Jean-Claude Horiot

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis

BACKGROUNDnSeveral trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival.nnnMETHODSnRandomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction.nnnFINDINGSn15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007).nnnINTERPRETATIONnAltered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: a French cooperative study of 1383 cases.

A French Cooperative study of 1383 cases with invasive carcinoma of the intact uterine cervix treated with radiation therapy alone, using the guidelines provided by G. H. Fletcher led to the following conclusions: The techniques of treatment were easily reproducible in 9 French centers, working in a prospective cooperative study; Results similar to those of the original study were achieved in Stages I and IIA (MDAH substaging) with a locoregional failure rate of 7%; In Stage IIB, the locoregional failure rate of 16% is also comparable in both studies; Locoregional failures in Stage III are slightly lower than those reported in Houston, probably reflecting differences in patients prognostic factors in France and Texas; The 5-year survival rate obtained in advanced Stages (UICC FIGO staging) are among the highest in the literature (76% in Stage IIb, 62% in Stage IIIa and 50% in Stage IIIb); The rate of severe complications remains acceptable and decreased throughout the study thanks to a better use of computer dosimetry.

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSEnThe aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy.nnnMATERIALS AND METHODSnData from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis.nnnRESULTSnFrom the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16).nnnCONCLUSIONSnThe only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Dose-volume analysis and the prevention of radiation sequelae in cervical cancer

We report a 9 year (1975-1983) experience of treatment of carcinoma of the uterine cervix by radiation alone. Computerized dosimetry conforming to the ICRU 38 recommendations was performed for all 348 patients analyzed. Late sequelae were graded as mild (grade 1), moderate (grade 2) and severe (grade 3). The overall rates were grade 3: 9.8%, grade 2: 18%, and grade 1: 19.5%. Of the moderate to severe sequelae, 48% were rectal, 15% rectosigmoid and 21% urinary. The complication rate was highly dependent on the type of intracavitary applicator: lowest for patients treated by two insertions of a standard Fletcher-Suit applicator (grade 3: 5.4%, grade 2: 14.4%) and highest for those receiving uterine stem plus vaginal line sources (grade 3: 29.5%, grade 2: 26%). For 183 patients treated with stem and standard ovoids, moderate and severe rectal and bladder sequelae were analyzed according to critical organ reference doses and reference treatment volumes as defined by ICRU 38, with the addition of a mean rectal dose. Zones of low, moderate and high risk could be defined on dose-volume plots using these parameters. Modification of treatment plans at the Cancer Institute G. F. Leclerc (CGFL) of Dijon according to these concepts produced a reduction in moderate and severe sequelae (grade 3: 14.4-3.4%) without a concurrent increase in pelvic failures. Although the zones of risk proposed can be used directly only with standard Fletcher-Suit applicators and comparable computer dosimetry, the concept can be applied to other systems.

Dental preservation in patients irradiated for head and neck tumours: A 10-year experience with topical fluoride and a randomized trial between two fluoridation methods

Since 1972, the dentures of 935 patients irradiated for head and neck carcinoma have been preserved after careful selection and according to well-defined criteria, using a prospective programme of daily applications of topical sodium fluoride gel. The results of 1-10 years follow-up are given. Four percent of the patients developed a diffuse dental decay and 1% a bone necrosis which can be related to the dental preservation. None of these complications occurred with careful patient selections nor when programme compliance was maintained. Post-irradiation dental extractions were performed in 29 cases with subsequent healing in all cases but one. The surgical technique of such extractions is described. In March 1980, a randomized protocol was activated to compare the use of the sodium fluoride gel to high content fluoride toothpaste (1350 ppm F-). Two hundred and twenty patients were entered. At 12-36 months follow-up, dental caries were observed in 3% of the patients receiving the fluoride gel as compared to 11% receiving the toothpaste (p = 0.1). However, none of the patients adhering to the programme instructions failed in either arm. Currently, it seems reasonable to state that preservation of teeth in irradiated patients should be the rule and not the exception, given good dental condition prior to treatment and patient cooperation. The 5 min daily application of fluoride gel is the most reliable method for prevention of post-irradiation dental caries. The twice daily use of high content fluoride toothpaste is a good alternative provided its limitations are well understood by the clinician and patient.

Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer.

From Feb. 1981 to Oct. 1984, a randomized clinical trial was carried out in the EORTC Radiotherapy Group, comparing classical radiotherapy 70 Gy/7 weeks to MFD (3 X 1.6 Gy/day for 10 days, 3 weeks rest, followed by a boost to 67.2 or 72 Gy), with or without Misonidazole (1 g/m2 every irradiation day, total 12 to 14 g/m2) in advanced head and neck cancer (all T3 and T4, all N2, N3 and N1 greater than 3 cm). A total of 523 patients were entered in the study. At the time of analysis (4/85), the median follow-up time was 64 weeks. No significant differences in survival or locoregional control could be demonstrated between the three treatment arms at this time. Whereas early mucosal reactions were heavier in the MFD-arms, no differences in late effects (fibrosis, edema, xerostomy) were found between the three treatment arms. Five patients (all MFD + Misonidazole) died with local complications (edema, necrosis). All five had cancer of the laryngopharynx and 3 of them died from a hemorrhage. Factors affecting prognosis were tumor site, tumor stage, nodal status, and histological differentiation.

Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix

Pelvic failures and late radiation sequelae were analyzed using the dosimetric parameters of ICRU Report 38 for 338 patients with Stage I-III carcinoma of the uterine cervix treated by radiation alone and followed for a minimum of 2 years. The pelvic recurrence rates were: Stage IB 5.1% (N = 118, 1% pelvis alone), Stage IIA 15.1% (N = 53, 9.4% pelvis alone), Stage IIB 15.8% (N = 76, 9.2% pelvis alone) and Stage IIIB 28.9% (N = 76, 17.1% pelvis alone). For Stages I and II pelvic failure was unrelated to cumulated lateral parametrial dose (CDPW) or reference volumes, but for Stage IIIB was higher for CDPW above 65 Gy. Overall complication rates were: grade 3-10.1% and grade 2-18.1% but were much lower for 176 patients treated with stem and ovoids (S + O: grade 3-5.7%, grade 2-15.7%) than for 43 receiving vaginal cylinders (grade 3-37.2%, grade 2-28%). Grade 3 rectal complications associated with cylinders were related to a maximal vaginal application over 1.50 cGy X m2 of total reference air kerma (or 2080 mgh) and cumulated rectal reference doses (CDRref) above 75 Gy. For the S + O group, grade 2 and 3 rectal complications increased with increasing reference volumes (hwt and HWT) and showed dose thresholds for CDRref and CDRmean (grade 3: 75 Gy). Prospective use of zones of risk defined graphically on a dose-volume plot (CDRref vs HWT) has reduced our severe complication rate without reducing local control. This technique requires individualization of patient therapy, rapid access to computerized dosimetry and the establishment of center- and applicator-specific risks of complications.

The EORTC randomized trial on three fractions per day and misonidazole (trial no. 22811) in advanced head and neck cancer: long-term results and side effects

From 1981 to 1984, a randomized study was done by the EORTC Radiotherapy Group comparing a fractionation schedule with three fractions per day (multiple fractions per day, MFD), with or without misonidazole, to conventional fractionation. The aim of the study was to obtain improved local and regional control and survival by shortening of the treatment time in the first 2 weeks of irradiation. Three fractions of 1.6 Gy/day (4-h interval) were given during 10 irradiation days to a total of 48 Gy. After 3-4-weeks interval, a boost was given to 67.2 or 72 Gy also in three fractions per day. This schedule was compared to an identical arm with misonidazole 1 g/m2/day and a third arm with conventional fractionation (70 Gy in 35 fractions, 7 weeks or 75 Gy in 44 fractions, 9 weeks). A total number of 523 patients was included in the study. Acute mucositis was much heavier in patients treated with three fractions per day (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 8: 1649-1655, 1982). Early results, communicated in 1986 (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 12: 587-591, 1986) showed no differences in treatment outcome between the three treatment arms. Long-term results and data on late effects are now available. Survival at 5 years was 18% (SE 1.9%) and locoregional control was 27% (SE 2.9%). No statistically significant differences could be observed between the three treatment arms.(ABSTRACT TRUNCATED AT 250 WORDS)

Late results of multiple fractions per day (MFD) with misonidazole in advanced cancer of the head and neck. A pilot study of the EORTC radiotherapy group

In the EORTC Radiotherapy Group, the feasibility of multiple fractions per day (MFD) was tested in a pilot study from 1978 to 1980. Three daily fractions of 1.6 Gy were given (4 h interval) during 2 weeks (total dose 48 Gy), with a boost to about 70 Gy after 3-4 weeks. In 53 of the 179 patients, misonidazole was given on every irradiation day (1 g/m2, total 13-14 g/m2). Data on tolerance and early treatment results were published previously; results with a minimum follow-up period of 3 years are now available. Survival (actuarial is 21% and locoregional tumor control was obtained in 34% of patients; no significant differences were seen between the subregions in the head and neck area. Survival is better in patients treated with misonidazole (probably due to selection), but locoregional control was identical as in patients treated without the sensitizer. In February 1984, 38 patients were alive, 35 without evidence of local tumor (5 after rescue surgery). Metastases were seen in 16% and a second tumor in 7% of patients. Seventeen patients (9%) died of causes, possibly related to treatment; necrosis was observed in 8 (4 with local tumor). Late effects in the long survivors were comparable to what is usually seen after high-dose radiotherapy.

Reference volume, milligram-hours and external irradiation for the Fletcher applicator

The ICRU Report 38 recommends the use of reference point doses and reference volumes for the reporting of intracavitary gynecologic therapy. The reference volume enclosed by the 60 Gy isodose for intracavitary therapy alone (which can be represented by hwt) and for combined external and intracavitary therapy (HWT) has no conceptual counterpart in the standard intracavitary systems. We report the relationship of the reference volumes (hwt and HWT) to milligram-hours (mgh) radium equivalent and to dose of external irradiation (XRT) for the Fletcher system. HWT and hwt are directly proportional to mgh, the proportionality constant depending on XRT but not appreciably on moderate changes in source geometry. HWT increases slowly with increasing XRT to about 30 Gy, then increases dramatically with even small increases in XRT. The reasons for this behavior and the possible clinical significance are discussed.