B. Maciejewski

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: Tumor dose-response and repopulation

In a retrospective study, local control of the primary tumor in 498 squamous cell carcinomas of the oral cavity and oropharynx was analyzed with respect to initial tumor volume, total dose after normalization for variations in fraction size, and to overall treatment time. Primary tumors were grouped into 4 sites, tongue (175), oral cavity including floor of mouth, faucial pillar, soft and hard palate and gingiva (210), tonsil (72) and buccal mucosa (41). Total doses of 60Co irradiation ranged from 30 Gy to 72 Gy, overall treatment times from 15 to 80 days and dose per fraction from 1.8 to 6 Gy. The large number of patients and diversity of dose fractionation patterns permitted assessment of the independent contributions to treatment outcome of stage, fraction size and overall treatment duration. The following conclusions were drawn: (1) Overall treatment time influenced strongly the probability of local tumor control. Over the interval of about 30-55 days used in treating most of this series of patients, an increase of 60 cGy per day, on average, was required for a constant control rate. (2) The increase in dose was attributed to accelerated tumor clonogen growth rate. Such accelerated growth could be a major determinant of failure in protracted regimens. (3) The accelerated rate of regrowth was similar for all tumor sites and stages. (4) The dose for tumor control was relatively independent of variations in fraction size within a range of about 1.6 Gy to 3 Gy: the alpha/beta value in the linear quadratic isoeffect equation was at least 15 Gy. (5) Local control at the primary site required an average of about 3 Gy more for each increase in T stage. This increase most likely reflected an increased number of tumor clonogens, not a decreased tumor cell radiosensitivity. (6) The probability of control at the primary site was less likely if lymph nodes were positive, but this association was only shown to be statistically significant for primaries classified here as oral cavity and oropharynx, not tonsil, tongue or buccal mucosa. (7) After allowing for differences in treatment parameters, especially for heterogeneity in overall treatment times, tumor control probability increased steeply with increase in total dose. (8) A general principle of radiotherapy, at least for squamous carcinomas of head and neck, should be to deliver the desired fractionated dose regimen without unnecessary interruptions and in the shortest time compatible with no reduction in dose below that tolerated by the late-responding normal tissues.

THE INFLUENCE OF THE NUMBER OF FRACTIONS AND OF OVERALL TREATMENT TIME ON LOCAL CONTROL AND LATE COMPLICATION RATE IN SQUAMOUS CELL CARCINOMA OF THE LARYNX

Three hundred and ten patients with T3/T4, N0, M0 squamous cell carcinoma were irradiated with 200 kV X rays with total doses ranging from 4,900 to 6,200 rad, given in 21 to 35 fractions in 32-63 days. After a minimum follow-up period of 3 years, the local control rate was 50%; 21 severe late complications were observed among the patients. The dependence of local control rate and of late complication rate on the dose per fraction and on overall treatment time was analyzed by various statistical methods. Whereas the late complication rate depended significantly on dose per fraction, local tumor control depended strongly on overall treatment time.

Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer – report on 3-year tumour control and normal tissue toxicity

Purpose: To evaluate tumour and normal tissues 3-year response to 7-day-a-week continuous accelerated irradiation (CAIR) compared to a conventional treatment (5 days per week) in a randomized trial. Materials and methods: One hundred patients with squamous cell carcinoma of the head and neck in stage T2‐4N0‐1M0 were entered into the trial between December 1, 1993 and June 30, 1996. Dose per fraction of 2.0 Gy (to the end of 1994), and 1.8 Gy (since January 1, 1995) was the same in both arms and delivered once a day at regular 24-h intervals to total dose in the range of 66‐72 Gy (depending on tumour stage). The only difference was overall treatment time being 5 weeks in the CAIR and 7 weeks in control arm. Results: Actuarial 3-year local tumour control was 82% in the CAIR and 37% in the control group (P , 0:0001) with reduction in local recurrence rate of 83%. Actuarial 3-year overall survival was 78 and 32% (P , 0:0001), respectively. Confluent mucositis was significantly more severe and lasted longer in the CAIR than in control arm. After 2.0 Gy fractions five of 23 patients (22%) in the CAIR developed early necroses over a period of 2‐4 months of follow-up which can be considered as a consequential to severe protracted acute mucosal reactions (CLE). For this reason dose per fraction was lowered to 1.8 Gy and the CLE was not observed again until now. Thus the overall rate of CLE decreased to 10%. Conclusions: The gain in tumour control is likely the effect of shortening of overall treatment time by 14 days and regular continuous dose delivery during the whole course of radiation therapy including weekends. A 7-day schedule produces more severe acute mucosal reactions lasting longer than in conventional fractionation, however tolerable by patients. Relatively high rate (22%) of CLE in the 7-day arm observed during the first year of the study was eliminated by decreasing dose per fraction from 2.0 Gy to 1.8 Gy. q 2000 Elsevier Science Ireland Ltd. All rights reserved.

Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity

PURPOSE Toxicity of an accelerated 7 days per week fractionation schedule (arm A) was evaluated and compared with a conventional 5 days per week treatment (arm B) in a randomized trial. MATERIALS AND METHODS Forty-four patients with squamous cell carcinoma of the head and neck in stage T2-4Nzero-1Mzero were included in the study. Total dose and dose per fraction of 2.0 Gy given once-a-day at 24 h intervals were the same in both arms of the trial. The only difference was the overall treatment time being 5 weeks in arm A and 7 weeks in arm B. RESULTS Analysis of severe mucosal reactions shows significant difference between arm A and B, with regard to both maximum score and duration of severe mucositis. Confluent mucositis (score > 15 according to the Dische system) lasting longer than 3 weeks developed in 48% of patients in arm A and only in 5% in arm B. In group A seven (30%) late effects (osteo- and soft tissue necrosis) occurred during 7-12 month follow-up with two reactions (10%) in group B being suspected as late effects. There was significant association between acute reactions and late effects in arm A, suggesting that the late effects are consequential. CONCLUSION The high incidence of severe acute reactions and consequential late effects suggests that the accelerated treatment in arm A (using daily fractions of 2.0 Gy, 7 days per week) gives unacceptable toxicity.

How fast is repopulation of tumor cells during the treatment gap

PURPOSE/OBJECTIVE Our goal was to analyze the repopulation of surviving tumor cells during a treatment gap in radiotherapy for head-and-neck cancer. METHODS AND MATERIALS Clinical material is based on the records of 1502 patients treated by radiotherapy alone in Maria Sklodowska-Curie Memorial Institute in Gliwice during the period between1980 and 1989. All patients had histologically confirmed squamous cell carcinoma of the larynx or pharynx. The mean gap duration was 9 days. Only 10% of patients were treated without gaps. The dose per fraction was in the range of 1.5 to 2.5 Gy. Patient data were fitted directly to the mixed linear-quadratic model using maximum-likelihood estimation. Tumor stage or tumor localization was introduced into the equation as a categorical variable. Tumor proliferation was estimated by dividing the treatment gaps into three groups: the first 2 weeks, second 2 weeks, and the period after 4 weeks of irradiation. RESULTS Tumor control probability was significantly correlated with radiation dose, tumor progression (according to TNM), overall treatment time, and gap duration. Laryngeal cancers had a better prognosis than cancers of the oro- and nasopharynx. Significant tumor repopulation was found after the first 2 weeks of radiotherapy. During the treatment gap, the proliferation rate was equal to 0.75 Gy/day. During the days with irradiation, repopulation was slower and equal to 0.2 Gy/day. CONCLUSION The repopulation of tumor cells is faster during a gap than during the normal days of irradiation. Accelerated repopulation probably starts soon after 2 weeks of irradiation.

PROGNOSTIC VALUE OF HEMOGLOBIN CONCENTRATION IN RADIOTHERAPY FOR CANCER OF SUPRAGLOTTIC LARYNX

PURPOSE The aim of this work is the estimation of correlations between hemoglobin concentration either before or after radiotherapy and local tumor control probability for laryngeal cancer. METHODS AND MATERIALS Retrospective analysis of 847 cases of laryngeal supraglottic squamous cell carcinoma treated with radiation alone was performed using maximum likelihood estimations, and step-wise logistic regression. All patients were in good initial performance status (Karnofsky index >70). The minimum follow-up time was 3 years. RESULTS Logistic regression showed that the hemoglobin concentration after radiotherapy is an important prognostic factor. There was a very strong correlation between hemoglobin concentration and tumor local control probability. Hemoglobin concentration at the beginning of radiotherapy does not correlate with treatment outcome, but any decrease of hemoglobin during therapy is a strong prognostic factor for treatment failure. CONCLUSIONS Although regression models with many variables may be instable, the present results suggest that hemoglobin concentration after treatment is at least as important as overall treatment time. It was not possible to find out whether the low concentration of hemoglobin is an independent cause of low TCP or whether it reflects other mechanisms that may influence both hemoglobin level and the TCP.

Acute mucositis in the stimulated oral mucosa of patients during radiotherapy for head and neck cancer

In 16 patients treated for squamous cell carcinoma of the oral cavity or oropharynx with an accelerated split course regimen, acute mucosal reactions were significantly less in the left buccal mucosa which had been repeatedly painted with 2% silver-nitrate solution for several days before radiotherapy than in the unpainted right buccal mucosa.

Dose-response curve and split-dose recovery in human skin cancer.

The data of 946 skin cancer patients treated with single doses or with 4, 8, 17, 40 or 47 fractions of X-rays were analysed using Strandquists formalism and the linear-quadratic model. The analysis of tumour control in relation to tumour size and fractionation schedule shows a strong correlation between tumour size and tumour control rate. For small tumours, single dose irradiation was as effective as fractionated treatment. For large tumours, a straight line was easily fitted to the TCD50 and TCD90 values plotted logarithmically against time or number of fractions; the exponent for overall treatment time was 0.27 and for number of fractions it was 0.31. With the linear-quadratic model, an alpha/beta ratio of 13.8 Gy was calculated. On the assumption that the number of clonogenic cells in the tumour increases in proportion to tumour volume, Do values between 0.76 and 1.33 Gy were calculated and cellular survival curves were constructed. The estimated clonogenic fraction of tumour cells is about 10(-3); no influence of hypoxic clonogenic cells on local tumour control with single doses could be demonstrated.

Role of short TE 1H-MR spectroscopy in monitoring of post-operation irradiated patients

Post-surgical radiation therapy is a routine procedure in the treatment of primary malignant brain tumors. Along with modest therapeutic effects conventional fractionated radiotherapy, in spite of any modifications, produces damage to non-malignant brain tissues lying within the treatment volume, the extent of which depends on radiation dose. Serial 1H-MRS allows non-invasive investigation of tissue metabolic profiles. In the present study the ratios of resonance signals assigned to the major 1H-MRS-visible metabolites (N-acetylaspartate, choline, creatine, inositol, lactate and lipid methylene group) were evaluated before, during and after post-surgical fractionated radiotherapy in brain regions close to and more distant from the tumor bed, receiving different radiation exposures (60 and < 40 Gy, respectively). The study group consisted of ten patients (aged 28-51). A MRI/MRS system (Elscint 2T Prestige) operating at the field strength of 2 T and the proton resonance frequency of 81.3 MHz has been used and the 1H-MR spectra were acquired using single voxel double-spin-echo PRESS sequence with a short TE. The spectra were post-processed with automatic fitting in the frequency domain. It was found that although the metabolite profiles depend on the dose obtained, but other stress factors (like surgery) seem to contribute to the overall picture of the metabolic status of the brain as well. In studies of early irradiation injuries, an increase of choline related ratios may serve rather as cell proliferation indictors than as cell injury ones, whereas the mI/Cr ratio appears as one of the first indicators of local irradiation injury. In order to establish the prognostic marker for early radiation damage, however, it seems necessary to analyze all visible metabolites as well. None of the metabolites separately may serve as such an indicator due to the complexity of tissue metabolism. Interestingly, MRI reveals no changes during the therapy process, whereas the metabolite ratios are being affected in the course of time, thus supporting the presumption that the 1H-MRS is a valuable method of radiation therapy monitoring.

Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk squamous cell head and neck cancer

PURPOSE To evaluate the normal tissue reactions and loco-regional control rates (LRC) in patients treated with 7-days-a-week postoperative continuous irradiation (p-CAIR) compared to conventionally fractionated 5-days-a-week postoperative radiotherapy (CF). MATERIALS/METHODS Between 2001 and 2004, 279 patients with high-risk squamous cell cancer of the larynx (158 pts.) or cancer of the oral cavity/oropharynx (121 pts.) were enrolled. They were stratified according to the primary cancer site (larynx vs. others) and the treating center and randomized to receive 63 Gy in fractions of 1.8 Gy given 5-days-a-week (140 pts: CF) or 7-days-a-week (139 pts: p-CAIR). RESULTS The acute and late toxicity was considered acceptable, although the proportion of patients with confluent mucositis was higher in p-CAIR compared to CF (60.0 vs. 33.3%). The actuarial 3-year LRC were 64 vs. 70% for CF and p-CAIR, respectively, p=0.32. A statistically significant improvement in 3-year LRC in p-CAIR arm appeared in a subset of the patients with cancer of the oropharynx/oral cavity (74% p-CAIR vs. 53% CF, p=0.02). By contrast, there was no improvement in LRC in a subset of the patients with cancer of the larynx (p=0.46). CONCLUSION An improvement in LRC attributable to acceleration of postoperative radiotherapy appeared restricted to the patients with cancer of the oropharynx/oral cavity. In patients with cancer of the larynx acceleration of postoperative radiotherapy did not have any beneficial effect.