Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

BACKGROUND: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Treatment of the elderly colorectal cancer patient: SIOG expert recommendations.

Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients >70 years of age. Elderly CRC patients, however, are understaged, undertreated and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing the potential for developing guidelines for the treatment of elderly (geriatric) CRC patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. It is hoped that these will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.

The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial.

PURPOSE: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer. PATIENTS AND METHODS: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented. RESULTS: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively. CONCLUSION: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

The quality assurance programme of the Radiotherapy Group of the European Organisation for Research and Treatment of Cancer: past, present and future.

As early as in 1982, the European Organisation for Research and Treatment of Cancer Radiotherapy Group established a quality assurance programme. In the course of 20 years, quality assurance procedures have become a vast and important part of the activities of the group. Today, the membership committee uses standard procedures based on minimal requirements to evaluate current members and new membership applications. Moreover, for every new trial, specific quality assurance procedures are an integral part of the preparation of the protocol and executed under the responsibility of the study coordinator. With the growing complexity of the radiotherapy techniques used in the framework of the more recent trials, quality assurance procedures have also become more complex including trial specific phantom based measurements. Future ways to evaluate all steps of the radiotherapy process using a common platform connecting all users with the internet are currently under development.

Conservative treatment of early glottic carcinomas with exclusive radiotherapy.

BACKGROUND: Early glottic carcinomas can be treated with radiotherapy or surgery with similar local control rates but with better functional results with radiotherapy. The aim of this study was to analyze the results of our experience of exclusive radiotherapy. PATIENTS AND METHODS: From 1975 to 2001, 155 patients with Tis, T1 and T2 glottic carcinomas were treated with exclusive radiotherapy. Prognostic factors of survival, local control and larynx-preservation rates were analyzed in uni and multivariate analyses. RESULTS: Median prescribed dose was 65 Gy in 44 days. Overall survival was 75% for the whole group, 75% for Tis, 85% for T1a, 72% for T1b, 59% for T2. Specific survival was 88% for the whole group, 75% for Tis, 94% for T1a, 90% for T1b, 69% for T2. Disease-free survival was 68% for the whole group, 75% for Tis, 77% for T1a, 51% for T1b, 58% for T2. Laryngeal preservation rate was 85% (133/155). Twenty-nine (29/155, 18%) patients developed a local relapse within 31 months. Out of the 10/86 (12%) T1a-Tis relapses, 7/10 patients underwent total laryngectomy and 79/86 larynx were preserved (92%). Out of the 8/22 (36%) T1b relapses, 4/8 patients underwent total laryngectomy. Out of the 11/47 (23%) T2 relapses, 8/11 patients underwent total laryngectomy. Increased overall treatment time, tumor stage, sub-glottis extension were associated with poorer local control. Second malignancies remain a major problem in the outcome of this population. CONCLUSION: Radiotherapy remains an efficient option in the treatment of early glottic carcinomas providing a high local control rate with excellent functional results in laryngectomy-free patients. This strategy should be discussed according to the tumor stage, feasibility of conservative surgery and patient's preferences.

Treatment implications for radiation-induced nausea and vomiting in specific patient groups.

Radiation-induced nausea and vomiting (RINV) affect the management and quality of life of cancer patients. Current guidelines for RINV prevention recommend prophylaxis with a 5-hydroxytryptamine (5-HT(3))-receptor antagonist for patients receiving moderately or highly emetogenic radiotherapy regimens. Randomised trials have compared such antagonists with conventional antiemetics, and have demonstrated their efficacy and safety. Special consideration is needed for antiemetic treatment in certain patient groups, particularly the elderly and those with renal or hepatic impairment. Radiation oncologists should be aware of the effect on antiemetic treatment of factors such as comorbid conditions (particularly cardiovascular disease), polypharmacy and drug-drug interactions, and choose the agent with the lowest potential for additional complications. The most appropriate antiemetic treatment to improve patient compliance and quality of life should ideally combine proven efficacy with uncomplicated administration and convenient dosing regimens.

The Quality Assurance programme of the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC): a critical appraisal of 20 years of continuous efforts.

In 1982, the European Organization for Research and Treatment of Cancer (EORTC) Radiotherapy Group established the Quality Assurance (QA) programme. During the past 20 years, QA procedures have become a major part of the activities of the group. The methodology and steps of the QA programme over the past 20 years are briefly described. Problems and conclusions arising from the results of the long-lasting QA programme in the EORTC radiotherapy group are discussed and emphasised. The EORTC radiotherapy group continues to lead QA in the European radiotherapy community. Future challenges and perspectives are proposed.

Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients?

The aim of this study was to identify patient-, tumour- or treatment-related factors associated with young age that might explain the higher risk of ipsilateral breast recurrence that occurs after breast-conserving therapy (BCT) in young breast cancer patients. In the 'boost versus no boost trial', 5569 early-stage breast cancer patients were entered. All patients underwent tumorectomy followed by whole breast irradiation of 50 Gy. Patients having a microscopically complete excision were randomised between receiving no boost or a 16-Gy boost, while patients with a microscopically incomplete excision were randomised between receiving a boost dose of 10 or 26 Gy. The 5-year local control rate was 82% for patients 60 years of age (P<0.0001). In young patients, the tumour was significantly larger and more often oestrogen and progesterone receptor-negative. Invasive carcinoma and the intraductal component were more often of a high grade. The intraductal component was more frequently incompletely resected in young patients. Re-excisions were performed more often (most probably due to a more frequent incomplete excision at the first attempt). The total volume of breast tissue removed at the tumorectomy was smaller in the younger patient group, even after including the volume removed during re-excision. When relating all these parameters (including age itself) to local control, the multivariate analysis stratified by treatment showed that age was the only independent prognostic factor for local control (P=0.0001). Including the boost treatment as a separate covariate, the analysis retained age and boost treatment as significant factors related to local control (P<0.0001). It was shown that the boost dose significantly reduced the 5-year local recurrence rate from 7 to 4% for patients with a complete excision (P<0.001). For patients 40 years of age or younger, the boost dose reduced the local recurrence rate from 20 to 10% (P=0.002). This large European Orgnaization for Research and Treatment of Cancer (EORTC) trial demonstrated an increased local recurrence rate in young patients. Although several associations between patient, tumour and treatment factors and age were found, that might explain the high local recurrence rate in the younger patients, it appears that age itself and the boost dose were the only factors that were independently related to local control.

Concomitant cisplatin and radiotherapy in a conventional and modified fractionation schedule in locally advanced head and neck cancer: a randomised phase II EORTC trial.

A randomised phase II trial was initiated to explore the feasibility of concomitant cisplatin and radiotherapy with conventional fractionation (CF) or multiple fractions per day (MFD) for patients with locally advanced head and neck malignancies. The MFD schedule was designed to achieve higher tumour concentrations of cisplatin at the time of irradiation by reducing the number of radiation treatment weeks from 7 to 3, allowing recovery from side-effects of both irradiation and cystostatic drugs during the rest periods, while keeping the same total dose and overall treatment time. Patients were randomised between a conventional fractionation scheme (CF) of 70 Gy in 7 weeks with 2 Gy per fraction with a daily dose of 6 mg/m(2) cisplatin and a modified fractionation scheme (MFD) delivering three fractions of 1.6 Gy per day, in weeks 1, 4 and 7, keeping the same overall treatment time and total dose. In the modified treatment regime, a daily dose of 10 mg/m(2) cisplatin was administered. 53 patients were entered in this trial and radiotherapy was given according to the schedule to all patients in both treatment arms. Cisplatin was given during the whole course of radiotherapy to only one quarter of the patients in the CF arm, stopping mostly after 5-6 weeks due to bone marrow depression and kidney toxicity, while patients in the MFD arm received it according to schedule. No difference was observed in acute and late toxicity in both treatment arms, while a similar or even better tumour response was obtained with MFD. A 67% higher daily dose of cisplatin concomitant with irradiation could be given in a 3-week multiple fractionation per day schedule, as opposed to the cisplatin given in the conventional daily fractionation schedule of 7 weeks with the same total radiation dose. Similar acute and late toxicities were seen in both treatment arms.

EORTC Radiotherapy Group: achievements and future projects. European Organisation for Research and Treatment of Cancer.

The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy (RT) Group will celebrate 27 years of activity in 2002. During its long history, the Radiotherapy Group has conducted a large number of studies which have provided valuable information on the radiation treatment of several disease sites. Group efforts have been concentrated on dose-effect studies, optimal fractionation schemes, combinations with other treatment modalities, and new radiotherapy techniques. The EORTC RT Group was the first in Europe to develop and introduce methodologies of Quality Assurance in radiotherapy. The RT Group actively collaborates with other EORTC Groups and international organisations. Currently, several phase III studies are being conducted in collaboration with European, North American and Australian organisations. The collaboration with RTOG led to the setting up of common systems for scoring late normal tissue effects. In the years to come, the Group will keep pioneering pivotal trials in radiotherapy and radio-chemotherapy. It will also explore combinations with novel therapies in phase I trials and implement innovative translational research programmes.

Quality assurance in radiotherapy: from radiation physics to patient- and trial-oriented control procedures.

The stepwise process of the EORTC Quality Assurance Programme in Radiotherapy is described in function of two main criteria: the targets of the quality control procedures implemented, in Radiation Physics and clinical research, by the EORTC Radiotherapy Group and the development of both trial- and patient-oriented quality systems. This exhaustive program, which started in 1982, is characterised by three main periods. The first one was fully dedicated to pioneer steps in Radiation Physics measurements, on-site audits and inventories of human resources, staff workload and department infrastructure in institutions participating to EORTC trials. During the second period, which started in the late 1980s, a series of quality systems were implemented to test the compliance of the investigators to follow protocol guidelines, through the use of standard and uniform control procedures like the dummy runs, in order to tackle systematic errors in the participating institutions. Finally, the third period, which took place in the 1990s, was essentially patient-oriented, thanks to large scale individual case reviews, to check the validity of data recording and reporting processes and trace random errors throughout the radiotherapy treatments. Most of the results collected during these two decades allowed the implementation of well codified quality control procedures which, nowadays, can be used outside the field of clinical research, by national societies or bodies willing to improve treatment standards on a large scale.

Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group.

OBJECTIVE: The purpose of this randomized multicenter study was to assess the impact on disease free and overall survival of low dose irradiation to para-aortic nodes and liver in patients with a locally advanced resected rectal cancer receiving a 50 Gy postoperative pelvic radiotherapy. PATIENTS AND METHODS: Main inclusion criteria were: a curative resection for a histologically proved carcinoma of the rectum, Gunderson-Sosin stages B2-B3, C1-C3, age <70 years. The patients were randomized between pelvic irradiation (Lim-XRT): 50 Gy in 25 fractions over 5 weeks and extended irradiation (Ext-XRT): same scheme/doses in the pelvis and extended fields on para-aortic nodes and liver, delivering 25 Gy in 19 fractions over 25 days. From 1983 to 1992, 484 patients were enrolled by 18 EORTC institutions and 29 patients were ineligible. The end-points were local and distant relapses, toxicity and survival. RESULTS: Compliance to treatment: 87.2% in Lim-XRT arm and 71.8% in Ext-XRT arm. Moderate acute hematological and hepatic toxicities were significantly increased in Ext-XRT arm. Among 325 patients at risk, 44 suffered a severe intestinal complication requiring surgery in 29. The 5- and 10-year estimates of disease free survival were respectively 42 and 31% in Lim-XRT arm and 47 and 31% in Ext-XRT arm (ns). The corresponding figures for overall survival were respectively 45 and 40% in Lim-XRT arm and 48 and 37% in Ext-arm (ns). The 10 years estimate of intra-pelvic failures was approximately 30% in both arms. Patients in Ext-arm appeared to have a slight shorter interval free of liver metastases (P=0.047). CONCLUSION: Low dose irradiation to the para-aortic nodes and liver did not improve survival for patients with resected adenocarcinoma of the rectum.

[Multicenter study on dose escalation with conformal and conventional radiotherapy for the treatment of localized prostatic cancer. Preliminary results of tolerance and quality of life]. / Etude multicentrique d'escalade de dose par radiothérapie conformationnelle pour le traitement du cancer localisé de la prostate. Résultats préliminaires de la tolérance et de la qualité de vie.

OBJECTIVE: To study the safety of conformal radiotherapy dose escalation up to 80 Gy for curative treatment of prostate cancer. MATERIAL AND METHODS: A multicentre trial sponsored by the PHRC include 164 patients under the age of 75 years with stage T1b-T3 N0 M0 prostatic adenocarcinoma, between 1995 and 1998. The prostate was treated at 5 dose levels: 18 patients at 66 Gy, 28 at 70 Gy, 49 at 74 Gy, 48 at 78 Gy, 21 at 80 Gy. The acute and delayed toxicity was graded according to a multidisciplinary glossary. Quality of life was evaluated before and one year after treatment using the EORTC QLQ-C30 questionnaire and additional questions. RESULTS: 89% and 55% of mild or moderate gastrointestinal and urinary adverse effects were observed during treatment, respectively. At long-term follow-up, of the 162 evaluable patients, 12.3% presented grade 2 adverse effects and 2.5% presented grade 3 adverse effects (1 case of haematuria, 2 urethral strictures, 1 bladder neck lesion) with no significant difference between the various dose levels. Two successive quality of life questionnaires were available for 119 patients: tiredness, pain and dyspnoea increased in parallel, but non-significantly in the groups receiving conventional doses or high doses. The proportion of patients reporting sexual activity without endocrine therapy decreased from 48% before treatment to 35% one year later. The proportion of patients with no clinical or laboratory signs of progression was higher in the high-dose group. CONCLUSION: No significant difference was observed between conventional dose levels and high dose levels in terms of toxicity or quality of life. As the adverse effects were acceptable, a randomized trial comparing 70 Gy and 80 Gy has been initiated.

[Secondary effects of brachytherapy in the treatment of coronary restenosis]. / Effets secondaires de la curiethérapie dans le traitement de la resténose coronaire.

Brachytherapy is proposed for the treatment or prevention of coronary restenosis with encouraging results, especially in intra-stent restenosis. The results of the first clinical studies show benefit, for example those of the American SCRIPPS trial with a 3 year follow-up. However, recent reports in the literature have described secondary effects associated with this technique: 1) stenoses occurring at the limits of the irradiated segments which are attributed to a proliferative effect of low doses on damaged tissue; 2) late occlusions at the irradiated site: their incidence is estimated at 9% at 6 months. The mechanisms of these thromboses are not understood but delayed re-endothelialisation probably plays a rôle; 3) finally, irradiation is associated with uncovered dissection probably related to delayed healing. Other long-term trials are necessary to provide a more complete assessment of the secondary effects of brachytherapy, especially with regards to their mechanisms, prevention and treatment.

[Prevention of pelvic recurrence by preoperative radiochemotherapy and total mesorectal excision of rectal carcinoma?]. / Verhinderung pelviner Rezidive durch präoperative Radiochemotherapie und totale mesorektale Exzision des Rektumkarzinoms?

Preoperative radiotherapy (RT) alone or in combination with a pre- or postoperative chemotherapy reduces the recurrence rate and increases the survival rate for patients with resectable rectal cancer. The therapeutic index, i.e. relationship between effects and side effects is objective of studies. Especially toxicities to the small intestine and to the sphincter function are evaluated. Preoperative radiotherapy achieves the best results. The treatment volume includes the mesorectum in case of continence maintaining surgery and includes the anal sphincter in case of abdominoperineal resection. To exclude the small intestine from the RT-field, we prefer the use of 3 or 4 field technique in a prone position with filled bladder, using an optimal field limitation. The Swedish study, which uses 25 Gy in five fractions per week leads to an increased rate of acute and late toxicities. A fractionation schedule using 45-50 Gy in five weeks should be preferred. During the radiotherapy the patient is followed-up once per week. If surgery is foreseen, it should take place as soon as 3 weeks after the end of radiotherapy. If a primary surgery is performed preoperatively, the operative finding should be discussed with the surgeon. Quality control programs have to certify optimal treatment of the patient by radiotherapist and surgeon.

Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation.

BACKGROUND: Radiotherapy prevents local recurrence of breast cancer after breast-conserving surgery. We evaluated the effect of a supplementary dose of radiation to the tumor bed on the rates of local recurrence among patients who received radiotherapy after breast-conserving surgery for early breast cancer. METHODS: After lumpectomy and axillary dissection, patients with stage I or II breast cancer received 50 Gy of radiation to the whole breast in 2-Gy fractions over a five-week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (2657 patients) or an additional localized dose of 16 Gy, usually given in eight fractions by means of an external electron beam (2661 patients). RESULTS: During a median follow-up period of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard-treatment group and 109 of the 2661 patients in the additional-radiation group. The five-year actuarial rates of local recurrence were 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), yielding a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose. Patients 40 years old or younger benefited most; at five years, their rate of local recurrence was 19.5 percent with standard treatment and 10.2 percent with additional radiation (hazard ratio, 0.46 [99 percent confidence interval, 0.23 to 0.89]; P=0.002). At five years in the age group 41 to 50 years old, no differences were found in rates of metastasis or overall survival (which were 87 and 91 percent, respectively). CONCLUSIONS: In patients with early breast cancer who undergo breast-conserving surgery and receive 50 Gy of radiation to the whole breast, an additional dose of 16 Gy of radiation to the tumor bed reduces the risk of local recurrence, especially in patients younger than 50 years of age.

Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study.

BACKGROUND AND PURPOSE: The aim of the study was: (1) to confirm the action of pilocarpine hydrochloride (Salagen) against xerostomia: (2) to correlate the response to dose/volume radiotherapy parameters. MATERIALS AND METHODS: From June 1995 to February 1996, 156 patients with severe radiation induced xerostomia received pilocarpine hydrochloride orally. IS mg per day with a 5 mg optional increase at S weeks up to a daily dose of 25 mg beyond 9 weeks. RESULTS: One hundred and forty five patients are fully evaluable. Treatment compliance was 75%. Thirty eight patients (26%) stopped treatment before week 12 for acute intolerance (sweating, nausea, vomiting) or no response. No severe complication occurred. Ninety ses en patients (67%) reported a significant relief of symptoms of xerostomia at 12 weeks. Within 12 weeks, the size of the subgroup ith normal food intake almost doubled (13-24 patients) while the size of the subgroup with (nearly) impossible solid food ingestion decreased by 38% (47 vs. 29 patients). The impact on quality of life was considered important or very important by 77% of the responders. CONCLUSIONS: No difference was found according to dose/volume radiotherapy parameters suggesting that oral pilocarpine hydrochloride: (1) acts primarily by stimulating minor salivary glands: (2) can be of benefit to patients suffering of severe xerostomia regardless of radiotherapy dose/volume parameters: (3) all responders are identified at 12 weeks.

Impact on treatment outcome and late effects of customized treatment planning in cervix carcinomas: baseline results to compare new strategies.

PURPOSE: The aim of the study was to determine the predictive factors of complications, to evaluate the impact of customized treatment planning on late normal tissue effects per stage, and to report disease-free survival (DFS) and local control (LC) rates. METHODS AND MATERIALS: From 1970 to 1994, 642 patients were treated with radiotherapy alone for carcinoma of the intact uterine cervix. According to the International Federation of Gynecology and Obstetrics (FIGO) substaging, 34% were Stage I, 39% Stage II, and 27% Stage III. The analysis was divided into three periods: 1970-1978 (use of standard prescriptions),1979-1984 (implementation of individual adjustments), 1985-1994 (systematic individual adjustments). Five-year DFS, LC, and complications rates were calculated using the Kaplan-Meier method. Predictive factors of complications were determined by univariate analysis using frequency tables and nonparametric t-tests. Multivariate analysis consisted of a polychotomous stepwise regression. RESULTS: The comparison of the three time periods showed a significant reduction of the external radiation dose (dose above 40 Gy in 47% of patients before 1979 vs. 36% after 1984), of the use of parametrial boost (55% vs. 39%), of the use of vaginal cylinder (28% vs. 11.5%), and of the HWT volume (combined intracavitary and external irradiation) (842 cc vs. 503 cc on average). The total sequelae/complications rate, all toxicity grades, all stages, all organs was 51%. Five-year actuarial rate per toxicity grade was: G1, 42%; G2, 23.5%; G3, 10%; G4, 3%. The three main predictive factors for rectal and bladder sequelae/complications (all toxicity grades) taking into account time period were: the increase of external radiation dose, the high dose rate at reference points, and the whole vagina brachytherapy. No G4 occurred in the third period. The rate of G3 complications dropped from 16% to 6% over time: from 5% during the first period to 0% during the third period in Stage I, from 8% to 6% in Stage II, and from 23% to 12% in Stage III. G3 currently describes a variety of clinical situations with a different impact on quality of life which justifies further refinements of definitions of late effects. In our experience the severity of G3 markedly decreased: less than one-third of G3 had a real impact on quality of life in the last period compared to more than two-thirds in the first period. Meanwhile, 5-year LC rates remained stable in Stages I and II, 91% and 85% respectively. Conversely they fell from 75% to 55% in Stage III, thus raising the problem of underdosage and/or more accurate staging with time. CONCLUSIONS: Customized treatment planning eradicated lethal complications and provided a significant decrease of G3 in all stages while maintaining high cure rates in early stages. Dose reduction should be considered with caution in Stage III.

[Complications of treatments of invasive cancers of the uterine cervix with intact uterus: results and prevention]. / Complications des traitements des cancers invasifs du col utérin sur utérus intact. Résultats et prévention.

The prospective record of acute and late toxicity after treatment of cervix carcinomas is a part of the description of treatment outcome as well as local control and survival. Due to the large number of scales and glossaries used, the comparison of the results from one study to another is often difficult. The French-Italian syllabus seems to be the most reliable scale, providing implementation of quality of life assessments. The main predictive factor of complications, which is not related to the treatment type, is the previous history of abdominal or pelvic surgery. The incidence and severity of complications occurring after surgery are related to the surgical procedure and to the amount of peri-uterine tissues removed. The increase in dose and volume of external irradiation and brachytherapy and the increase in dose rate of the low-dose rate brachytherapy are responsible for the radiotherapeutic morbidity. The significant decrease of severe complication rates during the last 15 years was obtained by the implementation of individual adjustments in treatment planning. The treatment strategies of early bulky and advanced carcinomas are changing. Concurrent radiotherapy and chemotherapy is becoming a standard, but its late toxicity needs to be documented by a longer follow-up. The optimisation of radiation therapy should remain a reference to evaluate the outcome and morbidity of the new combined strategies: the addition of chemotherapy will never compensate for less than optimal radiotherapy/brachytherapy planning.