D. Pontvert

Quality control of radiotherapeutic treatment of medulloblastoma in a multicentric study: The contribution of radiotherapy technique to tumour relapse

Between 06.86 and 11.89, 88 medulloblastoma or primitive neuroectodermic tumour (PNET) localised in the posterior fossa have been included in the M7 multicentric protocol, 82 received the totality of the radiotherapy treatment and were evaluable for this study. Twenty-two of these 82 patients relapsed: their radiotherapy treatment is analysed in the present study. In 10 cases out of the 22 relapses treatment failure was probably due to a radiotherapeutic imperfection. This study confirms the necessity of a strict radiotherapy control, particularly in multicentric study.

Induction chemotherapy in advanced head and neck tumors : results of two randomized trials

From March 1983 to December 1989, 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two randomized induction chemotherapy trials. The chemotherapy regimen of the first trial, which included 100 patients, consisted of two cycles of a combination of cisplatin, bleomycin, vindesine and mitomycin C; while that of the second trial, which included 108 patients, consisted of three cycles of a combination cisplatin, 5-fluorouracil by continuous infusion and vindesine. Local treatment was the same in the two trials: primary radiotherapy in all patients. The response was then evaluated; in the case of a poor response at 55 Grays surgery was performed; otherwise, radiotherapy was continued to full doses (possibly followed by salvage surgery). The tumor and lymph node responses to chemotherapy (complete and partial response) were higher in the second trial than in the first: 70% versus 50% for primary lesions, 47% versus 25% for lymph nodes. The toxicity of the two chemotherapy regimens was minimal. In the two trials, an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80% of the patients. The significance of the complete response at the end of the irradiation varies with the previous response to the chemotherapy. With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second, overall survival and disease-free interval were very similar in the two groups. The incidence of distant metastasis was significantly reduced (p less than 0.03) with chemotherapy. This trial suggests the need to test new chemotherapy protocols according to new schemes of treatment, with chemotherapy given concurrently with or following the completion of standard treatment by means of multicenter randomized trials.

Results of radiation therapy in carcinoma of the base of the tongue. The curie institute experience with about 166 cases

Between 1960 and 1980, 166 patients with squamous cell carcinoma of the base of the tongue were treated with primary irradiation at the Curie Institute (Paris, France). Distribution according to the TNM system 1978 International Union Against Cancer (UICC) was the following: 22 T1 lesions, 47 T2 lesions, 64 T3 lesions, and 33 T4 lesions. Regional nodes were not palpable in 50 cases, 35 had N1 nodes, 12 had N2 nodes, and 69 had N3 nodes. All patients received external beam radiation. The 2‐year, 3‐year, and 5‐year overall survival rates for all patients were, respectively, 45%, 37%, and 27%. Local control was significantly related to the initial status of the primary, to the tumor regression at the end of the radiation therapy, and to the histologic differentiation. The 2‐year local control was 96% for T1 lesions, 57% for T2 lesions, 45% for T3 lesions, and 23% for T4 lesions. Local control was 70% if the tumor regression was complete at the end of the treatment and 27% if the tumor regression was partial. No significant differences were found in primary local control with respect to degree of infiltration, age, and dose of radiation therapy over a dose of 60 Gy in 6 weeks. The 3‐year regional control was 86% for N0, 78% for N1, and 60% for N2 and N3. Among the tumor characteristics analyzed, the most useful ones for predicting local control and survival were clinical tumor staging parameters and tumor radiation‐induced regression. A new therapeutic approach based on the evaluation of the tumor regression at 50/55 Gy is under discussion.

Primary radiotherapy of squamous cell carcinoma of the oropharynx and pharyngolarynx: Tentative multivariate modelling system to predict the radiocurability of neck nodes

In a series of 1251 cases of squamous cell carcinomas of oropharynx and pharyngolarynx with clinically positive neck and treated primarily by radiation therapy a determinate group of 798 cases remained eligible for a multivariate analysis of the prognostic factors related to the regional outcome. Node size (p less than 0.0001), node fixity (p = 0.016) and T stage (p = 0.02) were the significant pretreatment factors independently predictive of neck node control. when regarding the treatment modalities in this determinate group of patients who received tumor doses of at least 55 Gy, only the treatment duration was found to be predictive (p = 0.002). Based on these factors, a multivariate model was constructed and tested by estimating the product-limit survival of the various groups of patients. The predictive accuracy of the equation was assessed by the log-rank test significance levels. The model may help to select, in many clinical situations, the appropriate approach of the management of metastatic neck disease, either by definitive radiation therapy or by combined modalities.

Selecting Patients for Exclusive Permanent Implant Prostate Brachytherapy: The Experience of the Paris Institut Curie/Cochin Hospital/Necker Hospital Group on 809 Patients

PURPOSE The aim of this study was to analyze overall and relapse-free survival in a cohort of 809 patients, 34% of whom corresponded to a higher-risk group than American Brachytherapy Society (ABS) criteria. METHODS AND MATERIALS Between January 1999 and September 2004, 809 patients were treated with permanent loose 125 iodine seed implantation (IsoSeed Bebig, Eckert and Ziegler) by the Paris Institut Curie, Cochin Hospital, and Necker Hospital group. Of these 809 patients, 533 (65.9%) corresponded exactly to ABS criteria. Two hundred and seventy-six patients (34.1%) had a prostate-specific antigen (PSA) level between 10 and 15, or a Gleason score of 7, or both (non-ABS group). RESULTS Overall 5-year survival was 98%, with no difference between the ABS group and the non-ABS patient subgroups (p = 0.62).Five-year relapse-free survival was 97% in the ABS group; it was significantly lower (p = 0.001) in the non-ABS group but remained satisfactory at 94%. On subgroup analysis, the results appeared to be better for the subgroup of patients with PSA 10-15 than for the subgroup with a Gleason score of 7. CONCLUSIONS Our results suggest that selected patients in the intermediate-risk group of localized prostate cancers can be safely proposed as recipients of permanent implant brachytherapy as monotherapy.

Impact of neck node radioresponsiveness on the regional control probability in patients with oropharynx and pharyngolarynx cancers managed by definitive radiotherapy.

We reviewed a series of 1,666 patients with squamous cell carcinoma of the oropharynx and pharyngolarynx treated with definitive radiation therapy to determine whether or not radioresponsiveness of the metastatic neck nodes is a reliable indicator of their radiocurability. In a determined group of 708 patients with clinically positive neck nodes, only one third of the adenopathies (247/759) completely regressed at the completion of the treatment. At 6 months, only ten percent of the nodes remained palpable. Lymph node clearance rates and halving diameter times were tumor size-dependent. Node clearance rate was also influenced by the site of the primary lesion. The impact of various parameters, both intrinsic and extrinsic to the tumor behavior, is discussed. Neck control probability was significantly higher for complete responders. In this group, the ultimate node control was as good for adenopathies larger than 6 cm as for the smaller ones. Tumor control probability directly related to clearance rate following radiotherapy. Finally, therapeutic implications are derived for nodal dose adjustments and optimal applicability of radiosurgical combinations.

Positron Emission Tomography/Computed Tomography Imaging of Residual Skull Base Chordoma Before Radiotherapy Using Fluoromisonidazole and Fluorodeoxyglucose: Potential Consequences for Dose Painting

PURPOSE To detect the presence of hypoxic tissue, which is known to increase the radioresistant phenotype, by its uptake of fluoromisonidazole (18F) (FMISO) using hybrid positron emission tomography/computed tomography (PET/CT) imaging, and to compare it with the glucose-avid tumor tissue imaged with fluorodeoxyglucose (18F) (FDG), in residual postsurgical skull base chordoma scheduled for radiotherapy. PATIENTS AND METHODS Seven patients with incompletely resected skull base chordomas were planned for high-dose radiotherapy (dose ≥70 Gy). All 7 patients underwent FDG and FMISO PET/CT. Images were analyzed qualitatively by visual examination and semiquantitatively by computing the ratio of the maximal standardized uptake value (SUVmax) of the tumor and cerebellum (T/C R), with delineation of lesions on conventional imaging. RESULTS Of the eight lesion sites imaged with FDG PET/CT, only one was visible, whereas seven of nine lesions were visible on FMISO PET/CT. The median SUVmax in the tumor area was 2.8 g/mL (minimum 2.1; maximum 3.5) for FDG and 0.83 g/mL (minimum 0.3; maximum 1.2) for FMISO. The T/C R values ranged between 0.30 and 0.63 for FDG (median, 0.41) and between 0.75 and 2.20 for FMISO (median,1.59). FMISO T/C R >1 in six lesions suggested the presence of hypoxic tissue. There was no correlation between FMISO and FDG uptake in individual chordomas (r = 0.18, p = 0.7). CONCLUSION FMISO PET/CT enables imaging of the hypoxic component in residual chordomas. In the future, it could help to better define boosted volumes for irradiation and to overcome the radioresistance of these lesions. No relationship was founded between hypoxia and glucose metabolism in these tumors after initial surgery.

Quantitative magnetic resonance and isotopic imaging: Early evaluation of radiation injury to the brain

PURPOSE Using magnetic resonance (MR) and isotopic imaging to investigate the cerebral alterations after highdose single-fraction irradiation on a pig model. We assessed the nuclear magnetic resonance (NMR) relaxation times as early markers of radiation injury to the healthy brain. METHODS AND MATERIALS A total of 17 animals was studied; 15 irradiated and 2 unirradiated controls. Pigs were irradiated with a 12 MeV electron beam at a rate of 2 Gy/min. Ten animals received 40 Gy at the 90% isodose, five animals received 60 Gy, and two animals were unirradiated. The follow-up intervals ranged from 2 days to 6 months. T1-weighted scans, T2-weighted scans, and scintigrams were performed on all animals to study neurological abnormalities, cerebral blood flow, and blood-brain barrier (BBB) integrity. T1 and T2 relaxation times were measured in selected regions of interest (ROIs) within the irradiated and contralateral hemispheres. A ratio T1 after irradiation/T1 before irradiation, and a ratio T2 after irradiation/T2 before irradiation, were calculated, pooled for each dose group, and followed as a function of time after irradiation. RESULTS Scintigraphy visualized the brain perfusion defect and BBB disruption in all irradiated brains. The ratio T2 after irradiation/T2 before irradiation was proportional to the effective dose received. The T2 ratio kinetics could be analyzed in three phases:an immediate and transient phase, two long-lasting phases, which preceded compression of the irradiated lateral ventricle, and edema and necrosis at later stages of radiation injury, respectively. The magnetic resonance imaging (MRI) observations correlated well with histological analysis. CONCLUSION The results show that quantitative imaging is a sensitive in vivo method for early detection of cerebral radiation injury. The reliability and dose dependence of T2 relaxation time may offer new opportunities to detect and understand brain pathophysiology after high-dose single-fraction irradiation.

Impact of cervical disease and its definitive radiotherapeutic management on survival: Experience in 2013 patients with squamous cell carcinomas of the oropharynx and pharyngolarynx

Two thousand thirteen patients with squamous cell carcinoma of oropharynx and pharyngolarynx were reviewed with regard to neck disease presentation and disease‐free survival after radical radiotherapy. All patients were staged according to both the AJCC1976 and the UICC1978 classifications. Causes of failure, disease‐free survival, and complication rates were assessed. Sixty percent had a clinically positive neck. The 3‐year disease‐free survival rates were 58%, 44%, 38%, and 25% for AJCC NO, Nl, N2, and N3 cases, respectively. Corresponding UICC figures were 58%, 46%, 26%, and 29%. Analyzed parameters were nodal stage, size, site and fixity, and location of primary. Complications attributed to neck disease did not exceed 3%. A critical appraisal of the nodal staging systems is derived from these sets of data.

Is reseeding from the primary a plausible cause of node failure

In a previous analysis of node failures in 1251 consecutive patients with node positive oropharyngeal and pharyngolaryngeal squamous cell carcinomas treated by external radiotherapy alone at the Institut Curie, the main reasons for patient exclusion were node recurrence associated with primary failure (N+T failures) and doses less than 55 Gy. These exclusions reduced the number of node failures from 399/1251 (32%) to 77/798 (10%). Multivariate analysis of node recurrence indicated that node size and fixity, treatment duration, and T stage of primary were significant (higher probability of isolated node failure for the T1-T2 primaries). In the present analysis, it is noted that 60% of the N+T failures were observed less than 1 month after the completion of the irradiation and, therefore, were not likely the result of reseeding from the primary tumor. When all 1251 patients were included in the analysis, the probability of nodal failure increased for larger nodes, T4 primaries, lower nodal doses, presence of contralateral node metastases, and nodal fixation to the surrounding structures. No influence of the primary site was found. Treatment duration was closely associated with total dose to the nodes. The best description of the data was obtained with a model including total dose and not treatment time. However, as in the previous analysis, the exclusion of low-dose (less than 55 Gy) treatments resulted in the loss of a significant dose-control relationship. We conclude that the majority of node failures is unlikely to result from reseeding from the primary tumor, and therefore should not be excluded from local-control analyses. From a more radiobiological point of view, the exclusion of palliative treatments is questionable when studying the effect of dose on local control.