W. Van den Bogaert

Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy

EORTC protocol 22791 compared once daily fractionation (CF) of 70 Gy in 35-40 fractions in 7-8 weeks, to pure hyperfractionation (HF) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day, in T2-T3 oropharyngeal carcinoma (excluding base of tongue), N0,N1 of less than 3 cm. From 1980 to 1987, 356 patients were entered. In the final analysis (June 1990), the local control was significantly higher (p = 0.02 log-rank) after HF compared with CF. At 5 years, 59% of patients are local disease-free in the HF arm compared to 40% in the CF arm. The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2. The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control (p = 0.007 log-rank). This improvement of locoregional control was responsible for a trend to an improved survival (p = 0.08 log-rank). There was no difference in late normal tissue damage between the two treatment modalities.

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer

BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Time-dose factors in radiotherapy: a review of the human data

The values for alpha/beta (fractionation sensitivity, or recovery capacity) for early and late reactions in human normal tissues are consistent with results from experimental animals. For breast treatments direct analysis indicates that for early reactions alpha/beta is in the range 7 to 11 Gy, while for late effects it is in the range 2 to 4 Gy. Data on recovery kinetics in human tissues is limited but these indicate that recovery may be slower in humans than in rodents. For early skin reactions the halftime of recovery is about 1 h, while for late telangiectasia it is more than 3 h. alpha/beta values for human tumors are more variable than in rodents: some are high (head and neck, lung, skin, cervix) and similar to those for early reacting normal tissues. Others are low, including melanomas, where alpha/beta was estimated at 0.6 (-1.1, 2.5) Gy, and liposarcomas, where direct analysis of cases surveyed from the literature suggested that alpha/beta = 0.4 (-1.4, 5.4) Gy. Repopulation kinetics is faster in the mucosa of the soft palate and faucial pillars (1.8 Gy/day) than in head and neck tumors (up to 1 Gy/day).

No age limit for radical radiotherapy in head and neck tumours

The elderly are often treated less aggressively in an attempt to preserve their quality of life with regards to toxicity. However, there are few data regarding the acute and late toxicity of radiotherapy (RT) in elderly patients. From February 1980 to March 1995, 1589 patients with head and neck cancers who enrolled in EORTC trials received RT and were available for analysis on RT toxicity. Patients over 65 years of age were in excess of 20%. Data regarding age and acute objective mucosal reactions were available for 1307 patients and 1288 had toxicity > or = grade 1. Age and acute functional mucosal reactions were registered for 838 patients and 824 patients had toxicity > or = grade 1. Bodyweight alteration during treatment was available in 1252 patients; it increased in 153 patients and decreased in 1099 patients. Late toxicities were examined only if they occurred before an eventual tumour failure in order to avoid confusion between effects of first- and second-line treatments. 749 patients were available for analysis of which 646 had late toxicity grade > or = 1. Survival and toxicity were examined in different age ranges from 50 to 75 years and over. There was no significant difference in survival between each age group. A trend test was performed to assess any correlation between age and the acute occurring toxicity. There was no significant difference in acute objective mucosal reactions (P = 0.1) and in weight loss > 10% (P = 0.441). In contrast, older patients had more severe (grade 3 and 4) functional acute toxicity (P < 0.001) than younger patients. We evaluated the probability of late toxicity occurrence in relation to time with the Kaplan-Meier method and the logrank test in each age group. Eighteen per cent of patients were free of late effects at 5 years, the logrank test showing no significant difference between ages (P = 0.84). In conclusion, chronological age is irrelevant for therapeutic decisions.

Human errors in data transfer during the preparation and delivery of radiation treatment affecting the final result: “garbage in, garbage out”

Due to the large number of steps and the number of persons involved in the preparation of a radiation treatment, the transfer of information from one step to the next is a very critical point. Errors due to inadequate transfer of information will be reflected in every next step and can seriously affect the final result of the treatment. We studied the frequency and the sources of the transfer errors. A total number of 464 new treatments has been checked over a period of 9 months (January to October 1990). Erroneous data transfer has been detected in 139/24,128 (less than 1%) of the transferred parameters; they affected 26% (119/464) of the checked treatments. Twenty-five of these deviations could have led to large geographical miss or important over- or underdosage (much more than 5%) of the organs in the irradiated volume, thus increasing the complications or decreasing the tumour control probability, if not corrected. Such major deviations, only occurring in 0.1% of the transferred parameters, affected 5% (25/464) of the new treatments. The sources of these large deviations were nearly always human mistakes, whereas a considerable number of the smaller deviations were, in fact, consciously taken decisions to deviate from the intended treatment. Nearly half of the major deviations were introduced during input of the data in the check-and-confirm system, demonstrating that a system aimed to prevent accidental errors, can lead to a considerable number of systematic errors if used as an uncontrolled set-up system. The results of this study show that human mistakes can seriously affect the outcome of patient treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

RADIOTHERAPY BY MULTIPLE FRACTIONS PER DAY (MFD) IN HEAD AND NECK CANCER: ACUTE REACTIONS OF SKIN AND MUCOSA

The feasibility of several unusual fractionation schedules in the radiotherapy of head and neck tumors was assessed, especially the acute reactions of skin and mucosa. All schedules were based on the principle of multiple fractions per day (MFD) leading to highly concentrated treatment series, alternating with rest periods. The fraction sizes used were between 1.6-2 Gy, overall treatment time was about 6 weeks, and total dose ranged from 60 to 67.2 Gy. The most important parameter that was modified was the size of the dose given in one treatment series. The first schedule consisted of two unequal radiation series: 48 Gy/12 days, followed by a second series of 19.2 Gy/4 days after a 3- to 4-week interval. All subsequent treatment schedules were divided in equal series: the first in 2 times 30 Gy, the second in 3 times 22.4 Gy, and the third in 4 times 16 Gy. Comparison of acute reactions in skin and mucosa after these irradiations to different dose levels has made it possible to obtain a precise idea of the time course in the development of radiation induced damage and of the dose-effect relationship. Such dose-response curves will be extremely useful in further studies on the dose-modifying effects of sensitizers and cytostatic drugs. Conclusions of this study: 1. In human oral mucosa, the threshold dose for the development of confluent mucositis (patches of 0.5 cm) after fractionated irradiation appears to be around 20 Gy. 2. Intervals of 12 days allow full repair of mucosa damage after a dose of about 20 Gy and repeating the irradiation leads to an identical reaction after second, third or fourth treatments, demonstrating that no cumulative effect exists for acute damage. This phenomenon could be exploited to reduce the acute side effects in radiotherapy. 3. The reactions observed in skin are less pronounced than those of mucosa, possibly due to the dose distribution of high energy photons. The changes are, however, slower to develop and intervals of 2 weeks are insufficient for the skin to fully recover from the radiation damage. Subsequent treatment series led to a cumulative reaction pattern. 4. Finally, a number of treatments were associated with misonidazole, an anoxic cell sensitizer, which did not appear to modify significantly the radiation reactions in either skin or mucosa.

Quality assurance in conservative treatment of early breast cancer. Report on a consensus meeting of the EORTC Radiotherapy and Breast Cancer Cooperative Groups and the EUSOMA (European Society of Mastology).

A consensus on a quality assurance programme of the treatment of early breast cancer was reached in a multidisciplinary meeting of surgeons, pathologists, radiotherapists, physicists and radiographers. Guidelines for treatment preparation and execution have been set up, including careful location and excision with marking of the primary tumour. The target volumes for irradiation of the whole breast and boost area have been defined. Radiation dose prescription rules, specification and checking procedures are given, together with measures to achieve a homogeneous dose within the target volume. The rules for a quality assurance programme in each clinic are designed for checking equipment and treatment method.

RADIOTHERAPY COMBINED WITH LOW-DOSE CIS-DIAMMINE DICHLOROPLATINUM (II) (CDDP) IN INOPERABLE NONMETASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A RANDOMIZED THREE ARM PHASE II STUDY OF THE EORTC LUNG CANCER AND RADIOTHERAPY COOPERATIVE GROUPS

UNLABELLED A randomized Phase II study was carried out to assess the feasibility and tumor response of radiotherapy combined with low dose cis-diammine dichloroplatinum (II), (cDDP), in patients with inoperable non-small cell lung cancer (NSCLC). One hundred patients were treated with either radiotherapy alone (arm I), with radiotherapy plus cDDP given once a week (arm II), or daily (arm III). The endpoints were acute and late toxicity and tumor response. Esophagitis was observed more frequently in the cDDP arms, but was severe in only 4% of the patients. Nausea and vomiting were more frequent and more severe in patients treated with the combination therapy. In 37% they required medication or were intractable (WHO, grade 3-4). There were no deficits in renal function when hydration schemes were used. Lung fibrosis was similar in the three arms, with an average of 75% of which 50% was severe. Response (complete and partial remission) was observed in 21 out of 34 eligible patients in arm I, in 20 out of 30 patients in arm II, and 20 out of 30 patients in arm III. The 1- and 2-year survival data were 38% and 14% for radiotherapy alone, 49% and 17% for radiotherapy and cDDP given once a week, and 50% and 32% for radiotherapy combined with daily cDDP. IN CONCLUSION a combination of concomitant cDDP and radiotherapy is tolerable. Based on these results, the study has been continued as a Phase III study with survival as most important end point.

Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary—medial supraclavicular irradiation in stage I-III breast cancer: the individual case review

To assess consistency among participants in an European Organisation for Research and Treatment of Cancer (EORTC) phase III trial randomising between irradiation and no irradiation of the internal mammary and medial supraclavicular (IM-MS) lymph nodes, all participating institutes were invited to send data from 3 patients in each arm as soon as they started accrual. The evaluation focused on eligibility, compliance with the radiotherapy guidelines, treatment techniques and dose prescription to the IM-MS region. Nineteen radiotherapy departments provided a total of 111 cases, all being eligible. Minor discrepancies were found in the surgery and pathology data in almost half the patients. Major radiotherapy protocol deviations were very limited: 2 cases of unwarranted irradiation of the supraclavicular region and a significant dose deviation to the internal mammary region in 5 patients. The most frequently observed minor protocol deviation was the absence of delineation of the target volumes in 80% of the patients. By detecting systematic protocol deviations in an early phase of the trial, recommendations made to all the participating institutes should improve the interinstitutional consistency and promote a high-quality treatment.