[Standards, Options and Recommendations: a multidisciplinary program to promote evidence-based oncology].
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Biomedical subjects
Publications and source records attributed to P Bey.
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Acute mucositis is common after radiotherapy for head and neck cancers. During the past 3 decades, there was a gradual evolution in the treatment modalities for locally advanced carcinomas (concomitant radio-chemotherapy, accelerated radiotherapy). These new strategies are accompanied by an increase in early mucosal reactions. At the present time, there is no widely accepted prophylaxis or effective treatment. Many traditional remedies or new agents seem ineffective (Sucralfate, Chlorhexidine, GM-CSF, Silver nitrate, Prostaglandin, anti-oxidants, Benzydamine hydrochloride), while others seem promising (Povidone-iodine, nonabsorbable antibiotic lozenges and antifungals, local GM-CSF, Glutamide, Low-energy laser, corticosteroïds). Radioprotectors are controversial and should be only used in experimental protocols and not in routine practice. However, some recommendations can be proposed: general prevention and global care before cancer therapy should be systematic (oral hygiene, dental and periodontal treatment, advice to avoid the use of tobacco and alcohol); frequent oral rinsing with a bland mouthwash (Povidone-iodine or others) should be used at the start of treatment because there are significant modifications of the oral microflora increased by a disturbed salivary flow; these mouthwashes could be associated with nonabsorbable antibiotic lozenges or antifungal topicals (bicarbonates, Amphotéricine B); Systematic percutaneous fluoroscopic gastrostomy should be decided before any aggressive treatments (concomitant radio-chemotherapy, accelerated radiotherapy); pain should be controlled; finally, the radiation technique should be optimized (mucosal-sparing block, conformal radiotherapy and intensity-modulated radiation therapy).
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PURPOSE: To evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients. METHODS AND MATERIALS: Between October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy. RESULTS: Results were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of </=1 ng/mL in the 120 patients who did not receive neoadjuvant androgen-deprivation therapy was significantly higher in the dose-escalation group and was directly related to the dose of radiation given. CONCLUSION: This multi-institutional study demonstrated the feasibility of escalating the dose of radiation to 80 Gy in prostate cancer patients.
PURPOSE: To evaluate the efficacy of postoperative brachytherapy alone (brachy) for Stage T1-2 squamous cell carcinomas (SCC) of the floor of mouth (FM) and the oral tongue (OT) with close or positive margins. METHODS AND MATERIALS: Between 1979 and 1993, 36 patients with T1-2 N0 (24 T1, 12 T2) OT (19), and FOM (17) SCC with close or positive margins following surgery underwent postoperative brachy. Mean patient age was 56 years (range 37-81) and sex ratio was 3.5:1 male:female. Mean surgery to brachy interval was 36 days (range 16-68). The technique used was interstitial Iridium-192 ((192)Ir) brachytherapy with plastic tubes and manual afterloading. Mean total dose was 60 Gy (range 50-67.4) at a mean dose rate of 0.64 Gy/h (range 0.32-0.94). Mean patient follow-up was 80 months. RESULTS: The 5-year actuarial overall and cause-specific survivals of the entire group were 75% and 85%, respectively. The local control was 88.5% at 2 years, with a plateau apparent after 23 months. Of the 4 local relapses, 2 were salvaged with surgery and external beam radiotherapy (EBR). No tumor or treatment factors, including tumor size, margin status, disease site, or radiation dose, were correlated with local control. The 2 head and neck second primaries underwent curative treatment on nonirradiated tissue. One patient developed a grade 3 sequelae (bone and soft tissue necrosis). Grade 2-3 chronic sequelae were seen in 7 of 17 and 3 of 19 FOM and OT tumors, respectively (p = 0.09). CONCLUSION: Postoperative brachy is a promising approach in T1-2 N0 OT and FOM SCC with close or positive margins. This approach is associated with high rate of locoregional control and low risk of chronic sequelae, obviates major surgery, avoids potential sequelae of EBR (xerostomia, dysgueusia, fibrosis), and avoids treatment of second head and neck primary on nonirradiated tissues.
The incidence of cancer will continue to increase more rapidly than the population in both industrialized and developing countries. The number of older patients will rise. Cancer will be a major health challenge in the future. Patients will become more and more involved in decisions relating to their care and their quality of life, behaving in a more adult way than hitherto. Specific treatments will continue to develop, leading to more cures and to longer survival for patients who are not cured. The fight against cancer could be organized in such a way as to make it possible to provide global care of patients through comprehensive cancer networks. Supportive care could increasingly take the form of continuous care covering every step in the fight against cancer, starting with prevention and screening.
Brachytherapy in velo-tonsillar region is not applied in all the institutions because of difficulties to learn it. For the implantation of wires in the soft palate, the Reverdin needle is replaced by a curved guide of angiocatheter 14 Gauge. This technique is easy and reduces the risk of tear mucosa.
It has been well established that arachidonic acid (AA) and its metabolism to leukotrienes plays an obligatory role in steroid production. The release of AA is regulated by hormone stimulation and protein phosphorylation. We have cloned a cDNA of a phosphoprotein with a molecular mass of 43 kDa (p43), purified from the cytosol of stimulated adrenal glands. This protein acts as intermediary in the stimulation of steroid synthesis through AA release, and has been found to be a member of a recently described acyl-CoA thioesterase family. In view of the mandatory role of this protein in the activation of AA-mediated steroidogenesis, the term Arachidonic acid-Related Thioesterase Involved in Steroidogenesis (ARTISt), is proposed for p43. The present study describes the production of the recombinant protein by cDNA expression in Escherichia coli and its functional characterization. Recombinant acyl-CoA thioesterase was capable to release AA from the respective acyl-CoA, and this activity was affected by well-recognized inhibitors of AA release and metabolism: 4-bromophenacyl bromide (BPB) and nordihydroguariaretic acid (NDGA). In addition, the inhibition of acyl-CoA thioesterase activity by NDGA correlates with the inhibition of steroid synthesis produced by this compound in adrenal cortex cells. Moreover, the recombinant protein was phosphorylated in vitro by PKA. These results provide the first evidence linking acyl-CoA thioesterases with the regulation of steroidogenesis, and support a regulatory role for acyl-CoA thioesterases in steroidogenic tissues, suggesting an alternative pathway for AA release in signal transduction.
3D-conformal-radiation therapy is now available according to progress in imaging and treatment planning. It gives three advantages: better coverage of clinical target volume, decrease of dose in organs at risk and in some cases possibility of escalating the dose in the clinical target volume. These three theoretical advantages are demonstrated for localized prostate adenocarcinomas. An increase of clinical and biological cure rate was demonstrated with 3D-CRT compared with conventional technique for the same dose. A decrease of acute and late complications was observed with 3D-CRT in historical comparisons and in randomized clinical trials. The most exciting point were the results of studies of escalating dose (+10 or 15%). There was a relationship between dose and clinical and biological cure rate. The french study of escalated dose showed a probability of clinical and biological cure rate at 36 months of 50% for doses between 66 and 70 Gy and 85% for doses between 74 and 80 Gy. In conclusion, 3D-CRT is becoming more and more important in the treatment of localized prostate carcinoma.
The synthesis of [1-[(5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl)carbonyl]-2-ethylpropy lcarbamic acid phenylmethyl ester (2; MDL 104,903), a potent inhibitor of calpain, is described. Synthesis of related compounds, which offer insights into the mechanism of action for 2, are also described, as is an O-acetyl prodrug derivative of 2.
PURPOSE: The aim of this study is to evaluate the response of Graves' orbitopathy to irradiation, and to specify the prognostic factors allowing one to better define the indications of orbital radiotherapy. METHODS AND MATERIALS: From 1977 to 1996, 199 patients received bilateral orbital irradiation delivering 20 Gy in 10 fractions and 2 weeks for a progressive Graves' orbitopathy. 195 patients were seen between 1 and 6 months after radiotherapy. The different symptoms were studied and their response to radiation was analyzed. Factors such as age, sex, evolution of thyroid disease, history of symptoms, and previous or combined treatments were analyzed. RESULTS: The results revealed that 50 patients (26%) had a good or excellent response, 98 (50%) had a partial response, 37 (19%) were stable, 10 (5%) had a progression of disease. The signs that best responded to radiotherapy were the infiltration of soft tissues and the corneal involvement. Responses of proptosis or oculomotor disorders were more complete when these signs were not advanced at the time of treatment. Irradiation seemed to have the same efficacy when applied as first-line treatment or after failure of corticosteroids. Neither modality of treatment of hyperthyroidism nor thyroid status at the time of orbital irradiation modified the results. The best results were recorded for early or moderately advanced presentation (p = 0.05). Patients treated within a delay of 7 months after the beginning of the ophthalmopathy had better responses than patients treated later (p = 0.10). CONCLUSION: Radiation therapy was successful in Graves' orbitopathy by stopping the progression of disease in almost all cases, by improving the comfort of patients, by obtaining objective responses, and by avoiding surgical treatments particularly when signs were moderate.
The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared and the Ki values versus chicken gizzard smooth muscle calpain were determined. The ketomethylene isosteres were significantly less potent than the corresponding dipeptide aldehydes, and this loss in activity is attributed to the absence of a critical interaction between the P1-P2 amide bond and the peptide binding region of calpain.
Medical decision making, especially in oncology, is more and more assisted by pre-established therapeutic protocols. But applying these protocols for particular cases is sometimes difficult; then, local expertise intervenes. For solving these difficult cases, Alexis-Vautrin like other centers, organizes committees for therapeutic decisions. This paper aims to describe, from a field study, the tools for medical decision making and the difficulties of using them. These result of the analysis of decision committee for breast cancers in a center using of protocols, which the first were established twenty years ago. This analysis was carried out by a team of oncologists and ergonomists; it stresses on collective decision making as a mean for adapting rules and exchanging knowledge. Furthermore, these findings lead to discuss using of decision committee for advancement and particularization of protocols themselves.
PURPOSE: To evaluate the prognostic value of tumor downstaging after preoperative radiation for resectable rectal cancer. METHODS AND MATERIALS: Eighty-eight patients with non-metastatic resectable rectal cancers (76 T3 and 12 T4) were treated with preoperative irradiation. Median dose was 40 Gy (30-46 Gy) delivered over 32 days (range 11-40). Seventeen patients received preoperative chemotherapy, two courses of 5-fluorouracil (5FU) 350 mg/m2/day and folinic acid 20 mg/m2/day; 5 days per week during the first and fifth weeks of radiotherapy. Surgery was performed with a mean delay of 46 days after completion of irradiation and included 66 abdominoperineal resections and 22 anal sphincter-preserving procedures. Postoperative chemotherapy was administered in 44 patients. RESULTS: Histological tumor stages were: complete histological response in 7%, pT2N0 in 19%, pT3N0 in 46%, and pT2-3N1 in 28%. Tumor downstaging occurred in 26%. No predictive factor of downstaging was statistically significant. The median follow-up was 33 months. The 3- and 5-year cancer-specific survival rates were 100% for the pT0N0 and pT2N0, respectively, 89% and 68% for pT3N0, and 64% and 0% for pT2T3N1. After preoperative irradiation, the pathological tumor stages remained a prognostic factor. Patients with downstaging (pT0T2N0) had significantly higher cancer-specific survival rates than the group without downstaging: 100% and 80% at 3 years, and 100% and 45% at 5 years; respectively (p = 0.011). The 3- and 5-year recurrence free-survival rates were 94% for the group with downstaging and 56% and 50%, respectively, for the group without downstaging (p = 0.002). CONCLUSION: Downstaging after preoperative irradiation in this retrospective study results in an improvement in local control and survival.
Enol acetates of a-keto esters with E configuration were prepared as potential prodrugs for human neutrophil elastase (HNE) inhibitors.
Six human cancer cell lines exhibiting a large range of sensitivity to 5-fluorouracil (5-FU) were evaluated for thymidylate synthase (TS) and p53 gene expression, TS and dihydropyrimidine dehydrogenase (DPD) activity, as well as cell cycle parameters, S-phase fraction (SPF), bromodeoxyuridine labelling index (LI) and S-phase duration (SPD). All these parameters were investigated for 7 days in asynchronously growing cell populations and compared with the cell sensitivity to 5-FU. No significant correlation was found between S-phase parameters and TS gene expression and/or activity. TS activity was higher in proliferating cells; however, it was not significantly higher in rapidly growing cell lines with short SPD. Neither TS gene expression nor activity was found to correlate with 5-FU sensitivity. On the another hand, a statistically significant correlation (P < 0.0001) was observed between LI and SPD and 5-FU sensitivity. The present results suggest that cell cycle parameters such as SPD and/or LI could be better parameters for 5-FU sensitivity prediction than TS gene expression and/or activity. This could be especially informative in cases of concomitant radio-chemotherapy as S-phase parameters are already proposed for hyperfractionated radiotherapy planning.
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Thirty-eight previously untreated patients with a histologically proved diagnosis of nasopharyngeal carcinoma were evaluated for in vivo cell kinetics before treatment by conventional radiation therapy. Thirty-seven tumors were analyzed by flow cytometry. Values of median potential doubling time (Tpot), labelling index (LI), and duration of S phase (Ts) were, respectively, 10.9 days, 3.8%, and 10.8 hours. In 35 cases, the results obtained from two biopsies of the same tumor were compared. A good reproducibility was obtained for LI and Tpot (P < 0.01). Thirty-one tumors were analysed by immunohistochemistry and labelling index (HLI) was determined in 24 tumors with a percentage of labelled cells varying from 6.1% to 39.2% (median value = 18.5%). No correlation was found between LI and HLI, but when observations were focused on the restricted group of DNA aneuploid samples, mean values of LI and HLI were closer (respectively, 12.8 +/- 4.5% and 18.3 +/- 7.7%) and a good correlation was obtained (P = 0.01). Moreover, no difference in proliferation was found between diploid and aneuploid tumors. Considering these results, a combined Tpot was calculated that allowed classification of tumors as highly or slowly proliferative.