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The aim of this paper is to draw the reader's attention to the problem of dissemination of costly innovations, particularly in the field of oncology, in a context of scarce resources.Comparison of five economic aggregates related to health and the gross domestic product captures the weight of this sector in the national economy but also its cost to the community. A focus on oncology shows that during the year 2004, the cost of cancer in France, all sites being taken into account, amounted to 10.9 billion euros and the societal cost to 32 billion euros (2% of gross domestic product). The cost of breast cancer (36% of all female cancers) reached 1.5 billion euros for treatment and 3.5 billion euros for societal expenses (0.2% of gross domestic product). Due to the significant, rapid expansion of these costs (+19.2% in 2006 and 18.5% in 2007 for diagnosis-related group outliers) but also to the scarcity of resources, the development of costly innovations remains problematic. This article, based on concrete examples of breast cancer treatment, provides information on the contribution of health technology assessment (particularly cost-utility and budget impact analyses) to public decision. Economic evaluation, in particular, cost-utility assessment, allows comparison of costs and consequences (generic result usually expressed in quality-adjusted life years) in order to prioritize diagnostic and/or therapeutic strategies and to make choices based on social acceptability. Budget impact analysis, without consideration of efficacy, makes it possible to balance the financing needs arising from the adoption of a costly innovation with the paying capabilities of a given institution.

Complete staging (extensive marrow investigation and meta-iodo benzylguanine (MIBG) scan) is considered as mandatory both at diagnosis and after chemotherapy for assessment of metastases in neuroblastomas. However the correlation between bone marrow invasion and uptake of MIBG at metastatic sites remains unclear. This study investigates whether MIBG alone is sufficiently sensitive to make these procedures redundant.20 children over one year of age, with histologically proven metastatic neuroblastoma were studied. Extensive bone marrow assessment and MIBG bone scan performed both at diagnosis and after completion of induction chemotherapy were reviewed.At diagnosis metastases were detected by marrow investigation alone in 2, MIBG alone in 2 and both procedures in 16. After induction chemotherapy metastases were detected by only marrow investigation in 2, by only MIBG in 3, by both procedures in 6 patients, and by none in 9.Whether marrow investigations and MIBG scan explore the same phenomenon remains unclear. However it appears that marrow disease that is histologically detectable may remain MIBG negative both at diagnosis and after treatment. Both procedures are still justified at time of diagnosis and evaluation of response.

Long term outcome and prognosis factors of patients with metastatic osteosarcoma were evaluated on 29 observations from 3 centres reviewed retrospectively. Twenty-nine patients less than 18 years old were treated from 1990 to 1998. Only 29 of these patients had received similar treatments associating chemotherapy and surgery, adapted according to histological and clinical response to treatment, as recommended by the SFOP. Overall survival at five years was 26%, and disease free survival 14%. Eight patients are alive, four in first complete remission (CR) and four in second CR. Three of the four patients alive in first CR had bone metastases at diagnosis. On univariate analysis, factors predicting survival are: the numbers of organs affected by metastatic lesions, the number of lung nodules and the type of surgery. This is, to our knowledge, the first report of long term survivors with bone metastases at diagnosis. Metastatic osteosarcoma prognosis remain poor. A randomised study would help to define the best possible treatment for this disease.

The organization of the management of pain and other symptoms all along the cancer disease, of psychological support and palliative care is a complex question that does not correspond to any perfectly established model, both in France and abroad. Different structures are implied in there care and coexist with an insufficient coordination: cancerology structures, structures of chronic pain management, structures of psycho-oncology, structures of palliative care. Some other assistances are more or less isolated inside the hospital: nutritional support, social assistance, action against tobacco and other addictions, volunteer work. Because of the evolution of practices and mentalities over the last ten years, the highlights of evident interfaces and complementary activities, the notions of "continuous care" and "integrated care" inside conventional departments, the budgetary and organizational restraints, it is now possible to propose a model of hospital structure adapted to the problem of supportive care. The creation is proposed from preexisting structures, consultations, units, departments of supportive oncological care according to the size of the institution. The structure should comply with some specifications, sometimes regulations, and to coordinate at best different competencies in the interest of the patients and medical teams : pain and symptoms management (of which palliative care is an important part), psycho-oncology, rehabilitation (functional rehabilitation, nutrition, social work, fights against addictions). A pooling of technology settings is one of its interest. The model can be applied in other domains than cancerology and in most health institutions.

Context. The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centers (FNCLCC), the 20 French comprehensive 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 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 identify consequences in terms of liability of the development of SOR guidelines and to formulate recommendations for the FNCLCC and medical doctors using SOR. Methods. Data have been identified by literature search on legal matters by CNEH's Legal Center JuriSanté, then submitted to a group of 8 experts. Results. The main conclusions of the present study are: 1)The SOR attest a high level of quality and methodological rigor; 2) according to legal considerations and in comparison to the available scientific data, the SOR guidelines can be considered as the state of the art in oncology at time of release; 3) the study identified six quality properties of Standards, Options and Recommendations (SOR): information contained in the SOR must be serious, accurate, reliable, complete, up-to-date and secure. The respect of these quality criteria is essential in the matter of liability; 4) when gathered, they can prevent the actors from being implicated on questions of liability. Specialists who use the SOR may avoid problems of liability, nevertheless evidence and the state of the art may evolve with time; 5) clinicians who do not use the SOR, may appear to be responsible for disasters, except if they can justify their medical decision (evolution of scientific knowledge or specific clinical circumstances, etc.); 6) therefore, SOR developers need to keep in mind these essential properties when SOR are prepared; 7) the SOR steering committee (COSOR) analysed the conclusions of the present legal study and defined a series of actions and procedures to guarantee the respect of the above quality criteria.

Non-Hodgkin's lymphoma consists of a group of disorders which is increasing for the last decades. In the USA, since the early 1970s, the incidence rate has increased by almost 60% and ranges from 3 to 4% per year, which is faster than for the majority of cancers. Important advances in our knowledge of histopathology together with new diagnostic tools, as well as the improvement of the registered data and ageing of the population, only partially explain this increase. Two viruses have been identified as possible etiologic agents for non-Hodgkin's lymphoma: the Epstein-Barr virus and HTLV-I. More recently, HHV8 and the hepatitis C virus have been incriminated in the occurrence of non-Hodgkin's lymphomas. Congenital and acquired immunodeficiencies (due to immunosuppressive therapy and viral disease such as Aids) might also represent predisposing factors. However, the epidemic HIV infection is the most strongly correlated with the increasing incidence of non-Hodgkin's lymphoma in the United States. Finally, epidemiologic studies indicate that environmental factors may play an important role in the etiology of non-Hodgkin's lymphoma, specially toxic chemicals used in farming.

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. For pediatric issues, this project is a collaboration between the FNCLCC and the French Society of Pediatric Oncology (SFOP). 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.To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the clinical care of osteosarcoma in children and adult.Data have been identified by literature search using Medline (1985-december 1998) and the expert groups personal reference lists. The main criteria considered were incidence, risk factors, prognostic factors and efficacy of treatment. Once the guidelines were defined, the document was submitted for review to 27 national and international independent reviewers, and to the medical committees of the 20 French Cancer Centres and, in particular, the 4 which have particular expertise in pediatric cancer management.The main recommendations for osteosarcoma management are that: 1) the clinical diagnosis is based on appropriate clinical and radiological findings; 2) the final diagnosis is pathological and the biopsy should be performed by the surgeon who will subsequently perform the definitive surgery; 3) surgical biopsy must be of adequate size and performed by an experienced surgeon; 4) the therapeutic strategy for osteosarcoma is based on surgery with neoadjuvant and adjuvant chemotherapy given in experienced centres. Inclusion of high dose methotrexate is recommended for children, and the dose of methotrexate must be adapted for adults. Inclusion of children in SFOP protocols and adults in EORTC and FNCLCC clinical trials is recommended; 5) treatment of metastatic osteosarcoma is based on chemotherapy and surgery to lung metastases which may be curative. Amputation is rarely appropriate. Inclusion of children in SFOP and of adult in EORTC and FNCLCC clinical trials for metastatic osteosarcoma is recommended; 6) at the present time, there are no clear data on which to base guidelines for timing and duration of follow-up studies in this condition.

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. For pediatric issues, this project is a collaboration between the FNCLCC and the French Society of Pediatric Oncology (SFOP). The main objective is the development of clinical practice guidelines to improve the quality of health care and outcomes 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.To develop a clinical practice guideline according to the definitions of Standards, Options and Recommendations for the clinical care of rhabdomyosarcoma and other soft tissue sarcoma in children and adolescents.Data have been identified by literature search using Medline (1985-may 1997) and experts group personal references lists. The main criteria considered were incidence, risk factors, prognostic factors and efficacy of cancer treatment. Once the guideline was defined, the document was submitted for review to 14 national and international independent reviewers, and to the medical committees of the 20 French Cancer Centres and, in particular the 4 which have expertise in pediatric cancer management, for agreement.The main recommendations for rhabdomyosarcoma management are: 1/ diagnosis is based on appropriate clinical and radiological findings; 2/ pathological and immunohistochemical studies are essential to confirm the diagnosis; 3/ surgery must be performed by an experienced surgeon. Surgery and radiotherapy must be as conservative as possible; 4/ therapeutic strategies for rhabdomyosarcoma depend on location and extends and are based on chemotherapy, surgery and radiotherapy. Inclusion of patients in SFOP, SIOP and IRS clinical trials is recommended; 5/ treatment of metastatic rhabdomyosarcoma is based on intensive chemotherapy, and surgery with or without radiotherapy; 6/ the management of non-rhabdomyosarcoma is based on the likelihood of sensitivity to chemotherapy; 7/ at the present time, there are no clear data on which to base guidelines for timing and duration of follow-up studies in these conditions.

Clinical practice guidelines have been defined as "systematically developed statements to assist practitioners and patients in their decisions about appropriate health care for specific clinical circumstances". Their objectives are to improve the quality of health care and to optimise the use of limited health care resources. However reduction of unnecessary costs of delivered health care is proceed most often in an implicit way by identifying inappropriate health care strategies. The increase of health care costs needs to look at this issue in a more explicit way and to consider costs in the guideline development process. The key objective of our study is to analyse the methodological aspects of dealing with cost issues in the guideline development process. The integration of cost issues is in fact limited by two major problems: first, the lack of economic evaluation for many strategies in the scientific literature and second, the lack of generalizability of the published results to temporally and/or geographically different settings. These difficulties are likely to result in the need for local cost evaluation (for a given setting), and though to make the guideline development process much more complex. Further methodological research is important to define the role of economic evaluation in clinical practice guidelines and to enable the integration of cost issues into the guideline development process. They should go closely together with international standardisation of the methodology for designing, conducting and reporting economic evaluation.

Prevalence of malignant neoplasm is a basic health indicator used in order to evaluate needs in medical equipment for treatment and follow-up of cancer patients. Data on prevalence are regularly published by Northern European countries. Thames and Connecticut cancer registries. In France available information on prevalence are scanty, because follow-up of cancer patients is not easy. Therefore, we used a statistical method to evaluate prevalence from incidence and mortality in the Rhône-Alpes area (France, 5,300,000 inhabitants) in 1990, using the department of Isère population based registry. For females, figures for breast carcinoma and colorectal carcinoma are respectively 25,000 and 5,700, and, for males, 5,700 colorectal carcinoma. For 5 year partial prevalence, these figures are respectively 11,300, 3,100 and 3,500. The ratio prevalence/incidence is 8.9 for breast in females, 5.8 for colorectal carcinoma in females and 4.8 for colorectal carcinoma in males with a steep decrease for 5 year partial prevalence (4 for breast carcinoma, 3.1 for females colorectal carcinoma and 2.9 for males colorectal carcinoma). These ratios are consistent with those observed elsewhere in Europe.

The usual sites of initial metastatic deposits in neuroblastoma are osteo-medullary. With modern therapies including megatherapy and hematopoietic rescue, prolonged survival is obtained. However, unusual metastatic sites are more and more often described during the prolonged evolution of these patients such as brain metastases. A case of isolated intracerebral metastatic relapse is reported here in a patient who had received 4 months before a megatherapy in first complete remission. Pathogeny and therapeutical implications are discussed.

CD44 gene products are potential markers of aggressiveness in different tumor models, a result which prompted us to study clinical neuroblastoma (NB) specimens. CD44 expression was determined by immunostaining of 52 NB with a monoclonal antibody (J173) directed against an epitope common to all CD44 isoforms. All tumors were from patients (pts) with newly diagnosed NB treated with standardized protocols. They were classified according to international criteria [11]. CD44 immunoreactivity was detected in 37 tumors (71%). CD44 was expressed in 100% of favorable NB stages (1, 2 or 4S), but only 50% of advanced NB (stages 3 and 4) (p = 0.0001), suggesting that the absence rather that the overexpression of CD44 is a signal of tumor aggressiveness. The cumulative event-free survival was significantly longer in pts with CD44-positive tumors as compared to pts with CD44-negative tumors (p10(-5)). More importantly, progression-free survival was also significantly higher in CD44-positive pts within the high-risk group (p0.01). In univariate analyses, we tested the prognostic value of tumor expression of CD44 in comparison with tumor stage, age, tumor histology and presence or absence of N-myc proto-oncogene amplification. All five measures had significant prognostic value. The expression of CD44 and the absence of N-myc amplification were the most powerful predictors of a favorable clinical outcome. In a multivariate analysis of these measures, CD44 expression and tumor stage were the only independent prognostic factors for the prediction of patient survival. NB is the first clinical model described in which tumor aggressiveness correlates with a repression rather than a stimulation of CD44 expression. We recommend the use of CD44 as an additional biological marker in the initial staging of neuroblastoma.

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.

Intensive chemotherapy and high dose chemotherapy with bone marrow transplantation are 2 complementary therapeutic procedures for non Hodgkin's lymphomas. In children, indications for BMT in NHL are limited to patients who fail to achieve complete remission and for patients in sensitive relapse. In adults, the role of BMT is also recognized for patients who fail to achieve remission with initial therapy. The advantage of either conventional regimens or massive therapy with BMT for patients with poor prognostic criteria is still under evaluation (LNH 87 protocol). The PARMA protocol tests, in a multicenter randomized study, the value of BMT for patients in sensitive relapse. Results of BMT for patients with refractory NHL and resistant relapse, remain poor. The role of BMT in low grade lymphomas is debatable. The trials for evaluation of massive chemotherapy and BMT in NHL will contribute to defining the potential role of this therapy in France: a potential 1,000 cases per year may be treated by this method.

Forty-seven patients with renal carcinoma were included in first line or rescue protocols of immunotherapy including IL2 alone or in association with LAK cells, INF alpha or TNF. The toxicity was mild and the mortality was 2% (1 patient). The response rate was 26%. Nineteen children with neuroblastoma received IL2 either alone or in combination with LAK cells. The morbidity and mortality were higher in patients with end stage disease who had previously received high dose and prolonged chemotherapy. In contrast, the toxicity was mild and transient in patients treated in the months following autologous bone marrow transplantation. The only complete response observed was in 1 child treated with IL2, 4 months after high dose chemotherapy and ABMT. Immunological analysis showed that the immunomodulatory effect of IL2 is very different depending on whether IL2 is used alone or in combination with other cytokines; moreover, the biological effect of IL2 is dependent on the immunological status of the patients prior to IL2 therapy.

Reviewed in this study are 40 patients treated by high-doses of alkylating agents followed by autologous marrow rescue for ovarian cancers. All patients received this therapy after extensive surgery and a median of 6 cycles of CDDP containing regimens (CAP or CHAP). All patients, except 4, who showed evidence of progression, had a second surgical exploration before the high dose chemotherapy. Conditioning regimens consisted of: melphalan at a dosage greater than 140 mg/m2 for all patients; in addition, 2 received Endoxan 120 mg/kg and 1 busulfan 16 mg/kg. Autologous marrow rescue was infused 24 h after the conditioning regimen. Severe, but reversible aplasia and mucositis were the most common toxicities. Three patients died from this procedure, 2 from infection and 1 from secondary leukemia. Twelve out of 15 patients evaluated responded (80%) showing evidence of activity in patients who did not respond to first line chemotherapy. Duration of response was short, especially for patients treated for progressive disease rather than in partial or complete response at the time of high doses chemotherapy. With a median follow up of 23 months (range 8.54) 19 patients survived (15 with non-evolutive disease) leading to a projected survival rate of 39% between 27 months and 5 years. These results are encouraging for poor risk patients who failed to respond to initial chemotherapy. For patients who have small or no residual disease after initial therapy, the place of such intensification should be confirmed prospectively in a larger cohort of patients.

In part I of this article, we reviewed the general aspects of childhood brain tumors. In part II, we present the most common neoplasms and their treatment. The quality of the surgical resection appears to be of first importance in the prognosis. Progress in radiotherapy and chemotherapy have contributed to the improvement of long-term results. However, they are responsible of late deleterious effects. Further progress in therapy must be assessed with in view a critical evaluation of the quality of life.

Sixty-five patients more than one year of age at diagnosis with stage IV neuroblastoma were prospectively treated since january 1983. Seventeen per cent were not consolidated with massive therapy and ABMT (progression: 3 cases; died at induction: 4 cases; died at surgery: 1 case; parental refusal: 2 cases) and all died. Among 49 evaluable cases, 31 were grafted in PR and 18 in CR or VGPR. Actuarial progression free survival at 35 months is 33% for the grafted group and 24% for the whole group. These results are better than previous experience of this group (8% at 30 months).

The pharmacokinetics of the alkylating agent melphalan was determined in a dialysed patient, 30 years old, who underwent unilateral orchidectomy for a malignant testicular tumor. Melphalan was included in a polychemotherapy treatment with eight 1-h infusions of 230 mg of etoposide (VP 16), then one 5-min infusion of 370 mg of melphalan (200 mg/m2) followed by autologous bone marrow grafting (ABMG). In this patient, melphalan pharmacokinetics was different from that of patients without important renal dysfunction for the area under the concentration curve (1,324 mg.l-1.min). However, with a melphalan elimination half-life of 80 min, ABMG could be performed, as usually, 24 h after melphalan administration. Plasma alpha-fetoprotein (AFP) concentrations showed that chemotherapy was efficient. Furthermore, we observed a modification of etoposide kinetics due to melphalan.

Since 1981 in the French Pediatric Oncology Society, a multidrug intensive-pulsed chemotherapy was proposed for bad prognosis B-cell lymphomas (stage II ORL, III and IV) and for B acute lymphocytic leukemias (B-ALL). Between 1981 and 1984, the nine-drug regimen was based on high-dose cyclophosphamide, high-dose methotrexate and cytosine arabinoside in continuous infusion (regimen LMB-81). No irradiation was performed. CNS prophylaxis was made by high-dose methotrexate and by intrathecal injections. No debulking surgery was recommended. Since 1984, considering the high rate of continuous remission, some modifications were made for reducing the duration and toxicity of the treatment of most B-cell lymphomas without CNS involvement (regimen LMB-84). For B-cell lymphomas with CNS involvement and B-ALL, an intensive high-dose multidrug combination was proposed (regimen LMB-86). Between 1981 and 1984, 153 children (stage II ORL: 6%, III: 63%, IV: 31%) were treated with the LMB-81 regimen. The overall disease-free survival rate is 69%. No relapse occurred after 12 months. Only two CNS relapses were observed. Among stage IV, a worse prognosis was associated with initial CNS involvement (disease free survival: 19%). On the contrary, bone marrow involvement was not an adverse prognostic factor. With the LMB-84, the overall disease free survival rate is 74%. A noteworthy reduction of toxicity is observed.

The most frequent solid tumors in the pediatric age group are central nervous system tumors. Despite dramatic improvements in neurosurgery, radiotherapy and chemotherapy, the overall prognosis remains poor, and is often associated with late deleterious effects, including neuropsychologic disorders, endocrine deficiencies and physical abnormalities. In part I, we describe the common presenting symptoms and signs in children with brain tumors. We expose the significant advances in histology, immunohistochemistry, cytogenetic, radiology and therapeutic approaches during the past ten years.

Immunological analysis is complementary of morphological analyses in the detection of neuroblastoma BM metastases. It attests the neuroblastic nature of rare pseudolymphocytic isolated cells. The combination of immunocytochemical technique (alkaline phosphate) and double-immunofluorescence technique allows the detection of as few as 10(-5) residual neuroblastoma cells. At the time of bone marrow harvest, it permits a precise evaluation of malignant cells in the graft.