused care delivery, may generate inappropriate inferences for a specific patient that the physician does not follow in practice. Rather than providing automated decision support, ONCODOC allows the clinician to control the operationalization of guideline knowledge through his hypertextual reading of a knowledge base encoded as a decision tree. In this way, he has the opportunity to interpret the information provided in the context of his patient, therefore, controlling his categorization to the closest matching formal patient. Experimented in life-size ONCODOC demonstrated good appropriation of the system by physicians with significantly high scores of compliance. We successfully tested the implemented strategy and the knowledge base in a second medical institution, giving then a noticeable example of reuse and sharing of encoded guideline knowledge across institutions.

A comparative study of Fas and Fas-ligand expression during melanoma progression.

BACKGROUND: Impaired regulation of apoptosis is known to be associated with the development of various cancers. Fas receptor (APO-1/CD95) binding to its ligand, Fas-ligand (Fas-L), has been shown to trigger apoptosis in various cell types. OBJECTIVES: In this study, we examined CD95 and Fas-L expression on primary and metastatic melanoma cells from patients to investigate a potential correlation between these measures of apoptosis and different disease stages. PATIENTS AND METHODS: Primary melanoma cells were obtained after surgical resection from 19 patients and metastatic cells from fine-needle aspiration of lymph nodes or palpable subcutaneous lesions in 25 patients. Normal skin cells were obtained at skin biopsy of 10 healthy donors. RESULTS: Flow cytometric analysis revealed that CD95 and Fas-L expression was detected in all the kinds of cell studied. In whole cell suspensions, CD95 expression was significantly higher (P < 0.0001) in normal skin cells than in melanoma cells, whatever the stage studied. By contrast, we observed an increase in Fas-L expression in melanoma cells compared with normal ones. Subsequently, using a double staining method, we studied these measures on HMB45+ cells, a specific marker for melanoma cells, and found that CD95 expression was significantly higher (P = 0.0005) in primary than in metastatic cells while Fas-L expression was significantly increased (P = 0. 0004) in metastatic compared with primary cells. Furthermore, a relationship was found between CD95 or Fas-L expression and Breslow thickness; as primary melanoma thickness progressively increased, the percentage of HMB45+ CD95+ cells decreased while that of HMB45+ Fas-L+ cells concurrently increased. CONCLUSIONS: These results suggest that downregulation of CD95 and upregulation of Fas-L in melanoma might be considered as concomitant with disease progression.

Management of advanced prostate cancer.

Most cases of advanced carcinoma of the prostate are hormonosensitive. The use of combined androgen blockade (CAB) seems to improve survival and quality of life, but only when combined with chemical castration by luteinizing-hormone-releasing hormone analog and without the use of steroidal antiandrogens. After CAB, further hormonal treatments remain efficacious, such as antiandrogen withdrawal followed by estrogens, aromatase inhibitors, and hormone-refractory prostate cancer multiple cytotoxic agents. For painful bone lesions, external beam radiotherapy, biphosphonates, and strontium 89 or samarium 153 provide pain relief. The use of new methods for the evaluation of response and quality of life will allow the rapid identification of effective treatments and permit powered phase III trials.

Effect of endogenous interleukin-6 on Fas (APO-1/CD95) receptor expression in advanced melanoma patients.

Interleukin-6 (IL-6) has been shown to support either autocrine or paracrine growth in melanoma, and may prevent programmed cell death in different cell types. We have previously demonstrated that the endogenous IL-6 level is significantly correlated with tumor burden and nonresponse to biochemotherapy in metastatic malignant melanoma patients. In the present study, we investigated the relationship between endogenous IL-6 and apoptosis signal through Fas (APO-1/CD95) receptor expression in 9 responder and 15 refractory patients with metastatic disease treated by biochemotherapy. Before any treatment, double immunostaining demonstrated that 61.5% of the tumor cells were HMB45+CD95+. At day 49 in refractory patients, a significant decrease (p = 0.04) of total Fas expression was observed. Furthermore, a significant reduction (p = 0.032) in the percentage of HMB45+CD95* cells occurred. An 11-fold increase in serum IL-6 level was detected (p < 0.002). This increase was negatively correlated (r = -0.2, p = 0.008) with the decrease in total Fas expression. However, in responding patients, no detectable decrease in Fas expression was observed, while a very low increase in serum IL-6 (2-fold) was detected. These results suggest that the increased endogenous IL-6 level in refractory patients may inhibit apoptosis via modulation of Fas expression. These preliminary results must be interpreted with caution, and further study with a greater number of patients is needed to understand the mechanism by which IL-6 inhibits apoptosis in melanoma.

Users' evaluation of OncoDoc, a breast cancer therapeutic guideline delivered at the point of care.

Despite the dissemination of computer-based "clinical practice guidelines" as decision support systems, low practical compliance rates are still observed. The reason commonly invoked is that such recommendations, suited to average patients, are not rules for all the patients. Rather than providing automatic decision support, OncoDoc allows the clinician to operationalize the implemented breast cancer therapeutic expertise through his hypertextual reading of the knowledge base. In this way, he has the opportunity to interpret the information provided in the context of his patient therefore controlling his categorization to the closest appropriate "average patient". After a four-month real-life experimentation of the system, a survey was conducted among the users. The observed compliance, significantly higher than the best figures found in the literature, and the clinicians objective and subjective evaluation of the system reinforced the implementation choices adopted in OncoDoc.

[Patient-centered consultation of "good practice guidelines": OncoDoc, a decision support system for the management of breast cancer patients]. / Consultation centrée-patient d'un 'guide de bonnes pratiques': OncoDoc, un système d'aide à la décision thérapeutique appliqué au cancer du sein.

Beyond considerations of cost-effectiveness, clinical practice guidelines (CPG) can reduce practice variations and thus improve the quality of care. However, despite the proliferation of implemented CPG and their wide diffusion thanks to Internet-based technologies, physicians' compliance with formal standards is weak. Developed according to a document-based paradigm, OncoDoc proposes an original framework for implementing CPG. Domain knowledge has been encoded as a decision tree whose branches are both exclusive and exhaustive. This generic knowledge is operationalized at the point of care by the interactive building, through hypertextual navigation, of a patient-based clinical context leading to specific therapeutic recommendations. OncoDoc has first been applied to the management of breast cancer patients and demonstrated within a full-scale experimentation in a clinical setting a compliance of 80 per cent.

Is there any relationship between interleukin-6/interleukin-6 receptor modulation and endogenous interleukin-6 release in metastatic malignant melanoma patients treated by biochemotherapy?

During recent years it has become clear that the production of most cytokines could play an important role in malignancies. We previously demonstrated that a high endogenous interleukin-6 (IL-6) level is significantly correlated with a high tumour burden and resistance to biochemotherapy in metastatic malignant melanoma patients. However, little is known about the origin of IL-6 and the pattern of IL-6 receptor (IL-6R) expression. In this report, we studied the expression of IL-6R and intracellular IL-6 using flow cytometry in tumour cells provided by fine-needle aspiration of lymph nodes and palpable metastatic lesions from 14 patients refractory to biochemotherapy and six responder patients. Moreover, we established the relationship between these parameters and the serum IL-6 level. Our results demonstrated that, following treatment, the percentage of HMB45-positive (HMB45+) cells expressing functional IL-6R, intracellular IL-6 or both IL-6R and IL-6 significantly decreased in patients refractory to biochemotherapy. In contrast, in responder patients the percentage of HMB45+ cells expressing IL-6R increased and those expressing IL-6 remained stable. Regarding the serum IL-6 level, an 11-fold increase was observed in the patients refractory to biochemotherapy, but only a 1.8-fold increase in the responder patients. In conclusion, in metastatic malignant melanoma patients with a poor prognosis, the endogenous production of IL-6 is concomitant with a decrease in functional IL-6R and intracellular IL-6 expression, suggesting the involvement of an IL-6/IL-6R complex.

[Clinical imaging of osteo-condensed metastases]. / Imagerie clinique des métastases ostéocondensantes.

INTRODUCTION: Due to the occurrence of osteoblastic metastases in the course of various cancers, particularly in the course of prostate cancer, we are faced with diagnosis and follow-up issues different from those associated with lytic metastasis. We therefore analyzed the respective advantages of imaging techniques. CURRENT KNOWLEDGE AND KEY POINTS: Most of the time, osteoblastic metastases are evidenced by standard radiography. Due to its ability to demonstrate metastases localization, extent and signs, CT scan is not only of value when osteoblastic metastases are suspected but also for patient's follow-up. MRI provides further information in regard to both the lesion content and osteoblastic degree. Though MRI must be performed after all other imaging procedures, it is of value for multiplanar study of the whole spine. FUTURE PROSPECTS AND PROJECTS: Studies focusing on either the lesion content and volume or helical CT are in progress and aim at better monitoring follow-up, while the objective of dynamic MRI studies is to better analyze lesion content.

[The role of new drugs in the treatment of locally advanced urothelial tumors of the bladder]. / Place des nouvelles drogues dans le traitement des tumeurs urothéliales de vessie localement évoluées.

Although the optimal management of muscle-invasive bladder cancer remains a continued subset of controversy, results achieved with either radical cystectomy, or radiation therapy or combinations of the two lead to cure rates of only 50% with up to 50% of patients who will develop metastases, usually within two years. For the past ten years, chemotherapy of advanced urothelial tumors has focused on cisplatin-based combinations such as methotrexate-vinblastine-adriamycin-cisplatin (M-VAC), cisplatin-methotrexate-vinblastine (CMV) or cisplatin-adriamycin-cyclophosphamide (CISCA). Such regimens have provided interesting results with responses rate up to 70% and some long term survival (in 10 to 20% of patients), but this has focused achieved with moderate to severe toxicity. Thus, if the chemosensitivity of advanced urothelial tumors is obvious, it is clear that a therapeutic plateau has been reached and only the search for new active agents can provide any hope to improve the results of these established regimens. Recently some single agents under investigation including taxanes (paclitaxel and docétaxel) and gemcitabine have been identified and have entered clinical development. Preliminary data of several phase II studies are now available and they appear promising, providing the basis of new combinations regimens that will attempt to improve results that have been achieved with standard regimens during the past decade. The activity of these new single agents and new combination are reviewed.

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin.

Tremendous progress has been made in the medical treatment of advanced colorectal cancer during the past 2 to 3 years, due to the availability of several new drugs. Of these new agents, irinotecan (CPT-11 [Camptosar]) seems to be one of the most active against advanced colorectal cancer. It is, therefore, a good candidate for combination with the more classic cytotoxic agents for this disease. This article summarizes several European phase I and II studies in which irinotecan has been combined with (1) fluorouracil (5-FU) alone, given as a repeated bolus injection or a protracted infusion; (2) 5-FU modulated by folinic acid (leucovorin) according to different schedules; or (3) mitomycin (Mutamycin). All of these studies have demonstrated clinical responses in patients with advanced colorectal carcinoma, including complete responses. The toxicity profiles of the various combinations seem to be acceptable; neutropenia and delayed diarrhea are the most frequent side effects. Large phase III studies are still warranted to demonstrate the benefit of these irinotecan-based regimens.

Hypertextual navigation operationalizing generic clinical practice guidelines for patient-specific therapeutic decisions.

Despite the proliferation of implemented clinical practice guidelines, there is still little evidence of physicians compliance to formal standards. The ONCODOC project proposes a framework for elaborating generic decision support guidelines in a document-based paradigm with a knowledge-based approach. It has been first applied to assist clinicians in the treatment of breast cancer patients. Therapeutic expertise has been encoded as a decision tree. The decision process is driven by the clinician who interactively browses a hypertext version of the decision tree. During the navigation, he incrementally assigns values to decision parameters on the basis of his free interpretation of his patient's condition and thus builds a clinical context leading to patient-specific therapeutic recommendations. These guidelines are distributed on a hospital intranet and are evaluated at the point of care in an oncology department.