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Objective: To assess the efficacy and toxicity of pegylated liposomal doxorubicin combined with gemcitabine as first-line chemotherapy in metastatic breast cancer patients in a phase II trial., Patients and Methods: All breast cancer patients with HER2-negative status, hormone refractory tumor, assessable targets, with preserved performance status, and who had not received chemotherapy earlier as treatment for their metastatic disease were eligible. The patients received pegylated liposomal doxorubicin (30 mg/m(2), venous injection, day 1) concurrently with gemcitabine (1000 mg/m(2), venous injection, days 1 and 8), 1 cycle every 3 weeks., Results: Although 38 patients should have been included, this study was prematurely discontinued after recruiting 20 patients because of excessive toxicity: 75% of the patients experienced grade 3 or 4 treatment-related toxicity, including neutropenia, thrombopenia, hand-foot syndrome, and stomatitis, which significantly affected the quality of life. Cardiac toxicity was mild. With regard to efficacy, 50% of the patients (95% confidence interval, 26%-74%) experienced tumor response. The response rate was 40% in patients who had earlier received anthracyclines as adjuvant therapy. Median progression-free survival and median overall survival were 8.8 months and 19 months, respectively., Conclusions: This combination was efficient, but not well tolerated. From these results, we could not recommend these doses for further assessment and lower doses should be preferred.

External factors such as eating habits and physical activity have an important impact on breast cancer risk. This paper reviews the literature on the relationship between breast cancer and lifestyle. It aims to produce recommendations regarding physical activity and dietary intake for clinical practice. Although strong clinical evidence of the impact of lifestyle modifications is still lacking, practising healthy eating should be encouraged for the prevention of cancer, its occurrence or relapse. Physical activity is recommended to avoid excessive weight gain. For example, the beneficial effects on the risk of breast cancer could be achieved by walking half an hour per day. Three to five hours per week of moderate physical exercise therefore should be recommended for optimising the reduction of the risk of cancer. For most women, moderate to intense activity, such as heavy housework, brisk walking, or dancing, could provide an effective level of activity to keep reduce the risk of breast cancer., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Less than 5% of vulvar, vaginal and ovarian malignant diseases are sarcomas. Adequate knowledge of these particular malignant diseases is essential for accurate diagnosis and for choice of surgical treatment, adjuvant therapy and efficient medical treatment in relapse. A crucial aspect in the management of women with these diseases is a multidisciplinary approach. Globally, presenting signs and symptoms of these sarcomas are non-specific of histological type but linked to initial location. In view of this, management should be undertaken by clinicians experienced in these particular malignancies. Long-term side-effects, particularly in children with sarcoma, adversely affect quality of life. New treatment strategies require special attention., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Recall dermatitis is a rare and poorly understood drug-related event. Activated by exposure to sunlight or Ultraviolet (UV), drug-related phototoxic reactions have been reported with conventional chemotherapy agents or antibiotics., Methods: Here, we report the first case of acute dermatologic photo-induced recall reaction secondary to sorafenib in a patient with renal cell carcinoma., Results: Four weeks after stopping sorafenib, a patient with renal cell carcinoma developed an acute erythematous and papulomatous eruption restricted to the hands after prolonged solar exposure. The erythematous region was very well demarcated, mimicking the cutaneous syndrome that the patient had presented at time he was receiving sorafenib., Conclusions: The suppression of the phototoxic reaction by corticosteroids strongly suggests that the immune system may have an important function in photo-recall reactions.

Objective: The purpose is to assess the physical activity of breast cancer patients using a questionnaire, the Population Physical Activity Questionnaire (POPAQ) and to compare the data with those from two female populations: one healthy population and one with a previous history of cardiovascular disease., Patients and Methods: This prospective study included 104 consecutive breast cancer patients who were addressed at the radiation oncology department, Institut de cancérologie de la Loire from March to July 2010. A questionnaire using factorial method was used for assessment of physical activity., Results: In the study population, the rest energetic expenditures of physical energy related to both rest activity and low intensity activity were higher than in the healthy patients (5,292±1,376 versus 5,520±1,248 kJ/24 h, P<0.05 and 2,583±681 versus 2,494±558 kJ/24 h, P<0.05, respectively). Conversely, the energetic expenditures of physical energy related to both high physical activity and intensive physical activity were lower than in the healthy population (882±441 versus 1,560±868 kJ/24 h, P<0.05 et 210±274 versus 340±621 kJ/24 h, P<0.05, respectively)., Conclusion: The POPAQ allows quantifying the daily physical activity and seems feasible in clinical routine in breast cancer patients. In our study, it was found that the physical activity of those patients was significantly different from that of a healthy population. Further investigations are necessary for better defining the true impact of such differences in terms of incidence and prognostic for mammary carcinoma.

The peritoneal carcinomatosis of ovarian cancer led to the development of optimal cytoreduction surgery completed by hyperthermic intraperitoneal chemotherapy (HIPEC). The main goal of this study is to evaluate the feasibility, tolerance and efficacy of this technique in patients with ovarian cancer. A retrospective monocentric study has evaluated 43 patients with HIPEC procedures from 1995 to 2009. After a complete cytoreduction surgery, a HIPEC procedure with cisplatin is performed. Data on complications and survival parameters were collected. Prognostic factors were also analyzed. Post-surgery complications included one death due to a septic shock (2.3%) and six patients have presented major complications (13.9%). The median of overall survival and progression free survival were 53.6 and 39 months, respectively. Patients with a primary complete surgical cytoreduction of the peritoneal carcinomatosis presented overall survival length of 131 months versus 84 months without initial complete resection (P &#60; 0.0001). Surgical cytoreduction combined with HIPEC is a feasible procedure with acceptable morbid-mortality rates. The initial complete resection of the peritoneal carcinomatosis significantly increases survival and represents a strong prognostic factor.

Platine-based chemotherapy agents are major drugs in oncology and are currently used in most solid malignancies. Of these, cisplatin has been the most widely used over past years. Its efficacy and toxicity have been both well documented in the literature. Carboplatin has a rather different toxicity profile and seems to be better tolerated than cisplatin. This might potentially impact on quality of life. Carboplatin has been assessed for treatment of most malignancies in which cisplatin has demonstrated its efficacy. This paper aims at reviewing and comparing the current indications in terms of efficacy and toxicity of cisplatin and carboplatin. Although cisplatin has demonstrated its superiority over carboplatin for treatment of lung cancers and germ-cell tumors, the tolerance of carboplatin is better than that of cisplatin. This might be taken into account for patients treated with non-curative attempt. Further studies should compare both chemotherapy agents for quality of life. Of course, carboplatin remains widely used for patients who are contra-indicated for cisplatin.

Since the 1990, chemoradiation has become the standard treatment for locally advanced anal cancer. Recent progress in molecular biology and the growing number of elderly patients invite the clinicians to personalize the multimodal therapy strategy. However, data about anal cancer and elderly patients or targeted therapy are extremely sparse. Indeed, national or international guidelines don't mention these two subjects. The purpose of this article is to make the state of art of the management of anal cancer and its interferences with geriatrics and molecular targeted therapy.

Background: Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer., Patients and Methods: Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety., Results: Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI., Conclusion: The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification.

Claudin gene expression is frequently altered in human cancers. Our aim was to improve the cytology diagnosis of malignancy in serous fluids with the quantification of claudins compared with various classic molecular markers using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) method. Peritoneal or pleural effusions of 56 patients were assessed as malignant from histological analysis and 19 as benign. Claudin 4 was the most significantly upregulated (68%) marker in patients with malignant effusions. In cytologically negative malignant effusions, claudin 4 was found increased in 8/18 fluids. Quantitative RT-PCR is a sensitive method for the detection of free cancer cells in serous effusions.

Cetuximab and panitumumab are anti-EGF receptor antibodies, used in the treatment of colorectal cancer. Phase I and II studies have shown an interest in these molecules, after failure of chemotherapy combining 5-fluorouracil, folinic acid and oxaliplatin (Folfox) or irinotécan (IFL and Folfiri). Cetuximab with irinotécan has been approved by regulatory authorities following the results of a randomized phase II study where the combination arm (cetuximab-irinotécan) was superior to cetuximab alone. Retrospective studies have highlighted the impact of KRAS mutational status in the efficacy of EGFR antibodies. KRAS mutation is associated with a lack of response. Subgroup analysis of prospective studies have confirmed these hypothesis in first and second line metastatic treatment in combination with chemotherapy and in third line in monotherapy. At present cetuximab is approved in combination with chemotherapy in patients with non mutated KRAS metastatic colorectal cancer while panitumumab is only approved in monotherapy after failure of conventional chemotherapy.

Unlabelled: The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer., Patients and Methods: Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15., Results: The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2., Conclusion: HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate., (Copyright 2008 S. Karger AG, Basel.)

Background: The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen., Methods: One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed., Results: The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome., Conclusions: FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC., ((c) 2006 American Cancer Society.)

Introduction: Anaemia is a common toxicity in cancer patients and epoetins (EPOs) are now an established treatment. The economic profile of EPO treatment was assessed in patients with breast cancer treated by adjuvant-chemotherapy., Materials and Methods: Two strategies were compared: without treatment by EPO and with the possible use of treatment by EPO (epoetin alfa) when required. The clinical effectiveness criterion was time adjusted to quality of life and economic data included only direct medical costs., Main Results: One hundred ninety-two patients were included. In the group with the strategy containing the possible use of EPO, 45.5% of patients effectively received EPO. A significant difference in the haemoglobin level profile over time was observed which provided a significant overall benefit of 0.0052 (p<10(-4)) quality-adjusted life year (QALY) associated with an extra cost of 1,615 (p<10(-4)). In the base case analysis, the cost per added QALY was estimated as 310,577 with the strategy containing the possible use of EPO., Conclusion: This robust result seems to be unacceptable, but the only relevant point of discussion might be the level of acceptable incremental cost-effectiveness ratio (ICER) for a patient.

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French regional cancer centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objectives: To elaborate clinical practice guidelines for patients with stomach adenocarcinoma. These recommendations cover the diagnosis, treatment and follow-up of these tumors., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. The Standards, Options and Recommendations are thus based on the best available evidence and expert agreement., Results: This guidelines presents the synthesis of the data concerning the evaluation of the therapeutic ones. The main questions concern the type of gastrectomy to realize (Total Gastrectomy or gastrectomy subtotal), the extent of the lymphadenectomy (D2, D3 versus D1, D3, D2 versus D4) and the role of postoperative chemotherapy and adjuvant concomitant chemoradiotherapy.

Context: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French Regional Cancer Centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objectives: To update clinical practice guidelines for first line palliative chemotherapy in patients with metastatic colorectal cancer previously validated in 1995, then updated in 1997 and published again in 1998. These recommendations do not cover second line treatment., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines have been developed, they are reviewed by independent reviewers., Results: This article is a summary version of the updated clinical practice guidelines with algorithms. The main questions addressed by the expert group in this update concerned (1) Which patients should be treated? (2) What is the best treatment duration? (3) Which treatment should be administered? The new data identified concerning which patients to treat and the duration of treatment were consistent with the data presented in the initial report and did not modify the original recommendations from 1997. The new data available represent stronger evidence than those in the original report (Two good-quality meta-analyses published since 1997). A new guideline concerning patients who are 75 years old or more has been added. Concerning, the new evidence identified has modified the guidelines for the therapeutic schema to adopt from 1997. These modifications concern irinotecan, oxaliplatin, oral fluoropyrimidines and methotrexate. Treatment with irinotecan or oxaliplatin associated with continuous 5FU infusion, modulated with folinic acid (LV5FU2-like) has become a standard. The use of oral fluoropyrimidines has become an option for patients who refuse hospitalisation or treatment by infusion. The use of methotrexate combined with 5FU is no longer recommended.

Context: "The Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French regional cancer centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objectives: To elaborate clinical practice guidelines for patients with stomach adenocarcinoma. These recommendations cover the diagnosis, treatment and follow-up of these tumors., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. The Standards, Options and Recommendations are thus based on the best available evidence and expert agreement., Results: Adjuvant radiation therapy alone is not a standard treatment for patients with stomach adenocarcinoma. Adjuvant concomitant chemoradiotherapy is not a standard treatment for patients with stage II or III stomach adenocarcinoma R0, with Dl or D2 lymphadenectomy who have undergone surgery. Following surgical resection, adjuvant concomitant chemoradiotherapy should be proposed to patients without denutrition with a lymphadenectomy < Dl (fewer than 15 lymph nodes examined) and those with T3 and/or N+ tumours following the protocol used in the MacDonald trials (SWOG-9008) (Level of evidence B1). Adjuvant concomitant chemoradiotherapy can be administered to patients without denutrition with DI or D2 lymphadenectomy and with involvement of regional lymph nodes (N2 or N3).

Introduction: Paclitaxel plus cisplatin is considered to be the standard first-line therapy for advanced ovarian cancer. Previous to this study, economic data on this combination resulted from randomised clinical trials (RCTs). Therefore, the objective of this study was to compare the clinical and economic outcomes associated with paclitaxel-cisplatin (PC) and cyclophosphamide-cisplatin (CC) regimens using a pragmatic perspective based on daily clinical practice in a French university hospital., Method: A retrospective cost-effectiveness analysis, from the hospital-payer perspective, was carried out as a before-after case study in fifty-nine consecutive women with verified International Federation of Gynaecology and Obstetrics (FIGO) stage II, III or IV ovarian cancer treated between 1995 and 2000. Median overall survival (OS) was used as the primary endpoint. The quality-adjusted time was assessed by the quality-adjusted time without symptoms or toxicity (Q-TWiST) method. Direct medical costs were collected for each patient. Monetary values for French prices in the year 2000 were used and converted to US dollars using an exchange rate of USD 1 = 7 French francs. Several univariate sensitivity analyses were carried out varying unit costs, medical practices and administration of paclitaxel., Results: The incremental cost of the PC regimen was USD 10,716 per patient. OS and quality-adjusted time were improved by 10.8 and 9.3 months with the PC regimen. The cost per life-year gained and per added QALY were USD 11,907 and USD 13,827, respectively. The robustness of the results was confirmed in sensitivity analyses., Conclusion: Our study suggests that PC may be a cost-effective regimen for advanced ovarian cancer in a French university hospital setting. We reported higher incremental costs and lower clinical benefits than RCT-based findings, suggesting that RCT-based findings were clearly balanced by our pragmatic approach based on clinical practices. Observational studies can provide complementary and balanced data for decision making.

Context: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients., Objectives: To define Clinical Practice Guidelines (CPG) for the diagnosis of carcinomas of unknown primary site., Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers., Results: The main recommendations for the diagnosis of carcinomas of unknown primary site are: 1) Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment. For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary. 2) An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies. This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. 3) A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later. 4) The clinician and pathologist should compare their opinions before and after the pathological diagnosis., (Copyright John Libbey Eurotext 2003.)

Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site., Patients and Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done., Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively., Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Purpose: To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site and to develop a simple prognostic model for the selection of patients in prospective clinical trials., Patients and Methods: Univariate and multivariate prognostic factor analyses were conducted in a population of 150 unselected patients and led to the construction of two successive classification schemes. An external data set of 116 patients enrolled onto two prospective trials was used for validation., Results: When studying clinical variables only, poor performance status (2 or 3) and presence of liver metastases were retained in the multivariate analysis. The first classification scheme consisted of three subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse prognostic factors. With the introduction of serum lactate dehydrogenase (LDH) levels in a further step, liver metastases were no longer significant. The second classification scheme therefore included poor performance status (relative risk [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, respectively (P <.0001). The 1-year survival rates were 45% and 11%, respectively. This second classification scheme was validated in an external data set: the median survival rates of patients assigned to the good-risk group and the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1-year survival rates were 53% and 23%, respectively., Conclusion: A simple prognostic model using performance status and serum LDH levels was developed and validated. It allows the assignment of patients into two subgroups with divergent outcome. Further prospective trials will be designed using this prognostic model.

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Cancer Centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery., Objectives: To develop clinical practice guidelines for carcinoma of unknown primary site (CUPS) patients according to the definitions of the Standards, Options and Recommendations project., Methods: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 81 independent reviewers., Results: The main recommendations for the management of patients CUPS are presented below: 1) An adapted immunochemistry test using a specific antibody battery should be performed for the anatomopathologic diagnosis. 2) The aim of the diagnosis is to identify specific anatomoclinical forms that can be treated by a specific treatment (standard, level of evidence B2). Except these forms, searching for the primary tumor site have no prognosis or therapeutic interest that can justify a systematic diagnosis assessment (standard, level of evidence B2). 3) The management of poorly differentiated neuroendocrine carcinoma consists of platin/etoposide based chemotherapy. There is no standard treatment for the differentiated forms. 4) Surgical node excision and adjuvant radiotherapy should be performed in case of epidermoid carcinoma with cervical node metastases. In the event of a non operable tumor, an irradiation should be performed. 5) The management of axillary node metastases in women with adenocarcinoma should be the same as the management of patients with lymph node metastases in breast cancer. If mammary MRI is negative, surgical treatment and mammary irradiation are not recommended and an axillary node excision should be performed. 6) The standard treatment for women with primary papillary serous carcinoma of the peritoneum is a surgical resection followed by chemotherapy, as recommended for ovarian cancer. 7) CUPS not belonging to any specific anatomoclinical forms can be treated by chemotherapy, symptomatic treatment alone or treatment based on biphosphonates in presence bone metastases.

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery., Objectives: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients., Methods: Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers., Results: The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

Purpose: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m(2)) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone., Patients and Methods: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m(2) and continuous 5-FU infusion 1.5 to 2 g/m(2)/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m(2), bolus 5-FU 400 mg/m(2), and continuous 5-FU infusion 600 mg/m(2)/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX4)., Results: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P =.02). From the start of treatment, median progression-free survival was 4. 7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively., Conclusion: This phase II study of oxaliplatin at 85 mg/m(2) in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.

Background: A pilot study of a new chemotherapy, the CIVIC regimen, was performed in 58 patients with metastatic breast carcinoma previously treated with chemotherapy with or without hormonal therapy (n = 41). Cisplatin, 20 mg/m2/day, was given (Days 1-5) every 21 days during a 1-hour intravenous (i.v.) infusion, and vinorelbine (VNB) was delivered at a dose of 6 mg i.v. bolus followed by VNB, 6 mg/m2/day, in continuous i.v. infusion (Days 1-5) every 21 days., Methods: Fifty-eight patients were included in this trial between June 1992 and March 1994 (median age, 46.5 years; range, 28-69 years). The number of previous chemotherapy in the adjuvant or metastatic phase were: 1 in 9 patients, 2 in 33 patients, and > or = 3 in 16 patients. Forty-four and 12 patients, respectively, were previously treated in metastatic phase with regimens containing anthracyclines and paclitaxel. Overall, 210 cycles were given (median, 3 cycles; range, 1-6 cycles)., Results: Among the 58 patients assessable for tumor response to the CIVIC regimen, 24 patients (41%) (95% confidence interval, 28-54) achieved an objective response (complete response or partial response) with 2 complete response (3%) and 22 partial response (38%). The median time to response was 11 weeks (range, 4-16 weeks). The median survival time from the initiation of the CIVIC regimen was 9.2 months (range, 0-45 months). The response rate was 43% (19 of 44 patients) in patients refractory to anthracyclines and 58% (7 of 12 patients) in patients with disease progression after treatment with anthracyclines and paclitaxel. Myelosuppression was the most frequent side effect. World Health Organization Grade 3 neutropenia occurred in 8 of 58 patients (14%) and in 41 of 210 cycles (20%), Grade 4 neutropenia occurred in 37 of 58 patients (64%) and in 63 of 210 cycles (30%), and Grade 3 and 4 thrombopenia occurred in 7 of 58 patients (12%) and in 9 of 210 cycles (4%). Grade 2 peripheral neuropathy was observed in 6 of 58 patients (10%) and in 12 of 210 cycles (6%), and Grade 3 peripheral neuropathy was observed in 3 of 58 patients (5%) and in 4 of 210 cycles (2%). The risk of Grade 2-3 neuropathy was significantly higher after the fourth chemotherapy cycle (14 of 23 patients vs. 3 of 35 patients: P = 0.00002)., Conclusions: The CIVIC regimen is effective and has acceptable tolerance in patients with metastatic breast carcinoma refractory to previous anthracycline- and/or paclitaxel-containing chemotherapy. Four cycles were found to provide the best toxicity-efficacy ratio.

The aim of this study was to evaluate the quality of care for terminal cancer patients at our institution, as assessed by families in a questionnaire sent 6 months after the death of the patient. We evaluated the quality of information given to the patients and to their families, the patients' "comfort" at the end of their lives (nursing, pain, psychological support) and the families' opinions about the practical conditions at the time of death (in our institution or at home). A total of 105 consecutive patients who died in our institution between January and June 1989 were included in the study; the vast majority had breast or head and neck cancers. We obtained a total of 48 answers from the 105 families that received the questionnaire. Of these, 87.5% were satisfied with the terminal nursing care, 77% were satisfied with the information given to patients and 60% with the information given to families. The treatment for pain was considered to be inefficient or incomplete by 21% of the families; 32 families (67%) considered that the death of terminal cancer patients should occur in the hospital where the patient had been treated and 12% felt that it should occur at home. This study led us to examine various means for improving the quality of care for our terminal cancer patients.

Renal-cell carcinoma (RCC) is one of the human cancers which respond best to immunotherapy. To better characterize the mechanism of the immune response in RCC, we analyzed the T-cell receptor (TCR) beta-chain repertoire in primary RCC, metastases and paired peripheral blood lymphocytes (PBL) from 9 patients. For 3 of these, we analyzed T cells recovered from normal kidney, or from tumor-involved lymph nodes as well as tumor-infiltrating lymphocytes (TIL) expanded in vitro for adoptive immunotherapy. The initial semi-quantitative RT-PCR method for definition of the Vbeta gene usage was not informative enough to distinguish intratumoral clonal T-cell expansions. In contrast, the length pattern analysis of the complementary determining regions 3 (CDR3) allowed oligoclonal T-cell populations to be detected in fresh TIL form the 9 patients with RCC. Furthermore, these oligoclonal TIL populations were not present in normal renal tissue, autologous PBL or tumor-involved lymph nodes. Different clonal T-cell expansions were identified in the primary tumor and in a pulmonary metastasis from the same patient. The detection of clonal T-cell populations observed in RCC suggests an in situ expansion in response to potential tumor antigens. This report provides an overall and accurate description of the T-cell repertoire in a significant number of samples from patients with RCC.

Cachexia frequently occurs in cancer patients. Indeed, this syndrome affects about 50% of hospitalized patients. This clinical entity may be described by different characteristics: appetite and weight loss, several metabolic abnormalities, possible influence of cytokines, poor prognosis. During the last decade, several papers have shown the beneficial activity of medroxyprogesterone acetate (MPA) and megestrol acetate (MA) in cancer cachexia. Seven randomized trials emphasized their activity on patients weight and appetite. Megestrol acetate doses in those trials are different: from 160 mg/24 h to 1600 mg/24 h; this drug is similar to MPA in terms of clinical and pharmacological properties. Iatrogenic toxicity due to MA and MPA is mild, but numerous questions still subsist: optimal date of introduction during the course of the disease, posology, treatment duration and its impact on quality of life of cancer patients.

Muco epidermoïd tumors of the lung are rare tumors, derived from the minor salivary gland tissue of the proximal tracheo bronchial tree. We distinguish high grade and low grade malignity tumors. Authors are presenting two cases reports of mucoepidermoid tumors of the lung with a very aggressive behavior and a review of the literature. Attention is drawn to the difficult differential diagnosis with adenosquamous carcinoma of the lung.

We conducted a Phase II trial using an intensive regimen combining interleukin-2 (IL2), interferon-alfa-2b (IFN), and lymphokine-activated killer (LAK) cells. The aim of this study was to evaluate the toxicity and the efficacy of this combination in selected patients with metastatic renal cell carcinoma. Thirty-one assessable patients were treated with at least one cycle of a regimen consisting of 20 x 10(6) IU/day s.c. IFN for 5 days, followed 2 days later by i.v. injections of 24 x 10(6) IU/m2/day IL2 every 8 h together with i.v. bolus of 5 x 10(6) IU/m2/day IFN every 8 h during 5 days. After a 6-day break, during which four leukophereses were performed, this i.v. combination was administered along with the LAK cell reinjections for a maximum of 5 days. Twenty-seven patients underwent the two parts of the first course of treatment; respectively, 42% and 46% of the planned dose of IL2 and IFN were administered. Several severe toxicities were observed including two treatment-related deaths. Significant tumor responses were observed in seven patients, including two complete remissions. Two of these patients remain alive without evidence of disease 36 and 40 months after treatment, respectively. This intensive regimen of IL2 together with IFN and LAK cells cannot be recommended even in selected patients with metastatic renal cell carcinoma. In addition, our results argue against the concept of a dose-response relationship in this setting.

Between October 1987 and June 1992, 244 patients with metastatic renal carcinoma were referred to our Institute. One hundred and sixty-nine were included in immunotherapy protocols. The 40 most recent patients were included in the ongoing multicentric randomised Crecy study. The previous patients were treated with IL2 as a continuous infusion or high doses intravenous IL2 combined with alpha interferon (IFN) or a combination of IL2 and IFN as subcutaneous low doses. Some patients received as rescue treatment a combination of IL2 with Tumor Necrosis Factor (TNF). First line immunotherapy with cytokines gave 14-25% response rates in these patients with 5-10% of complete persistent remissions. The most intensive regimen was responsible for the most severe toxicity as well as the highest response rate. TNF does not appear to be of great concern since its systemic administration induced important limiting toxicities. This work emphasizes the need for prospective studies in order to evaluate the optimal mode and schedule of treatment as well as to investigate the impact of immunotherapy on survival.

Interleukin 2 (IL2), like Interferon alpha (IFN), is active in metastatic renal cancer, considered to be a chemoresistant cancer. 20 to 30% of objective responses, including 5 to 10% of complete remissions are reported with various protocols of IL2 administration. The considerable toxicity is now well controlled, allowing treatments to be administered in standard wards or even on an outpatient basis by subcutaneous injection. IFN, generally given as long-term treatment, achieved average response rates of between 15 and 20%. Although IL2 and IFN have been granted Product Marketing Authorization in France, the modalities of optimal administration, the place of the combination of IL2-Interferon alpha and the factors predictive of response to treatment still remain unclear.

Interleukin (IL) 6 was measured in the serum of 138 patients with metastatic renal carcinoma before the initiation of IL-2 treatment. IL-6 was detectable in 66 patients with renal cancer (48%) and in only 8 of 70 normal adults (11%). Serum C reactive protein (CRP) and IL-6 levels are correlated, suggesting that IL-6 is involved in CRP increase in these patients. The interval between diagnosis of the primary tumor and metastasis was shorter in patients with a detectable serum IL-6 and/or serum CRP level greater than 50 mg/liter. Serum IL-6 and CRP levels were higher in subgroups of patients previously defined as having a poor life expectancy according to the Eastern Cooperative Oncology Group criteria. Pretreatment concentrations of IL-6 and CRP were higher in patients who experienced progressive disease after IL-2 treatment. Patients with detectable IL-6 had a shorter survival from the beginning of IL-2 treatment than patients without circulating IL-6 (median, 8 versus 16 months). Similarly, the median survival from the beginning of IL-2 therapy of patients with CRP levels greater than 50 mg/liter was 6 months, compared to 16 months in those with CRP levels below this threshold. None of the 21 patients with serum IL-6 concentrations greater than 300 pg/ml achieved response to any of the three IL-2 regimens. This subgroup has a median survival of 5 months after IL-2 treatment and consisted of 15% of the patients in our series. These results indicate that serum IL-6 and CRP levels are adverse prognosis factors in patients with metastatic renal cell carcinoma. Serum IL-6 level could help in the selection or stratification of the patients in future IL-2 trials.

The application of gene transfer technology to human gene therapy has been intensively investigated during the last decade. The first human clinical trials in adenosine deaminase deficiency and metastatic melanoma recently demonstrated the feasibility and safety of using retroviral gene transduction for human gene therapy. Many problems remain to be solved for a better understanding of the functioning of genes to be transferred, a better efficiency of gene transfer and genetic correction by site-specific targeting in vivo, a better knowledge of the biological properties of target cells such as totipotent hematopoïetic stem cells. Clinical developments are expected in genetic diseases (immunodeficiency, thalassemia, hemophilia) and non genetic disorders (lymphokine gene therapy for cancer).

We have investigated the serum concentrations of TNF, IL-1 and IL-6 in 49 patients with metastatic renal carcinoma receiving interleukin 2 (IL-2) or a combination of IL-2 and interferon alpha (IFN). Our results demonstrate that IL-2 and/or IFN induce an increase of serum concentrations of IL-1 and TNF in 95% and 75% of the patients respectively. Serum IL-6 levels increase in 44% of the patients. Serum concentrations of IL-1 and TNF remain elevated 48 hours after the end of IL-2 infusion. IL-1 and TNF levels are higher in patients receiving a combination of IL-2 and IFN. TNF and IL-1 levels in serum are significantly higher in responders to IL-2 treatment 48 hours after the end of IL-2 infusion. These two biological criteria enable a subgroup of patients with a very low response rate to IL-2 to be defined. The persistent increase of these cytokines in serum indicates a persistent activation of the immune system lasting after the end of IL-2 treatment which could be involved in the antitumor response.

This multicentric pilot study was conducted in order to evaluate the feasibility of early interleukin-2 (IL2) after high dose chemotherapy requiring autologous bone marrow transplantation (ABMT). BCNU at 800 mg/m2 was followed, 3 days later, by the reinjection of the bone marrow cells. At day 4, IL2 at 18 x 10(6) i.u./m2/day was given as a continuous infusion during a minimum of 6 days (first phase of study) or for 6 more days after 1 day break (second phase of the study). Twenty patients were included. Toxicity was not negligible, with one toxic death, but IL2 therapy does not damage the haematological recovery of most patients. However, a 6-day IL2 treatment period only appears tolerable. In 18 evaluable patients, three responses were observed: one complete response (CR) of short duration in a non-Hodgkin's lymphoma, one CR (24 months +) and one partial response (PR) (6 months) in two patients with metastatic gastric adenocarcinoma. This study confirms that IL2, restricted to a 6-day treatment period, is feasible immediately after high-dose chemotherapy requiring ABMT without haematological problem in most patients. The response rate was unexpected for a pilot study and this combined therapy obviously requires further study.

The treatment and prognosis of periarteritis nodosa associated with hepatitis B virus were reconsidered from a series of 13 patients representing 32.5 per cent of the 40 patients with periarteritis nodosa admitted during the same period. HBs and HBe antigens were present in every case, and hepatitis B virus replication was demonstrated by the finding of viral DNA in serum. One patient had anti-HBc IgM's. Five patients were treated with corticosteroids, cyclophosphamide and occasional plasma exchanges. All were cured or achieved complete remission. Eight patients were treated with plasma exchanges and vidarabine, either as first-line therapy (3 cases) or after failure of corticosteroids and/or immunosuppressants (5 cases). This treatment was clinically effective in 5/8 cases, including 3 with seroconversion. The 2 patients in whom the combined treatment failed were given corticosteroids; one of them also had plasma exchanges. The 8th patient died after a few days of treatment. Eleven of the 13 patients are still alive and either cured or in complete remission. Two patients who developed severe chronic hepatitis after steroids were discontinued received vidarabine alone: arrest of viral replication was obtained in both cases, with emergence of an anti-HBe (but not anti-HBs) antibody. The overall positive virological response rate to vidarabine alone or combined with plasma exchanges was 50 per cent. When vidarabine was prescribed as treatment of acute periarteritis nodosa (the 2 cases where it was used for chronic hepatitis being excluded), this response rate was 37.5 per cent. This, in patients with periarteritis nodosa associated with hepatitis B virus immunosuppressive drugs should be withdrawn and replaced by plasma exchanges and antiviral agents. This would be the first-line treatment to be replaced by corticosteroid therapy if it fails.