J.C. Horiot

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.

Late effects toxicity scoring: the SOMA scale

The two large organizations that initiate and coordinate multicenter clinical trials in Europe and in North America, the EORTC and the RTOG, have recently formed specific subcommittees or working groups to update their systems for assessing the late injury to normal tissues. This is regarded as necessary in order to standardize and improve the recording so that there can be uniform reporting of toxicity, at agreed and regular intervals in different clinical studies. Many centres have devised their own scales for recording such injury, some of which record all the raw data as it is derived from the patient, while others give a single score on a scale of l-5 to indicate the severity of the overall response. With such a variability in detailed recording of the information on morbidity it is difficult, or even impossible, to compare the outcome of different clinical studies, separated either geographically or chronologically, and indeed there is even a risk of drift within a study in the long period from initiation through to its completion, In the European cooperative studies there is the further need to ensure that the recording of data is uniform against a background of many different languages being used in the consultation between the doctor and the patient By autumn 1993, the EORTC and RTOG working groups had each reached a quite advanced stage in their own organizations towards rationalizing the scoring of late injury. It was then recognized that there would be a great advantage if these two organizations could agree on a common scale, to enable direct comparison of the benefits emerging from the different therapeutic approaches that are being investigated by them.

Late effects toxicity scoring: The soma scale

The two large organizations that initiate and coordinate multicenter clinical trials in Europe and in North America, the EORTC and the RTOG, have recently formed specific subcommittees or working groups to update their systems for assessing the late injury to normal tissues. This is regarded as necessary in order to standardize and improve the recording so that there can be uniform reporting of toxicity, at agreed and regular intervals in different clinical studies. Many centres have devised their own scales for recording such injury, some of which record all the raw data as it is derived from the patient, while others give a single score on a scale of l-5 to indicate the severity of the overall response. With such a variability in detailed recording of the information on morbidity it is difficult, or even impossible, to compare the outcome of different clinical studies, separated either geographically or chronologically, and indeed there is even a risk of drift within a study in the long period from initiation through to its completion, In the European cooperative studies there is the further need to ensure that the recording of data is uniform against a background of many different languages being used in the consultation between the doctor and the patient By autumn 1993, the EORTC and RTOG working groups had each reached a quite advanced stage in their own organizations towards rationalizing the scoring of late injury. It was then recognized that there would be a great advantage if these two organizations could agree on a common scale, to enable direct comparison of the benefits emerging from the different therapeutic approaches that are being investigated by them.

The predictive value of cell kinetic measurements in a European trial of accelerated fractionation in advanced head and neck tumors: An interim report

The value of cell kinetic measurements in head and neck tumors in predicting which patients will benefit from accelerated fractionation radiotherapy regimens is being tested in a multicenter European trial (EORTC trial 22851). This paper reports on the first analysis of the correlation of kinetics with outcome in this trial. A proportion of patients in both the accelerated arm (72 Gy in 5 weeks, 1.6Gy per fraction, 45 fractions) and the conventional arm (70-72 Gy in 7-8 weeks, 1.8-2.0 Gy per fraction, 35-40 fractions) were given an i.v. injection of 100 mg/m2 IUdR (iododeoxyuridine) before treatment, and a tumor biopsy was taken several hours later. The potential doubling time of the tumor (Tpot) was obtained from a flow cytometric analysis of tumor cell nuclei using an anti-IUdR antibody. From a total of 260 patients entered in the trial, 53 have undergone kinetic analysis. Adequate IUdR labeling was seen in 47 patients (88.7%), from which the mean value for Tpot was found to be 4.5 +/- 2.5 days (+/- S.D.). Of the IUdR labeled patients, 30 have now been followed up for at least 1 year, 17 with conventional and 13 with accelerated radiotherapy. These patients were split into those with fast and those with slowly growing tumors, the dividing line being the median Tpot value of 4.6 days. After conventional 7-week radiotherapy, 2 of 6 patients with fast growing tumors obtained local control compared with 8 of 11 with slow growing tumors. A small difference in local control was seen been fast and slow tumors in the accelerated arm (5/9 vs. 3/4). These preliminary data support the hypothesis that patients with fast growing tumors do poorly with conventional radiotherapy and that pretreatment kinetic measurements can select patients at risk. The predictive power of the method must await the final analysis of trial results.

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 <or=35 years, 85% for patients aged 36-40 years, 92% for patients 41-50 years, 96% for patients 51-60 years and 97% 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.

The volume effect in radiation-related late small bowel complications: results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma

PURPOSEnThe purpose of this study was to quantify the correlation between irradiated small bowel volume and late occurring small bowel complications.nnnMETHODSnSmall bowel volumes in the high-dose region were measured using orthogonal barium films for 203 patients treated for rectal carcinoma with pelvic postoperative radiotherapy to 50 Gy in an EORTC multicentric study.nnnRESULTSnThe 5-year estimate of late pelvic small bowel obstruction requiring surgery was 11%. No correlation between the irradiated small bowel volume and obstruction was detected. The actuarial 5-year estimate of chronic diarrhea varied from 31% in patients with irradiated small bowel volumes below 77 cm3 to 42% in patients with volumes over 328 cm3. This correlation was significant in the univariate and multivariate analysis (p = 0.025). The type of rectal surgery significantly influenced the incidence of chronic diarrhea and malabsorption, the actuarial 5-year estimate being 49% and 26% after low anterior resection and abdominoperineal resection, respectively (p = 0.04).nnnCONCLUSIONSnThis study demonstrated that there is a volume-effect in radiation-induced diarrhea at a dose of 50 Gy in 25 fractions. No volume-effect for small bowel obstruction was detected at this dose-level in pelvic postoperative radiotherapy. A review of the literature data on small bowel obstruction indicates that the volume effect at this dose level can only be demonstrated in patients who were treated with extended field radiotherapy (estimated small bowel volume 800 cm3) after intra-abdominal surgery.

Age is not a limiting factor for radical radiotherapy in pelvic malignancies.

BACKGROUND AND PURPOSEnPelvic radiotherapy (RT) toxicity in the elderly is poorly documented. We developed a study aiming to evaluate whether or not a limit of age could be identified beyond which toxicities in patients receiving pelvic RT were more frequent or more severe.nnnMATERIAL AND METHODSn1619 patients with pelvic cancers enrolled in nine EORTC trials, RT arms, were retrospectively studied. Patients were split into six age ranges from 50 years to 70 years and over. Survivals and late toxicity occurrence were calculated with the Kaplan-Meier method and comparison between age groups with the logrank test. A trend test was done to examine if chronological age had an impact on acute toxicity occurrence.nnnRESULTSnSurvival was comparable in each age group for prostate (P = 0.18), uterus (0.41), anal canal cancer (P = 0.6) and slightly better for the younger group of rectum cancer (P = 0.04). A total of 1722 acute and 514 late grade > or = 1 were recorded. Acute nausea/ vomiting, skin complications and performance status deterioration were significantly more frequent in younger patients. There was no trend toward more aged patients to experience diarrhea (P = 0.149) and after adjustment on RT dose, acute urinary complications were observed equally in each age range (P = 0.32). Eighty percent of patients were free of late complication at 5 years in each age range (P = 0.79). For the grade > 2 late side-effects, a plateau was observed after 1 year at near 9% without any difference (P = 0.06) nor trend (P = 0.13) between age-groups.nnnCONCLUSIONnAge per se is not a limiting factor for radical radiotherapy in pelvic malignancies.

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.

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

PURPOSEnTo 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.nnnPATIENTS AND METHODSnFive 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.nnnRESULTSnAt 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.nnnCONCLUSIONnAn 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.

A quantified approach to the analysis and prevention of urinary complications in radiotherapeutic treatment of cancer of the cervix

This paper is the report of a dosimetric study of 79 urinary complications after radical radiation treatment (1975-1979) of 624 cervical uterine tumors. Treatment consisted of external irradiation (25 MeV linear accelerator) and intracavitary irradiation (Fletcher-Suit-Delclos applicator). Dosimetric-computerized studies were expressed as the maximum bladder dose on the trigone, as proposed by the I.C.R.U. Bladder doses were actually studied as a function of intracavitary irradiation and intracavitary + external irradiation. The results show a significant difference in patients with and without complications based on the dose reaching the bladder. The relative contribution of external therapy and intracavitary irradiation and their value can serve as one of the primary indicators for predicting complications. These values should be determined before placement of intracavitary sources. We found that the dose to the critical organs cannot be defined as a single number. These results argue in favor of adapting individual patient therapy based on rectal and bladder dosimetry and may be adjustable to all treatment modalities.