First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

Specific inhibition of polyamine oxidase in vivo is a method for the elucidation of its physiological role.

N1-Methyl-N2-(2,3-butadienyl)-1,4-butanediamine (MDL 72521) and N1,N2-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527) are specific, potent, enzyme-activated, irreversible inhibitors of polyamine oxidase in vitro. These compounds are also capable of completely inhibiting polyamine oxidase in mouse tissues at intraperitoneal doses greater than 20 mg/kg. Enzyme activity reappears in the various organs within 2-3 days to 50% of the control values. Irreversible inhibition of polyamine oxidase in mice led to decreased putrescine (30-40%) and spermidine (10-20%) levels in liver and some other organs. At the same time N1-acetylspermidine and, to a lesser extent, N1-acetylspermine were accumulating at rates which are assumed to be related to the rates of polyamine degradation. Even after treatment with polyamine oxidase inhibitors over a period of 6 weeks at doses which produced complete inhibition of polyamine oxidase in all organs, including the brain, neither toxic effects nor changes in body weight or behaviour were observed.

The specificity of two proteinases that cleave adjacent to arginine, C1 esterase and acrosin, for peptide p-nitroanilide substrates.

Relative values of Vmax/Km for hydrolysis of 40 peptide p-nitroanilides catalyzed by human Cl-s and human acrosin are reported. For Cl-s, Ac-Lys(gamma Cbz)-Gly-Arg is the optimum sequence, but 25% of the substrates have (Vmax/Km)rel greater than 0.25 compared to this sequence. The best acrosin substrate tested has the sequence Tos-Gly-Pro-Arg, although (Vmax/Km)rel greater than 0.15 for more than half of the substrates. Proline at P2 is preferred by acrosin. Both enzymes prefer arginine at P1 greater than or equal to 3-fold over lysine and will not accept citrulline. In addition, occupancy of site S3 may yield an increase in Vmax/Km of greater than or equal to 10-fold with either enzyme, but many residues are accepted at S2, S3 and S4. Thus, an acrosin assay using Tos-Gly-Pro-Arg p-nitroanilide as a substrate is more than 20-times as sensitive as existing assays with blocked arginine derivatives.

Non-Hodgkin's lymphomas in 137 patients aged 70 years or older: a retrospective European Organization for Research and Treatment of Cancer Lymphoma Group Study.

The results of a European Organization for Research and Treatment of Cancer (EORTC) retrospective study on non-Hodgkin's lymphoma (NHL) in elderly patients (greater than or equal to 70 years of age) seen in Europe in 1984 are reported. A precodified form was sent to 55 European institutes in order to evaluate the incidence of NHL in the elderly with regard to natural history, treatment-related toxicity, response, and survival. Thirteen institutes participated in the study. One hundred thirty-seven cases of NHL were observed in the elderly during 1984, making up 28% of the total number of NHL seen in those institutes. The median age was 77 years; 21% of the patients had favorable (low-grade) and 73% unfavorable (intermediate- and high-grade) histology, according to the Working Formulation. Stage at presentation was localized (I and II) in 60% and advanced in 37% of the patients. Most of the physicians used standard therapy regimens at reduced doses, from the beginning of the treatment. Sixty patients (44%) underwent a "conservative" treatment (one or two antineoplastic drugs or local field radiotherapy) and 77 (56%) an "aggressive" treatment (polychemotherapy regimens or extended field radiotherapy). Response was similar between the two treatment groups, but severe and lethal toxicity was significantly higher among patients treated with aggressive therapy. Prospective randomized studies are clearly needed to define the optimal treatment in elderly patients with advanced unfavorable NHL.

Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology.

PURPOSE: With the aim of decreasing undesirable side effects of therapy, we investigated the reduction of both chemotherapy and radiation therapy (RT) in children with Hodgkin's disease, and compared Adriamycin (doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France), bleomycin, vinblastine, and dacarbazine (ABVD) alone to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in favorable cases and assessed the effectiveness of low-dose RT (20 Gy) after good response to chemotherapy. PATIENTS AND METHODS: A French national study began in 1982 that included 238 pediatric patients with Hodgkin's disease. Initial staging was clinical and without laparotomy. In patients with localized disease (IA-IIA), an equivalence trial compared the effectiveness of four cycles of ABVD with two cycles of ABVD that were alternated with two cycles of MOPP. Patients with more advanced disease (IB-IIB-III-IV) received three courses of MOPP that was alternated with three courses of ABVD. All of the patients who achieved a good remission after chemotherapy were administered 20 Gy RT, which was limited to the initially involved areas for localized disease, and encompassed the paraaortic nodes and the spleen as well for more advanced stages. When a good remission was not obtained, 40 Gy RT was administered. RESULTS: At the completion of chemotherapy, 227 patients (97%) were considered good responders, whereas 11 did not achieve a good remission. With a median follow-up of 6 years, the 6-year actuarial survival was 92% and the disease-free survival was 86%. The relapse-free survival in favorable stages was 90% in the ABVD arm and was 87% in the MOPP and ABVD arm. In June 1987, inclusion of stage IV patients was discontinued because of poor results. CONCLUSIONS: Present findings indicate that (1) in favorable stages, ABVD alone and alternating MOPP and ABVD are equivalent, and (2) chemotherapy followed by 20 Gy RT represents a valid therapeutic approach in the vast majority of children with Hodgkin's disease.

[Radiation oncology training in France: demography, analysis of motivations of the young specialists, evaluation of the training]. / Dynamique et évaluation de la formation des internes en radiothérapie en France en 2005.

During the 5 past national courses organised by the French society of radiation oncology (SFRO), three different types of survey were performed to analyse demography, motivations and quality of training of the young specialists. During the 5 past years, 50 radiation oncologists were training for the whole country (about 15 per year were graduated). A recent increase the number of young specialists is observed with a total number of 50 in 2000 to 75 in 2005. Nevertheless, the number of young specialists is dramatically insufficient and exposes for the future to an important demographic crisis. Analysis of motivations of choice for radiation oncology confirms the influence of a practical stage of oncology during the second cycle of the medical studies for 60% of the young specialists. Analysis of practical and theoretical training was performed according to the point of view and living experiences of the students. On the other hand, informations from teachers were less complete. Some needs are emphased as: 1) the quality of the follow during the training (importance of the recent implementation of a logbook); 2) importance of theoretical and practical training at the radiotherapy department; 3) help and incentive for research and scientific publication.

Radiosensitivity of multicellular tumour spheroids obtained from human ovarian cancers.

The radioresponsiveness of immunologically characterised (KL1, antivimentin and OC125) human ovarian carcinoma cells, obtained from effusions or solid tumours, was assayed in vitro using the multicellular tumour spheroids (MTS) three-dimensional model. Great interspecimen variabilities were observed in MTS doubling time (1.0-8.5 days), as well as in the doses inducing a 50% decrease in the MTS individual volume (ID50) (0.56-9.15 Gy), or in the overall population MTS number (SCD50) (1.9-15.7 Gy) and the residual/initial MTS individual volume ratio after 2 Gy irradiation (RSV2) (10-88%). The doubling time, DNA-ploidy and S-phase fraction did not correlate with the ID50. Significant correlations were found between the new parameters defined (RSV2 and ID50) and the SCD50, a well-accepted local control parameter. These parameters demonstrated their usefulness for studying the radiosensitivity of MTS prepared from human ovarian tumour biopsies.

Breast cancer in patients treated for Hodgkin's disease: clinical and pathological analysis of 76 cases in 63 patients.

In a retrospective multicentric analysis, 63 women treated between 1941 to 1988 for Hodgkin's disease (HD) subsequently developed 76 breast cancers (BC). The median age at diagnosis of HD was 26 years (range 7-67), and 22 women (35%) were 20 years old or less. Exclusive radiotherapy (RT) was used in 36 women (57%) and combined modalities with chemotherapy (CT) in 25 (39%). Breast cancer occurred after a median interval of 16 years (range 2-40) and the median age at diagnosis of the first BC was 42 years (range 25-73). TNM classification (UICC, 1978) showed 10 T0 (non-palpable lesions) (13%), 20 T1 (26%), 22 T2 (29%), 8 T3 (11%), 7 T4 (9%) and 9 Tx (12%), giving altogether a total of 76 tumours, including, respectively, 5 and 8 bilateral synchronous and metachronous lesions. Among the 68 tumours initially discovered, 53 ductal infiltrating, one lobular infiltrating and two medullary carcinomas were found. Moreover, two fibrosarcomas and 10 ductal carcinoma in situ (DCIS) were also found. Among 50 axillary dissections for invasive carcinomas, histological involvement was found in 31 cases (62%). 45 tumours were treated by mastectomy, without (n = 35) or with (n = 10) RT. 27 tumours had lumpectomy, without (n = 7) or with RT (n = 20). 2 others received RT only, and one only CT. 7 patients (11%) developed isolated local recurrence. 20 patients (32%) developed metastases and all died; 38 are in complete remission, whereas 5 died of intercurrent disease. The 5-year disease-specific survival rate by the Kaplan-Meier method was 61%. The 5-year disease-specific survival rate for pN0, pN1-3 and pN > or = 3 groups were 91%, 66% and 0%, respectively (P < 0.0001) and 100%, 88%, 64% and 23% for the T0, T1, T2 and T3T4 groups, respectively. These secondary BCs seem to be of two types: a large number of aggressive tumours with a very unfavourable prognosis (especially in the case of pN > 3 and/or T3T4); and many tumours with a 'slow development' such as DCIS and microinvasive lesions, especially in patients treated exclusively by RT. Moreover, a very unusual rate of bilateral tumours (21%) was observed. These secondary BC could be 'in field', in 'border of field' or 'out of field'. However, a complete analysis of doses delivered by supradiaphragmatic irradiation was often very difficult, due to large variations in several parameters. We conclude that young women and girls treated for HD should be carefully monitored by clinical examination, mammography and ultrasonography.

Radiation therapy alone for medically inoperable patients with adenocarcinoma of the endometrium.

Surgery with adjuvant radiation is the definitive method for treating patients with Stage I and II FIGO endometrial carcinoma. However, radiation therapy alone becomes the only curative alternative for patients who presented with severe, acute, and chronic medical illnesses which prevented surgical management. We report on 104 such patients treated at Centre Alexis Vautrin in Nancy (FRANCE) between 1975 and 1984. The minimum follow-up was 2 years, the maximum was 11 years. Fifty-two patients were treated by association of external irradiation (RT) and curietherapy (CUR), and 52 by curietherapy alone. The median age of the patients was 68.8 years with a minimum of 43 and maximum of 89 years old. Ninety-six patients (92.3%) were obese. Forty-nine (47.1%) were hypertensive. Forty-one (39.4%) had cardiovascular diseases, 25 (24%) had diabetes mellitus, and 13 (12.5%) had history of phlebitis. Seventy-nine patients (75.9%) were Stage I FIGO, 15 (14.4%) were Stage II, 4 patients (3.8%) were Stage III, and 6 patients (5.7%) were Stage IV. The 5- and 10-year overall absolute survival was 51.6% and 35.9% respectively. The 5- and 10-year determinate survival was 65.9% and 58.6% respectively. The 5- and 10-year absolute survival of patients treated by combination RT + CUR was 59.6 and 49.8% respectively. The 5- and 10-year survival of patients treated by CUR alone was 42.3% and 27% significantly worse (p = 0.025). The 5- and 10-year determinate survival for Stage Ia was 82.1%, 71.4% and for Stage Ib 64.6% and 64.6% respectively. The difference was not significant (p = 0.18). While the 5- and 10-year determinate survival for Stage II was 56.2% and 56.3%, significantly worse than Stage I patients (p = 0.043). Tumor differentiation (G) was found to be a significant prognostic factor in survival (p less than 0.05). Local failure was seen in 9 patients (8.6%) 5 in association with distant metastasis (DM). The 5- and 10-year actuarial local control were 87.6% and 85.1% respectively. Severe complications occurred in 18 patients (17.3%). Five of these patients are still alive with a mean follow-up of 8.8 years (minimum 6 years and maximum 11 years). The rate of complications had considerably diminished after 1980, as techniques improved and computerized dosimetry was used.

Factors affecting local control and survival after treatment of carcinoma of the rectum by endocavitary radiation: a retrospective study of 97 cases.

PURPOSE: Endocavitary radiation therapy constitutes an alternative to surgical therapy for some early rectal carcinomas. We studied the prognostic factors for locoregional or metastatic relapse after endocavitary radiation, and their impact for therapeutic strategy. METHODS AND MATERIALS: Our study reports the outcome of 97 patients with adenocarcinomas of the rectum treated from 1978 to 1998 by endocavitary irradiation (100 Gy), exclusive or combined with an interstitial brachytherapy boost of 20 Gy. The indications consisted mostly of polypoid, mobile tumors, less than 4 cm in diameter, and well differentiated. But the indications were extended to elderly patients, who presented with a high surgical risk or who refused mutilating surgery. RESULTS: The mean follow-up was 82 months. One patient presented with an isolated distant metastatic relapse, and 27 patients presented with locoregional recurrence, surgically salvaged in 16 cases. Disease-free survival was 71% at 5 years and 68% at 10 years. Multifactorial analysis suggests that clinical stage T1A, well-differentiated tumors, and early and complete response are favorable prognostic factors for disease-free survival. Response to therapy is the most powerful prognostic factor for relapse. CONCLUSION: This retrospective study confirms the efficacy of endocavitary radiotherapy combined with brachytherapy as a safe conservative treatment in well-selected patients.

The study of tumoral, radiobiological, and general health factors that influence results and complications in a series of 448 oral tongue carcinomas treated exclusively by irradiation.

PURPOSE: Our aim was to study the different factors that influence the results and complications in a series of 448 carcinomas of the oral tongue treated from January 31, 1972 to December 31, 1986, by brachytherapy (Br) +/- neck dissection (181 cases) or combination of external beam irradiation and brachytherapy (EBI + Br) (267 cases). METHODS AND MATERIALS: The patients distribution (TNM classification 1979) was: 125 T1, 186 T2, 128 T3, 9 T4Tx, 78% N0, and 22% N+. We used guide gutter or plastic tubes technique (Paris system dosimetry). Results at 5 and 10 years are: local control 68% and 64%, locoregional control 58% and 53%, specific survival 45% and 39%, and overall survival 44% and 27%. RESULTS: In the univariate analysis for local control (LC) and overall survival (OS), we considered the tumoral factors. At 5 years, the LC for T1, T2, T3 are 93%, 65%, and 49%, and the OS 69%, 41%, and 25%, respectively (p < 0.002). The lesions of the undersurface of the tongue have a better LC (77%) than other localizations (64%) (p = 0.02). For general factors, the index of general health condition, age, and sex were not significant for LC, but proved significant for OS (p = 0.01). Significant radiobiological factors: the safety margin (expressed by the ratio treated surface on tumoral surface > or = 1.2) is significant for LC and OS. This is the same if the interval between EBI and Br is < or = 20 days. Neither the dose rate, the spacing between the sources, the total dose, nor Br dose were significant, but the last two were adapted according to the infiltration. In the univariate study for grade 2 and 3 complications (tissue and bone), the surface treated (> 12 cm2), and the dose rate > 0.7 Gy/h were significant. CONCLUSION: The multivariate study showed that the small size of the lesion is the most important factor for local control, with brachytherapy alone for T1T2N0 and the number of days between EBI and brachytherapy < or = 20 days. For the complications, the most important factors are the total dose > 80 Gy and a treated surface > 12 cm2.

Conservative treatment by irradiation of epidermoid carcinomas of the anal margin.

PURPOSE: Few series have described treatment results of anal margin tumors as defined in the UICC 87 classification. The purpose of this article is to describe experience with an uncommon condition in a single cancer center. METHODS AND MATERIALS: From 1971 to 1995, 32 patients with carcinoma of the anal margin were irradiated with a curative intent, and 31 were followed-up for more than 6 months (mean = 4.5 years). There were 9 T1, 15 T2, 7 T3, and 1 T4 (vulvar), with 26 N0 and 6 N1. There was a minor invasion of the lower canal in 17 patients. The histological types were 24 squamous cell and 7 basocellular carcinomas, and 1 Paget's disease. The treatment was a combined External Beam Irradiation (EBI) and Brachytherapy (BT) in 16 patients, an exclusive BT in 12 patients, and an exclusive EBI in 4 patients. No prophylactic inguinal irradiation was delivered. RESULTS: The 5-year actuarial results are as follows: overall survival = 67%, specific survival = 89%. The only prognostic factor was nodal involvement (p < 0.001). T-stage, T-size, age, sex, and treatment schedule were not significant. The overall local control was 77%, and 93.5% after salvage. Two N0 patients relapsed in inguinal areas (one was salvaged). Twenty-six percent presented a Grade 3 or 4 late complication, necessitating a temporary colostomy in only one patient. The sphincter conservation reached 84% for the whole series, 80% for patients followed-up 5 years or more, and 89% for cured patients. CONCLUSION: Results are similar to other series, and seem better than for anal canal cancer. We recommend exclusive irradiation. There is no data recommending concomitant chemotherapy. Depending on the tumor size and localization, the tumor boost can be applied by EBI or BT. Surgery is reserved for small tumors far from the canal or for salvage. An inguinal prophylactic bilateral irradiation should be recommended for N0, with tumors over 4 cm.

Place of radiotherapy in the treatment of Graves' orbitopathy.

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.

Initial chemotherapy and low-dose radiation in limited fields in childhood Hodgkin's disease: results of a joint cooperative study by the French Society of Pediatric Oncology (SFOP) and Hôpital Saint-Louis, Paris.

To minimize the drawbacks of treatment we had shown in a previous study that it was possible after chemotherapy to limit the radiation fields to the involved areas only. Pursuing our policy of deescalation, we started in January 1982 a study in 29 French pediatric and hematologic centers, with two aims: (1) To compare the efficacy of 4 cycles of two different chemotherapeutic regimens (4 ABVD vs 2 MOPP + ABVD) in early stages (CSIA and II A) while other stages would receive 6 cycles of the same regimen (3 MOPP + 3 ABVD); (2) To evaluate the efficacy of irradiation given at a low dose (20 Gy) in the patients who had a minimum 70% reduction of the size of their nodes (good responders). From January 1982 to March 1987, 174 patients were entered in this study, of whom 157 completed their treatment program at the time of analysis. On completion of chemotherapy, 94% were considered as good responders and were irradiated to 20 Gy. Only 6 patients received a mediastinal boost (up to 40 Gy). Of the 6% (10/157) poor responders a complete remission was obtained in 6 after 40 Gy. Among the good responders, 5 patients relapsed, with only 3 within an area irradiated to 20 Gy. So that 4 nodal relapses occurred among 364 involved lymph areas. The actuarial survival at 42 months (median 30 months) is 95% (IA + IIA = 100%, IB + IIB + III = 94% and IV = 80%) and the disease-free survival 88% (respectively 94, 93 and 54). Until now there is no statistically significant difference between the 2 randomized arms. This study shows that it is possible to achieve a durable remission in most children treated with a less toxic protocol eliminating or reducing Nitrogen Mustard and reducing the dose of irradiation. Less late complications and sequelae are expected with a longer follow-up.

Salvage irradiation by brachytherapy of velotonsillar squamous cell carcinoma in a previously irradiated field: results in 73 cases.

PURPOSE: The salvage brachytherapy performed in patients presenting velotonsillar carcinoma in a previously irradiated field is evaluated in terms of local control, complications and survival. METHODS AND MATERIALS: Between 1976 and 1990, 73 patients presenting with velotonsillar squamous cell carcinoma in a previously irradiated area were treated at Center Alexis Vautrin with brachytherapy along using an 192Ir implant (afterloading technique) with curative intent. According to the UICC 1987 TNM classification, there were 45 T1 N0, 20 T2 N0, one T3 NO, one T3 N2 and six Tx Nx. RESULTS: The 5-year actuarial local control for T1 N0 and T2 N0 are 80% and 67% respectively. The regional relapse rate was 10% in both groups. Grade 2 complications occurred in 13% of patients and these were neither related to the volume treated nor the dose rate. There were no Grade 3 or 4 complications. The 5-year specific survival is 64%, with a plateau after the 5th year, but the 5-year overall survival is only 30%. Fourty-two percent of the patients in this series died from another carcinoma. All but two of these were related to continued alcohol and tobacco intoxication. CONCLUSION: We conclude that brachytherapy alone (60 Gy) is optimal treatment for patients presenting with velontonsillar carcinoma in a previously irradiated field. The greatest challenge is the screening of these patients and the prevention of subsequent head and neck cancers. Recognizing the fact that these patients are at high risk for subsequent malignancies of upper aerodigestive tract, lung and esophagus, close surveillance is necessary for: (a) early diagnosis and prompt treatment; and (b) development of prevention strategies of field cancerization.

Influence of tumoral, radiobiological, and general factors on local control and survival of a series of 361 tumors of the velotonsillar area treated by exclusive irradiation (external beam irradiation+brachytherapy or brachytherapy alone)

PURPOSE: To evaluate statistically the factors influencing the therapeutic results. METHODS AND MATERIALS: A statistical study was carried out concerning 361 patients treated from 1977 to 1991 for velotonsillar carcinoma. They received either brachytherapy alone (18) or a combination of external beam irradiation and brachytherapy (343 patients) using an afterloading iridium technique in plastic tubes. The distribution of patients according to the localization was: 128 tonsils, 134 soft palates, 9 posterior pillars, 63 anterior pillars, and 27 glossotonsillar sulcus. The patients were staged as follows: 90 T1, 141 T2, 119 T3, 2 T4, 9 Tx with 230 N0, 93 N1, 9 N2, 20 N3, and 9 Nx. RESULTS: The results at 5 and 10 years show: local control 80% and 74%, locoregional control 75% and 70%, overall survival 53% and 27%, specific survival 63% and 52%, respectively. The univariate study shows at 5 years a better local control for T1T2 (87%) compared with T3 (67%) with p = 0.00004. The locoregional control is better for N0 (80%) than for N+ (55%) with p = 0.002. This is the same for the overall survival (59% vs. 42%, p = 0.002). Tumors with an extension to the mobile tongue or the base have a poor prognosis (p < 0.002). The radiobiological factors show less recurrences if the total duration of the treatment is < 55 days, the number of days between External Beam Irradiation and brachytherapy is < 20. The security margin seems important also. CONCLUSIONS: For the combination external irradiation and brachytherapy, the multivariate study for local control shows that ony T, localization, and the total duration of treatment are significant. For complications, classified into four grades, only the dose rate is significant.

Velotonsillar squamous cell carcinoma: 277 cases treated by combined external irradiation and brachytherapy--results according to extension, localization, and dose rate.

From 1977 to 1987, 277 patients with velotonsillar cancer (oropharyngeal cancer excluding base of tongue and valleculae) were treated by brachytherapy either alone (14 patients) or combined with external beam irradiation (263 patients) using a new afterloading Iridium-192 technique. The distribution of patients according to the localisation was as follows: 106 tonsillar region, 98 soft palate, 45 anterior pillar, 8 posterior pillar and 20 pharyngoglossal sulcus. According to the UICC TNM classification of 1979, the patients were staged as follows: 65 T1, 103 T2, 101 T3, 8 TX. 172 patients were NO, 74 N1, 3 N2, 20 N3 et 8 NX. According to the tumor extension, the 5 year actuarial local control, locoregional control, specific survival and overall survival by T stage (T1 [65 pts], T2 [103 pts.], T3 [101 pts]) were respectively: local control: 89%, 86%, 69%; locoregional control: 84%, 80%, 67%; specific survival (excluding patients dead with intercurrent disease or second cancer): 78%, 62%, 46%; overall survival: 62%, 53%, 43%. No local recurrence was detected after 3 years. According to the localization, the tumors arising from the tonsillar region, the soft palate and the posterior pillars (A Group) had a better prognosis than the tumors arising from the anterior pillars and glossotonsillar sulcus (B Group). The complications were classified into four grades according to their extension and duration: Grade 1 (minor) with very small tissue ulcer which healed within 2 months with medical treatment (20%). Grade 2 (moderate) (5%), grade 3 (severe) (1.4%), grade 4 (fatal) (0.4%). The dose rate seemed to be relatively higher in patients with grade 2 and 3 complications (70 cGy per hour on average) versus the dose rate of patients without complications (50 cGy per hour) but the difference was not significant. In conclusion, the brachytherapy boost after external irradiation can be performed under favourable conditions with an acceptable rate of complications. It was set out in order to attempt to improve the local control of the tumor while preserving the salivary function and lessening the muscular fibrosis. It shows how experienced the team is, however only a randomized study would allow to state whether this technique brings about a real improvement especially as for tumors T2 or T3.

Complications following definitive irradiation for cancers of the oral cavity and the oropharynx (in a series of 1134 patients).

PURPOSE: To study the rate and severity of complications in a series of 1134 patients treated by definitive irradiation for tumors of the oral cavity (772 cases) or the oropharynx (361 cases). METHODS AND MATERIALS: Patients were staged as 29.5% T1, 42% T2, 26% T3, 2.5% T4-Tx, and 74.5% N0 tumors. We treated 364 patients with brachytherapy only (192Ir) for the primary lesion. External irradiation and brachytherapy were combined for 770 patients. RESULTS: The results included local control and survival. Out of 1134 patients, 330 had 376 complications. Grade 1 complications occurred in 20% of the patients, Grade 2 in 9%; Grade 3 in 4%; and Grade 4 in 0.2%. Of the Grade 1 complications, 78% were soft tissue and only 24% were bone complications. For the more severe grades (2, 3, and 4), there were 56 soft tissue complications and 90 bone complications out of 1340 patients. The statistical analysis included tumor-related factors and treatment-related factors. For the first two factors, only tumor location was significant. The treatment-related factors significant for complications were studied in univariate and multivariate study. This multivariate study confirmed that for soft tissue complications dose rate and volume treated were important (p < 0.001). It also confirmed that for bone complications, total dose > 80 Gy, dose rate > 0.7 Gy/h, and the absence of leaded protection of the mandible were all important factors. CONCLUSION: This statistical study should allow future reduction of severe complications (Grades 2, 3, 4), if treatment factors inducing them can be taken into account. This is not always possible for very large tumors.

Cervical lymph node metastasis from an unknown primary: is a tonsillectomy necessary?

PURPOSE: The detection of an infraclinical primary by tonsillectomy in case of cervical lymph node of an epidermoid carcinoma with unknown primary after a radical neck dissection, allows avoiding irradiation of the normal larynx. The aim of this study is to quantify the rate of tonsil primary to justify this procedure. METHODS AND MATERIALS: From 1969 to 1992, 87 patients had a tonsillectomy as part of the workup for cervical nodal metastasis of an epidermoid carcinoma with unknown primary. The mean age was 57 years (range: 39-75 years) and the sex ratio was 8.6. Sixty-seven patients had a single cervical adenopathy (17 N1, 30 N2a, 5 N3, 15 Nx), and 20 patients multiple cervical adenopathies (17 N2b, 3 N2c). The treatments included always an irradiation to the node areas (50 Gy), and to the pharyngolarynx in case of normal tonsil (50 Gy), or to the tonsil if it was the primary (50 Gy with a brachytherapy boost of 20-25 Gy). In this last case, the larynx could be protected. RESULTS: Tonsillectomy never induced specific complication. Out of 87 patients, 26% had a tonsil primary. There was not specific histological differentiation in this group. In the 67 patients with a single cervical adenopathy, 31% had a tonsil primary (6 N1, 7 N2, 1 N3, 7 Nx). It was a subdigastric adenopathy in 38%, a submandibular in 28% and a midjugulocarotidian in 23%. Among the 17 patients N2b, none had a tonsil primary. In the three patients N2c, two presented a tonsil carcinoma (two subdigastric nodes). CONCLUSION: Tonsillectomy allows avoiding irradiation of normal larynx in 26% of patients who have a cervical lymph node with unknown primary. It should be performed in case of a single node of the subdigastric, midjugulocarotidian or submandibular area or bilateral subdigastric adenopathies.

Conservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications.

UNLABELLED: We analyzed in a retrospective series of patients treated by conservative irradiation for an epidermoid cancer of the anal canal (ECAC) the prognostic factors of locoregional control (LRC), survival, late severe complications (LSC), and sphincter conservation (SC). METHODS AND MATERIALS: From 1976 until 1994, 118 patients presenting with an ECAC were conservatively treated (mean age, 65 years). According to the 1987 International Union Against Cancer (TNM) classification, they were: 19 T1, 70 T2, 22 T3, 7 T4, 94 N0, and 24 N1-3. The treatment started with external beam irradiation (EBI) (36 Gy in 3 weeks or 45 Gy in 5 weeks). Concomitant chemotherapy (5-fluorouracil and mitomycin C) was delivered to 31 patients. Two months later, a boost of 20 Gy was delivered by interstitial 192Ir brachytherapy to 101 patients and EBI in 5. Twelve other patients had an abdominoperineal resection (APR). The mean follow-up was 6 years. RESULTS: At 5 years the overall survival was 60%, and specific survival (SS) was 75%; it was 94% for T1, 79% for T2, 53% for T3, and 19% for T4. In multivariate analysis, tumor size (> or = 4 cm), node involvement, and no response to the EBI were factors of poor prognosis for SS. Thirty-two locoregional recurrences occurred of which 21 were local recurrences in the 106 patients treated by a conservative schedule. Only tumor size and response to the EBI were prognostic factors on multivariate analysis for local and LRC. A total of 17 patients presented with LSC (Grade 3, 16 patients; and Grade 4, 1 patient), which was treated by APR in 4 patients and colostomy in 11 (of which 7 were definitive). The only significant prognostic factor for LSC in the multivariate analysis was the total extrapolated response dose of irradiation. The definitive rate of SC after conservative treatment in cured patients was 100% for T1, 82% for T2, 58% for T3, and 100% for T4. Since 1989, improvements of the technique have allowed reduction of the LSC in maintaining the same local control. CONCLUSION: The results of this series are similar to those of the literature. The confirmation of pretherapeutic prognostic factors related to response to the treatment should allow us to adapt the therapeutic intensity for each case to obtain better tumor control, with as few sequelae as possible, to yield a better rate of SC.