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S Hoffstetter

Publications and source records attributed to S Hoffstetter.

At least 19 recordsLinked to original sources

[Preoperative brachytherapy for clinical stage I and II endometrial carcinoma: results from a series of 780 patients with a 10-year follow-up].

AIMS OF THE STUDY: Retrospective analysis of patients treated by preoperative brachytherapy for endometrial carcinoma. PATIENTS AND METHODS: From 1973 to 1994, 780 consecutive patients with a clinical stage I-II endometrial carcinoma were treated with brachytherapy followed by surgery and pelvic irradiation if necessary. Tumour was staged according to 1979 UICC classification. There were 462 T1a, 257 T1b, and 61 T2, 62% were well differentiated. Brachytherapy consisted in one low dose rate endocavitary application. Sixty grays were delivered on the reference isodose. Surgery consisted in a TAH/BSO (Piver II) and was performed 6 weeks later. Nodal pelvic irradiation was indicated in case of unfavourable pathological prognostic factors. RESULTS: Median follow up was 122 months. Five year survival rates were: 84% for overall survival, 86% for survival without recurrence, 92.8% for local control, and 3.8% for late complications. Pronostic factors were age, stage, differentiation, grade and postoperative extension. Multivariate analysis showed only age, differentiation and postoperative extension to be independent prognostic factors. CONCLUSION: If for stage 1, initial surgery has now replaced preoperative brachytherapy in most cases because it allows to identify initial prognostic factors, preoperative brachytherapy remains the most interesting option for stage 2 endometrial carcinomas.

Adult↗

[Total body irradiation in France in the past twenty years].

A review of the activity and techniques of total body irradiation (TBI) in France in the last 20 years is presented. In order to have on overall view of the activity and techniques of total body irradiation in France, the group of cancer centre radiation oncologists sent a questionnaire to all the cancer centres or public hospitals radiotherapy departments dealing with this treatment. Thirty-six questionnaires were sent and thirty-one departments answered. Three departments do not offer this treatment. Five departments did not answer. Results, therefore, concern the activity of the 28 departments that agreed to give detailed and clear answers. A total of 10 630 TBIs have been documented, 850 to 900 TBI have been done each year since 1995. Single fraction TBIs are used in only five centres and are being progressively abandoned. For multiple-fraction TBIs, the techniques described here are the ones used in 1999, at the time the questionnaires were sent. A majority (98%) of the teams used linear accelerators. The collected data are synthesised in tables. Nowadays, single fraction TBIs are only indicated in exceptional cases. Most of the TBIs are fractionated in six twice-daily fractions with pulmonary shielding to limit the dose between 6 and 11 Gy depending on departments' protocols and pathologies.

Bone Marrow Transplantation↗

[Brachytherapy of endometrial cancers].

Endometrial adenocarcinomas rank third as tumoral sites en France. The tumors are confined to the uterus in 80% of the cases. Brachytherapy has a large place in the therapeutic strategy. The gold standard treatment remains extrafascial hysterectomy with bilateral annexiectomy and bilateral internal iliac lymph node dissection. However, after surgery alone, the rate of locoregional relapses reaches 4-20%, which is reduced to 0-5% after postoperative brachytherapy of the vaginal cuff. This postoperative brachytherapy is delivered as outpatients treatment, by 3 or 4 fractions, at high dose rate. The uterovaginal preoperative brachytherapy remains well adapted to the tumors which involve the uterine cervix. Patients presenting a localized tumor but not operable for general reasons (< 10%) can be treated with success by exclusive irradiation, which associates a pelvic irradiation followed by an uterovaginal brachytherapy. A high local control of about 80-90% is obtained, a little lower than surgery, with a higher risk of late complications. Last but not least, local relapses in the vaginal cuff, or in the perimeatic area, can be treated by interstitial salvage brachytherapy, associated if possible with external beam irradiation. The local control is reached in half of the patients, but metastatic dissemination is frequent. We conclude that brachytherapy has a major role in the treatment of endometrial adenocarcinomas, in combination with surgery, or with external beam irradiation for not operable patients or in case of local relapses. It should use new technologies now available including computerized afterloaders and 3D dose calculation.

Adenocarcinoma↗

Cervical lymph node relapses of head-and-neck squamous cell carcinoma: is brachytherapy a therapeutic option?

PURPOSE: To report the results of interstitial brachytherapy (IBT) without salvage surgery for isolated cervical lymph node relapses. PATIENT AND METHODS: From 1970 to 1989, 84 patients were treated; 76 patients had relapsed in sites of previous external beam radiation. In 72 patients, IBT was sole salvage treatment (mean, 56.5 Gy). In 12 patients IBT (mean, 38 Gy) was combined with further external beam radiotherapy (mean, 41 Gy). RESULTS: Local control in the neck was 49% at 1 year, 31% at 2 years, and 0% at 5 years. Overall survival was 33% at 1 year, 13% at 2 years, and 1% at 5 years. Significant toxicity occurred in 35% (7% fatal). Multivariate analysis shows survival after salvage was better for patients who had achieved initial control for > or =18 months before relapse (0% vs. 13% at 3 years, p < 0.0002). Lymph node control was better for patients who received total salvage dose > or =60 Gy (0% vs. 56% at 3 years, p = 0.0004). CONCLUSION: Given its poor efficiency and its toxicity, IBT must be considered only when surgery is contraindicated and if lymph node relapse occurs after a minimal interval of 18 months.

Adult↗

Efficacy of external fractionated radiation therapy in the treatment of meningiomas: a 20-year experience.

BACKGROUND: This is a retrospective analysis of a series of meningiomas treated by radiotherapy. MATERIALS AND METHODS: From 1978 to 1997, 45 patients with intracranial meningiomas were referred for external fractionated radiotherapy at Centre Alexis Vautrin. All patients were given 50-70Gy to the tumor bed (median: 56Gy), 1.8-2Gy per fraction. RESULTS: Evaluation was performed in June 1999 using the Kaplan-Meyer actuarial method with a median follow-up of 30 months (range: 1-166), relapse-free survivals (RFSs) were 75% at 5 years and 67% at 8 years; overall survival (OS) was 74% at 5 and 8 years. For the 26 benign histologically documented lesions, RFSs were 95% at 5 years and 81% at 8 years; OS was 85% at 5 and 8 years. One major radiation-induced complication occurred in this series (decline of cognitive function). According to the indication of radiotherapy, we divided the series into four groups: postoperative irradiation after a first subtotal resection (11 patients), 5-year RFS was 90%; after first recurrence (+/-salvage surgery, 14 patients), 73%; after further recurrence (+/-salvage surgery, 11 patients), 67%; as exclusive treatment (nine patients), 80%. Atypical and malignant lesions (n=7) all relapsed before 24 months of follow-up, all patients but one died before 42 months. Age at the time of irradiation (> or =60 vs. <60 years) and radiotherapy dose (> or =60 vs. <60Gy) did not influence local control or OS. Atypical and malignant lesions (WHO grades II and III) meningiomas had a worse outcome than benign lesions (WHO grade I, P<0.01). CONCLUSIONS: These results compare favorably with previously published data. External fractionated radiotherapy is well tolerated and effective. There is still a debate about the place of radiotherapy in the treatment of meningiomas: after subtotal resection, should radiotherapy be given postoperatively or at the time of progression? Should radiotherapy replace surgery when the risk of postoperative sequellae is high? Prospective randomized trials would be required to address these issues.

Adult↗

[Standards, Options and Recommendations for the surgical management of carcinoma of the endometrium].

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the surgical management of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the surgical management of carcinoma of the endometrium are: 1) where-ever possible, surgery is the primary treatment of both localised and advanced disease; 2) surgery is performed according to the stage of the cancer and the status of the patient; 3) surgery for stages I and II disease entails total abdominal hysterectomy and bilateral salpingo-oophorectomy. A modified radical hysterectomy is undertaken in cases of macroscopic cervical involvement. An omenectomy is recommended for serous papillary types. Pelvic lymphadenectomy for the purposes of precise staging is undertaken if the patient is of good performance status and without bad pronostic factors. Para-aortic lymphadenectomy can be undertaken to determine involvement of para-aortic nodes; 4) surgery for stages III and IV: radical surgery must be undertaken if at all possible with additional treatment as indicated. In the case of advanced disease, debulking surgery is indicated.

Algorithms↗

[Standards, options, and recommendations for the radiotherapy of patients with endometrial cancer. FNCLCC (National Federation of Cancer Campaign Centers) and CRLCC (Regional Cancer Campaign Centers)].

OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the radiotherapy of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the radiotherapy of carcinoma of the endometrium are: 1) For grade 1 and 2 stage IA tumours, follow-up alone is standard as additional treatment. For grade 1 and 2 stage IB tumours, vaginal brachytherapy or follow-up alone are options. For grade 3, stage IB tumours and stage IC disease, there are two treatment options: external pelvic radiotherapy with a brachytherapy boost or vaginal brachytherapy. 2) Treatment for stage II disease can be preoperative when stage II disease has been suggested by a positive endometrial curettage. Postoperative vaginal brachytherapy is given for stage IIA tumours if the penetration of the myometrium is less than 50% or if the tumour is grade 1 or 2. In the case of deep penetration, or higher grade disease, or for stage IIB external radiotherapy with brachytherapy boosting must be undertaken routinely. 3) After surgery, for stage IIIA disease, either external pelvic radiotherapy or abdomino-pelvic radiotherapy is indicated, along with medical treatment in certain patients. For stage IIIB tumours, postoperative external radiotherapy with brachytherapy (if possible) should be undertaken. For stage IIIC tumours, standard treatment is external (pelvic or pelvic and para-aortic) radiotherapy followed or not by a brachytherapy boost. In case of extrauterine sites involved abdomino-pelvic irradiation is recommended. 4) Standard treatment for inoperable stage I and II disease is external radiotherapy and brachytherapy. For patients with inoperable stage III or IV disease, treatment is often symptomatic, combining external radiotherapy and medical treatment.

Brachytherapy↗

Postoperative brachytherapy alone for T1-2 N0 squamous cell carcinomas of the oral tongue and floor of mouth with close or positive margins.

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.

Adult↗

In vivo potentiation of radiation response by topotecan in human rhabdomyosarcoma xenografted into nude mice.

The lack of new highly efficacious drugs for cancer treatment promotes the search for innovative therapeutic modalities. The authors reported the results leading to the definition of parameters needed to demonstrate a possible radiopotentiation by topotecan (TPT) on two representative human rhabdomyosarcomas (RMSs) xenografted into nude mice. Experimental studies of radiopotentiation with different doses of topotecan showed that concomitant association of topotecan and RT for 5 consecutive days provided a synergistic therapeutic effect. Response rates were statistically higher with the radiochemotherapeutic combination (P < 0.001). Efficacy enhancement factors of this combination compared with the sum of the antitumoral activity of these treatments separately administrated were 1.54 and 1.60, respectively, on both rhabdomyosarcomas. Moreover, the efficiency of the combination of radiotherapy at the dose of 20 Gy with topotecan (12.5 mg/kg) was not statistically different from that of radiotherapy at the dose of 40 Gy. According to microscopy results, the analyses performed at different periods after topotecan treatment alone, radiotherapy alone, and their combination seemed to show that tumoral repopulation by malignant cells is as fast as the dose of radiotherapy and/or topotecan is low. Furthermore, lesions observed with the dose of 40 Gy were similar to those obtained with the association of topotecan at the dose of 12.5 mg/kg and radiotherapy at the dose of 20 Gy. In conclusion, all clinical and pathological results are consistent with a radiopotentiation effect of topotecan on the two xenografted human rhabdomyosarcomas and are currently leading to the design of clinical studies.

Adolescent↗

Impact of targeting deviations on outcome in medulloblastoma: study of the French Society of Pediatric Oncology (SFOP).

PURPOSE: To correlate targeting deviation in external beam radiation therapy with site of relapse in a prospective study of 174 patients treated for medulloblastoma. METHODS AND MATERIALS: Between February 1992 and February 1998 the radiotherapy treatment records were reviewed by a panel of radiation oncologists for 174 children treated with radiation therapy for medulloblastoma. The review was done without knowledge of patient outcome. Patterns of relapse were correlated with the results of the quality control review. RESULTS: Among the 174 patients five relapsed before the start of radiotherapy. One hundred sixty-nine patients were evaluable for correlation between targeting deviation and site of relapse. Number of major deviations in radiation therapy treatment is strongly correlated with the risk of tumor relapse (67% [95% CI: 28-91] of 3-year relapse rate in patient group with 2 major deviations and 78% [95% CI: 35-96] with 3 major deviations). This is particularly correlated with relapse in the frontal region of the brain: 5 relapses occurred in the frontal region in patients with major deviation in this area. An erroneous choice of electron beam energy is also linked with craniospinal fluid (CSF) relapse (3-year relapse rate of 68% [95% CI: 42-86]). Minor deviations in therapy technique are slightly associated with an increased risk of relapse in the same range as the group with only one major deviation. CONCLUSION: The quality of medulloblastoma radiation therapy technique is strongly correlated with outcome. Pretreatment central quality assurance review or standardized computer-designed blocks would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy.

Adolescent↗

Nonmetastatic pelvic Ewing sarcoma: report of the French society of pediatric oncology.

BACKGROUND: Since January, 1984, 59 children with histologically confirmed Ewing sarcoma of the pelvic bone have been treated with three successive chemotherapy protocols recommended by the French Society of Pediatric Oncology. The purpose of the current study was to evaluate the role of surgery and/or radiotherapy in local progression-free, disease-free, and overall survivals (LPFS, DFS, and OS, respectively). PROCEDURE: We retrospectively examined 59 children treated for nonmetastatic, pelvic Ewing sarcoma over the last 12 years. All were first treated with chemotherapy according to the current French protocol. Six patients developed progressive disease before local treatment and were excluded for local control and survival analysis. Local treatment was surgery alone in 17 cases, radiation therapy in 27 cases, and surgery plus radiation therapy in 9 cases. RESULTS: With a median of follow-up of 6.5 years, no significant differences in local control or survival were observed with the three chemotherapeutic protocols. Of the 53 patients evaluable for local control, 6 relapsed locally only, 8 had local and distant relapses, and 9 had distant metastases only. The 5-year OS rate was worst for patients with radiotherapy alone compared to those with surgery or combined modality treatment (44 % vs. 72 %, P = 0.043). The 5-year LPFS and DFS rates were worst in the radiotherapy-alone group but not significantly (63% vs. 79%, P = 0. 22 and 42% vs 71%, P =0.07, respectively). The importance of surgery to OS and DFS was confirmed by multivariate analysis (P = 0.026 and P = 0.048, respectively). One surviving patient was diagnosed with in-field fibrosarcoma, which was presumably radiation induced. CONCLUSIONS: Despite intensive, multiagent chemotherapy, survival from pelvic Ewing sarcoma has not improved over the past decade; however, the survival rate does not seem to be worse than that from Ewing sarcoma at other locations, insofar as at least 50% of the patients were cured. Surgery or a combination of surgery and radiation therapy are the best local treatment; exclusive radiation therapy should be reserved for patients with inoperable lesions or partially or nonchemosensitive tumors or when surgery would be an amputation.

Adolescent↗

[Interstitial brachytherapy in infiltrating cancer of the bladder. The Nancy experience].

PURPOSE: From 1975 to 1996, 98 patients with infiltrative vesical carcinomas were treated at the Centre Alexis Vautrin by conservative surgery and interstitial brachytherapy (192lr). The mean follow-up was about eight years. From this retrospective non randomized study, we tried to determine the tolerance to this treatment. MATERIALS AND METHODS: There were 86 men and 12 women. The mean age was 63 years. We found three pTis tumors, 28 stage pT1 tumors, 38 stage pT2 tumors, 24 stage pT3A tumors, four stage pT3B tumors and one stage Tx tumors. The therapeutic scheme consisted of pelvic radiation therapy (3 fractions of 3,5 Gy) immediately followed by lymphadenectomy (for stage pT3 tumors) and by cystotomy or partial cystectomy during which we inserted brachytherapy plastic tubes. The delivered dose was 50 Gy for superficially infiltrative tumors and 30 Gy for deeply infiltrative tumors; at the lowest dose, the treatment ended with external beam irradiation. RESULTS: At 5 years the control rate was 72%, the specific survival 80% and the global survival 71%. Twenty-nine patients had a local recurrence. Of these, seven underwent total cystectomy. Thirty-seven patients developed 43 complications; 35 were intravesical, 10 (28%) were estimated to be higher than grade 2 because of technical problems that led us to modify the technique. CONCLUSION: It is essential to develop close collaboration between surgeons and brachytherapists, to select patients and to use a rigorous technique. Interstitial brachytherapy for infiltrative vesical carcinomas thus yields both high local control and satisfying results in regard to patient's well-being.

Brachytherapy↗

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.

Adult↗

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.

Adult↗

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.

Analysis of Variance↗