Continuous Hyperfractionated Accelerated Radiotherapy Research Articles

38 Pattern of recurrence after continuous, hyperfractionated, accelerated radiotherapy (CHART) in non-small cell lung cancer

38 Pattern of recurrence after continuous, hyperfractionated, accelerated radiotherapy (CHART) in non-small cell lung cancer

Toxicity and outcome of a phase II trial of taxane‐based neoadjuvant chemotherapy and 3‐dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer

The objective of this study was to evaluate prospectively the acute and late adverse effects of taxane/carboplatin neoadjuvant chemotherapy and 3-dimensional, conformal radiotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC). Forty-two patients were entered into a nonrandomized Phase II study of continuous, hyperfractionated, accelerated radiotherapy (CHART) week-end less (CHARTWEL) to a dose of 60 grays (Gy). Three cycles of chemotherapy were given over 9 weeks before radiotherapy. Dose escalation with paclitaxel was from 150 mg/m2 to 225 mg/m2. Systemic toxicity to chemotherapy was monitored throughout. Radiation-induced, early, adverse effects were assessed during the first 9 weeks from the start of radiotherapy, and late effects were assessed from 3 months onward. Overall survival, disease-free survival, and locoregional tumor control also were monitored. Twenty percent of patients failed to receive chemotherapy as planned, primarily because of neutropenia. The incidence of Dische Dictionary Grade >or=2 and Grade >or=3 dysphagia was 57.5% and 10%, respectively, with an average duration of 1.2 weeks and 1.5 days, respectively. By 9 weeks, <3% of patients were symptomatic; and, eventually, all acute reactions were healed, and there has been no evidence of consequential damage. At 6 months, the actuarial incidence of moderate-to-severe pneumonitis was 10%. During this time, all patients were free of severe pulmonary complications. Actuarial estimates of Grade >or=2 late lung dysfunction were 3% at 1 year, 10% at 2 years, and remained at this level thereafter. The actuarial 3-year locoregional control and overall survival rates were 54% and 45%, respectively. Neoadjuvant chemotherapy followed by 3-dimensional, conformal CHARTWEL 60-Gy radiotherapy in patients with advanced NSCLC was feasible and was tolerated well. Historic comparisons indicated that locoregional tumor control is not compromised by the use of conformal techniques.

Endogenous Markers of Two Separate Hypoxia Response Pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) Are Associated With Radiotherapy Failure in Head and Neck Cancer Patients Recruited in the CHART Randomized Trial

Randomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial. There are two distinct hypoxia inducible factors (HIFs) that control different gene response pathways and we assessed them both with endogenous markers of hypoxia, hypoxia inducible factor HIF-2 alpha (HIF-2) and carbonic anhydrase CA9, an indicator of HIF-1 alpha (HIF-1) function. Tissue from pre-RT biopsies performed in 198 of 918 patients recruited was analyzed for the immunohistochemical expression of HIF-2 and CA9. A significant association of high HIF2 and of high CA9 reactivity with poor locoregional control (P < .0001 and P = .0002, respectively) and poor survival (P = .0004 and 0.002, respectively) was noted. In multivariate analysis, HIF-2 and CA9 maintained their independent prognostic significance. Coexpression of both pathways had an additive effect, supporting their independent role. The uni-directional hypothesis, that a benefit from randomization to CHART should be seen in the nonhypoxic tumors, was supported by the data (one-tailed P = .04). Expression of endogenous markers of hypoxia for the HIF-1 and HIF-2 pathway is strongly associated with radiotherapy failure. Using immunohistochemical methods it is possible to identify subgroups of HNSCC patients who are highly curable with radiotherapy, or who are excellent candidates for clinical trials on hypoxia-targeting drugs in two distinct pathways.

Hypoxia Response Pathways and Radiotherapy for Head and Neck Cancer

Tumor hypoxia has been recognized as a potential cause of failure of treatment with ionizing radiation of carcinomas, both in in vivo animal models and in human cancers such as head and neck carcinomas. The degree of hypoxia is highly variable in human tumors, and tumor reoxygenation can take place during fractionated radiotherapy, hence adding complexity to this phenomenon and making it difficult to predict the response of individual tumors to radiation exposure. In this context, the study by Koukourakis et al in this issue of the Journal of Clinical Oncology aimed to analyze by immunohistochemistry two endogeneous hypoxic tumor markers, the hypoxia inducible factor HIF-2 alpha and the carbonic anhydrase CA9, correlating expression of these markers in tissues with the outcome of patients after radiotherapy. A strong correlation between both HIF-2 alpha and CA9 immunoreactivity was found, for both locoregional control and survival, confirming the importance of tumor hypoxia in head and neck cancer. One interesting feature of their study was to address this question in the frame of the large randomized CHART (Continuous Hyperfractionated Accelerated Radiotherapy) trial, which compared two regimens of radiotherapy. The first regimen was conventional radiotherapy delivering 66 Gy in 6.5 weeks and the second was accelerated radiotherapy, delivering 54 Gy in only 12 days. The overall outcome of the patients with these two regimens was not different. However, one hypothesis to explain the absence of benefit from the more intense regimen was that the time course of this regimen was too short to allow tumor reoxygenation during the course of radiotherapy. In addition, the relatively low total dose (54 Gy) and the small dose per fraction (1.5 Gy) used in the accelerated regimen could have been relatively ineffective in overcoming radioresistance by hypoxia. Confirming this hypothesis, no benefit was found with the accelerated regimen in the group of hypoxic tumors. The number of patients analyzed (n 198) was relatively limited, and the methodology used did not allow firm conclusions. One of the drawbacks of the study was that tumor hypoxia was measured only initially and could not be neasured throughout the course of treatment. Despite these limitations, there is some suggestion from the Koukourakis study that tumors presenting with initial hypoxia, as assessed by immunohistochemistry, were more likely to experience failure with the accelerated regimen. In contrast, tumor hypoxia had no influence on the outcome after conventional radiotherapy, which may allow sufficient time for tumor reoxygenation. This hypothesis is appealing, but needs to be further investigated and confirmed. It might allow one to perform adaptive radiotherapy, and identify among tumors those that could be candidates for hypoxic modifications and/or accelerated radiotherapy. A recent work by Overgaard et al, used another hypoxiarelated marker, the serum level of osteopontin, in a randomized trial that compared in a series of head and neck cancer patients’ radiotherapy with and without an hypoxic sensitizer (nimorazole). The only group of patients who benefited from the hypoxic modification was the one in which high levels of serum osteopontin (suggesting tumor hypoxia) were found, strongly suggesting that measuring tumor hypoxia before radiotherapy may help to individualize irradiation in a more rational way. A further randomized study performed recently by Hicks et al used positron emission tomograph F18-misonidazole imaging (before the onset of radiochemotherapy) for tumor hypoxia in a series of patients with head and neck carcinomas. The patients were randomly assigned to receive tirapazamine, which is cytotoxic, specifically in hypoxic conditions. The control rate of tumors which were hypoxic and received tirapazamine was much higher than that of tumors that were hypoxic and did not receive tirapazamine, but fluorouracil instead. These results, taken together with the study of Koukourakis et al, suggest that evaluating tumor hypoxia before radiotherapy may help to identify tumor characteristics that may allow one to adapt the radiation regimen and hypoxic modifications and bring new insights to the field of radiotherapy and tumor hypoxia.

1021 POSTER Comparison of Cumulative Incidence (Cl) and Kaplan-Meier (KM) estimates on late normal tissue outcome in the presence of competing risks: Evidence from CHART (Continuous Hyperfractionated Accelerated Radiotherapy) Head and Neck Study

1021 POSTER Comparison of Cumulative Incidence (Cl) and Kaplan-Meier (KM) estimates on late normal tissue outcome in the presence of competing risks: Evidence from CHART (Continuous Hyperfractionated Accelerated Radiotherapy) Head and Neck Study

The Use of Lung Dose–Volume Histograms in Predicting Post-radiation Pneumonitis After Non-conventionally Fractionated Radiotherapy for Thoracic Carcinoma

To assess the use of lung dose-volume histogram (DVH) parameters (specifically V20Gy) in the prediction of radiation pneumonitis for non-conventional fraction sizes used in the treatment of lung cancer. Patients requiring computed tomography planning for thoracic radiotherapy between January 1999 and January 2002 were identified. The patients receiving radical or high-dose palliative radiotherapy had DVH produced routinely during planning. These were retrospectively reviewed and the case notes accessed for additional pre-treatment parameters, demographics and evidence of radiation pneumonitis. The severity of the pneumonitis was then scored using Radiation Therapy Oncology Group criteria. Data were analysed using the SPSS computer program. One hundred and sixty consecutive patients were reviewed. Ninety patients received hypofractionated treatment (fraction size > 2.5 Gy) and 57 continuous hyperfractionated accelerated radiation therapy (CHART) (fraction size 1.5 Gy). Lung V20Gy values ranged from 3% to 53%, with a median value of 24%. Only six patients reported grade 2, and 16 patients grade 3 pneumonitis. Two patients developed fatal, grade 5 pneumonitis. No correlation between pneumonitis score and V20Gy or other possible predictive factors was found. The 15% grade 2-5 pneumonitis rate we document is at the lower end of the spectrum reported in other studies. This suggests that using published data on limiting V20Gy values to reduce the risk of radiation pneumonitis can be extrapolated to planning treatment with non-conventionally fractionated radiotherapy.

Predicting the Future From Trials of the Past: Epidermal Growth Factor Receptor Expression and Outcome of Fractionated Radiation Therapy Trials

The epidermal growth factor receptor (EGFR; HER 1; ErbB1) has been at the center of an explosion of translational research over the past 20 years. The EGFR is expressed or overexpressed in a large number of malignancies, including non–small-cell lung (NSCLC), head and neck, esophageal, gastric, colorectal, breast, prostate, bladder, renal, pancreatic, and ovarian cancers. EGFR expression is often found in association with increased expression of its ligands, most notably epidermal growth factor (EGF), tumor growth factor-alpha, or amphiregulin. EGFR activation and signaling affects many aspects of cell biology relevant to malignant transformation, including cell cycle progression, migration and invasion, differentiation, and cell survival. The antiapoptotic effects of EGFR activation may be particularly relevant to the assessment of treatment outcomes in patients afflicted with EGFR expressing tumors have been ascribed to regulation of Bcl-2 family members. In this issue, Bentzen et al examine EGFR expression status in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to Continuous Hyperfractionated Accelerated Radiotherapy (CHART) versus conventionally fractionated radiotherapy. The EGFR index was defined as the proportion of tumor cells with EGFR membrane staining. Significant benefit in locoregional tumor control from CHART was seen in patients with head and neck squamous cell carcinoma with high EGFR expression (2P .010) but not in patients with low EGFR expression (2P .85). By contrast, EGFR expression status was not linked to patient survival or rate of distant metastases. Bentzen et al used immunohistochemical analysis to assess EGFR expression levels, which raises some technical concerns. First, manual methods of immunohistochemical scoring of antigen expression as used in this report are fraught with variability. This variability may explain the lack of association of EGFR expression with other biomarkers evaluated in this study (Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index). Another concern centers on the retrospective analysis of archived tissue stored for different periods of time. The CHART head and neck phase III trial accrued patients over 5 years from March 1990 to April 1995. During this extended period, oxidation of antigens/DNA/RNA may have occurred. A recent editorial in the Journal of Clinical Oncology by Meropol refers to work by Atkins et al in support of the notion that extended storage of tissue sections over time affects the sensitivity of EGFR immunostaining. However, despite these concerns, the study by Bentzen et al provides an interesting new perspective on intratumoral EGFR expression as a variable with obvious relevance to the design of fractionated radiotherapy. Several reports have illuminated molecular mechanisms leading to enhanced expression of the EGFR in epithelial malignancies. In addition to gene amplification, sequence analysis has revealed polymorphisms of intron 1 of the EGFR gene characterized by (CA)n dinucleotide repeats of different lengths that regulate transcription rates of the EGFR in cell lines and in tumor tissues in patients. The length of the (CA)n dinucleotide repeat tract is inversely correlated with the transcriptional activity of the EGFR gene. Further investigation of EGFR sequences expressed by tumor cells has also revealed alterations that primarily affect the activation state of the receptor rather than the expression levels. For example, in patients with colorectal cancer, a polymorphic variant of the EGFR gene (HER-1 R497K) has JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2

P-718 Continuous hyperfractionated accelerated radiotherapy (CHART)in non small cell lung cancer: A single centre experience as standard treatment

P-718 Continuous hyperfractionated accelerated radiotherapy (CHART)in non small cell lung cancer: A single centre experience as standard treatment

Molecular biomarkers and site of first recurrence after radiotherapy for head and neck cancer

The prognostic significance of a panel of molecular biomarkers in head and neck squamous cell carcinoma (HNSCC) for first failure site (primary (T), nodal (N) or distant (M)) was analysed in 309 patients randomised to continuous hyperfractionated accelerated radiotherapy (CHART) vs. conventionally fractionated radiotherapy. Multivariate competing risks analysis was performed using an accelerated failure-time model. First-order interactions between each marker and trial arm were also tested. Bcl2-positivity increased the time to T- and N-failures, increasing cyclin D1 score decreased the time to N-failures. A random proliferative pattern and low Ki-67 decreased the time to M-failures. A high CD31 score was associated with a significantly longer time to T-failure after CHART, but not after conventional fractionation. Risks of T-, N- and M-failures could be estimated for individual patients. Competing risks analysis of failure sites allows the rational selection of patients for more aggressive loco-regional or systemic therapy.

P-160 Acute radiation oesophagitis following treatment of NSCLC with Continuous Hyperfractionated Accelerated Radiotherapy (CHART)

P-160 Acute radiation oesophagitis following treatment of NSCLC with Continuous Hyperfractionated Accelerated Radiotherapy (CHART)

Radiation pneumonitis following treatment of non–small-cell lung cancer with continuous hyperfractionated accelerated radiotherapy (CHART)

Purpose To determine whether partial volume lung irradiation influences the risk of developing acute radiation pneumonitis after the treatment of non–small-cell lung cancer with continuous hyperfractionated accelerated radiotherapy (CHART). Methods and materials We conducted an analysis of 32 patients treated with CHART at the Gloucestershire Oncology Center. Twelve patients were treated using conventional two-dimensional treatment techniques and received elective nodal irradiation (ENI). Their treatment plans were subsequently recapitulated using a three-dimensional treatment planning system. Twenty patients were planned using this system from the outset. For these patients, elective nodal irradiation was omitted. Dose–volume histograms (DVH) were constructed and several parameters analyzed for their ability to predict for the development of pneumonitis. Results Univariate analysis revealed that the percentage lung volume receiving more than 20 Gy (V 20) and the mean lung dose are of predictive value for the development of pneumonitis after CHART. There is a strong correlation between these two parameters. Importantly, partial volume lung irradiation using CHART appears to be better tolerated than conventionally fractionated radiotherapy. The omission of ENI considerably reduces V 20. Using a commonly employed 3-beam technique it was also noted that the shape of the planning target volume (PTV) in the transverse plane (expressed as an elliptical index) affects the conformity of the V 20 isodose to the PTV. This influences the scope for dose escalation with irregularly shaped tumors. Conclusions In relation to acute radiation pneumonitis, CHART appears to have a superior therapeutic index than conventionally fractionated radiotherapy. V 20 and mean lung dose are useful factors for predicting the risk of this complication. The use of these parameters will aid the selection of optimal treatment plans and provides a basis for future dose escalation studies.

Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas

Purpose: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma. Methods and Materials: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D prolif of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given. Results: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently. Conclusions: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.

A Systematic Overview of Radiation Therapy Effects in Non-Small Cell Lung Cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for non-small cell lung cancer (NSCLC) is based on data from 4 meta-analyses and 31 randomized trials. Moreover, data from 12 prospective studies, 12 retrospective studies and 6 other articles were used. In toal, 65 scientific articles are included, involving 18 310 patients. The results were compared with those of a similar overview from 1996 including 28 172 patients. The conclusions reached can be summarized as follows: <list id="l1" type="5"> <item>Extensive clinical experience indicates that radiotherapy for medically inoperable patients or patients refusing surgery with NSCLC stage I/II prolongs survival, 15-20% of these patients reaching long-term (5-year) survival. However, no randomized trials have addressed this issue.</item><item>There is strong evidence that postoperative radiotherapy in radically resected stage I/II NSCLC does not prolong survival compared with observation alone.</item><item>There is some evidence that continuous hyperfractionated accelerated radiotherapy (CHART) is associated with increased survival compared to conventional radiotherapy in locally advanced NSCLC and also in medically unfit patients with stage I/II NSCLC. However, the benefit is limited to squamous cell histology.</item><item>There is strong evidence that combined modality treatment with platinum-based chemotherapy and radiotherapy, either neoadjuvant or concomitant, is superior to radiotherapy alone in terms of survival in locally advanced unresectable NSCLC and should be the standard of care in patients with good performance status.</item><item>There is some evidence that concomitant chemo-radiotherapy is associated with increased survival compared with sequential chemo-radiotherapy, albeit at the price of increased toxicity.</item></list> Comment: Combined chemo-radiotherapy of primary non-resectable stage III NSCLC followed by surgery in responders lacks evidence from prospective randomized trials and cannot be recommended for routine use. <list id="l2" type="5"> <item>There is strong evidence that radiotherapy can palliate symptoms associated with the intrathoracic tumour burden.</item><item>There is some evidence that two large fractions may be as effective as conventional schedules consisting of 10-13 smaller fractions in terms of palliation of symptoms.</item><item>There is some evidence that endobronchial brachytherapy for palliation of symptoms associated with endobronchial tumours is not superior to external beam radiotherapy.</item></list>

Treatment of head and neck cancer with CHART and nimorazole: phase II study

Causes of failure of radiotherapy in squamous cell carcinoma of the head and neck probably include repopulation and hypoxia. Very accelerated schedules such as continuous hyperfractionated accelerated radiation therapy (CHART) overcome the repopulation problem but allow limited time for reoxygenation, so a hypoxic-cell sensitizer may be especially beneficial. Nimorazole is the only such agent to have shown a significant effect in a randomized controlled trial in head and neck cancer. Accordingly we studied the combination of CHART and nimorazole. Sixty-one patients with advanced stage III (21) or IV (40) squamous cell carcinoma of the head and neck unsuitable for surgery were treated in a phase II study of the combination. The radiation dose was 56.75 Gy in 36 fractions in 12 consecutive days. Nimorazole was administered orally or enterally 90 min before radiotherapy at a dose of 1.2, 0.9, and 0.6 g/m(2) with the first, second and third daily fractions, respectively. This dosage consistently yielded plasma concentrations above 30 microg/ml. All the patients have been followed for a minimum of 2 years since treatment. Loco-regional control at 2 years is 55%, stage III 62% and stage IV 50%. Normal tissue effects were the same as those previously seen with CHART, except for a possible slight increase in acute skin reaction. Nimorazole toxicity was somewhat greater than with once daily administration in previous studies. Grade 3 nausea or vomiting occurred in 22% of patients. Two patients developed grade 1 peripheral neuropathy, and one patient died during treatment of encephalopathy, which was probably an idiosyncratic reaction to the drug. Local control rates are higher than those previously seen with CHART, suggesting a positive effect of nimorazole. Further studies of hypoxia-modifying agents with accelerated radiotherapy are warranted, and nimorazole is the simplest of these.

From CHART to CHARTWEL in Non-small Cell Lung Cancer: Clinical Radiobiological Modelling of the Expected Change in Outcome

CHART (Continuous Hyperfractionated Accelerated Radiotherapy) has been shown to improve the tumour control probability and survival relative to conventional radiotherapy in patients with inoperable non-small cell lung cancer (NSCLC). CHARTWEL (CHART Weekend-less) is a further development of this schedule escalating the physical dose to 60 Gy while maintaining the low dose per fraction of 1.5 Gy. In this schedule, three fractions, with a minimum interval of 6 h between fractions, are delivered 5 days per week. This extends overall treatment time from the 12 days of CHART to 18 days. Radiobiological modelling is used to estimate the expected tumour control and normal tissue morbidity after CHARTWEL relative to CHART. The estimations are based on the outcome of the CHART trial and published values for dose-fractionation and dose-response parameters for human tissues and tumours. Two new estimates of quantitative radiobiological parameters for early normal-tissue morbidity after chest irradiation are reported here. For radiation pneumonitis, the dose recovered per day is estimated at 0.44 Gy/day with 95% confidence limits 0.07 Gy/day and 0.80 Gy/day. For oesophagitis, the normalized dose-response gradient, gamma50, is estimated at 2.1 with 95% confidence limits 1.4 and 3.6. With regard to normal tissue effects, the increase in total dose when going from CHART to CHARTWEL is moderated by the slightly longer overall treatment time in case of early morbidity while the introduction of the weekend gaps may moderate the effect for late-responding normal tissues with a long repair halftime. Tumour control at 3 years is expected to increase by some 7-14 percentage points (from 19% to 26-33%) whereas the incidence of moderate and severe early oesophagitis and pneumonitis is expected to increase by about 2 percentage points. The incidence of late morbidity, lung fibrosis and oesophageal strictures, is expected to increase by 3-4 percentage points. The analyses conclude that CHARTWEL is likely to improve the therapeutic ratio relative to CHART.

The optimal fraction size in high-dose-rate brachytherapy: dependency on tissue repair kinetics and low-dose rate

Background and Purpose : Indications of the existence of long repair half-times on the order of 2–4 h for late-responding human normal tissues have been obtained from continuous hyperfractionated accelerated radiotherapy (CHART). Recently, these data were used to explain, on the basis of the biologically effective dose (BED), the potential superiority of fractionated high-dose rate (HDR) with large fraction sizes of 5–7 Gy over continuous low-dose rate (LDR) irradiation at 0.5 Gy/h in cervical carcinoma. We investigated the optimal fraction size in HDR brachytherapy and its dependency on treatment choices (overall treatment time, number of HDR fractions, and time interval between fractions) and treatment conditions (reference low-dose rate, tissue repair characteristics). Methods and Materials : Radiobiologic model calculations were performed using the linear-quadratic model for incomplete mono-exponential repair. An irradiation dose of 20 Gy was assumed to be applied either with HDR in 2–12 fractions or continuously with LDR for a range of dose rates. HDR and LDR treatment regimens were compared on the basis of the BED and BED ratio of normal tissue and tumor, assuming repair half-times between 1 h and 4 h. Results : With the assumption that the repair half-time of normal tissue was three times longer than that of the tumor, hypofractionation in HDR relative to LDR could result in relative normal tissue sparing if the optimum fraction size is selected. By dose reduction while keeping the tumor BED constant, absolute normal tissue sparing might therefore be achieved. This optimum HDR fraction size was found to be largely dependent on the LDR dose rate. On the basis of the BED NT/TUM ratio of HDR over LDR, 3 × 6.7 Gy would be the optimal HDR fractionation scheme for replacement of an LDR scheme of 20 Gy in 10–30 h (dose rate 2–0.67 Gy/h), while at a lower dose rate of 0.5 Gy/h, four fractions of 5 Gy would be preferential, still assuming large differences between tumor and normal tissue repair half-times and equal overall treatment time. For the same fraction size, an even larger normal tissue sparing can be obtained by prolongation of the HDR overall treatment time. Conclusion : Radiobiologic model calculations presented here aim to demonstrate that hypofractionation in HDR might have its opportunities for widening the therapeutic window, but definitely has its limits. For each specific combination of the parameters, a theoretical optimal HDR fraction size with regard to relative or absolute normal tissue sparing can be estimated, but because of uncertainty in the biologic parameters, these hypofractionation schemes cannot be generalized for all HDR brachytherapy indications.

Failure-specific prognostic factors after continuous hyperfractionated accelerated radiotherapy (CHART) or conventional radiotherapy in locally advanced non-small-cell lung cancer: a competing risks analysis.

The aim of this study was to identify possible failure-specific prognostic factors in non-small-cell lung cancer. Clinical outcome was analysed in 549 patients participating in the randomized controlled trial of CHART vs conventional radiotherapy. Local failure and distant failure with or without concurrent local relapse were subjected to a competing risk analysis using an accelerated failure-time model with a log-logistic hazard function. Randomization to CHART (2 P = 0.005), increasing age (2 P = 0.036) and female sex (2 P = 0.09) was all associated with a prolonged interval to failure. Advanced clinical stage was associated with a decreased interval to failure (2 P = 0.004) and a significantly increased risk (2 P = 0.009) of failing in distant rather than in local position. From this model, prognostic indices for local and distant failure were estimated for each individual patient. Competing risk analysis allows identification of patients with different failure patterns, and may provide a means of stratifying patients for intensified local or systemic therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial

Background and purpose: Early reactions after radiotherapy for head and neck cancer may become the limiting factor in current attempts to intensify loco-regional therapy through altered fractionation or combination of radiotherapy with chemotherapy. The aim of the present study was to quantify the dependence of early reactions on the dose-fractionation used in radiotherapy and on patients’ age and radiation field size. Patients and methods: The data analyzed are from the randomized controlled trial of CHART (continuous hyperfractionated accelerated radiotherapy) vs. conventional radiotherapy in head and neck cancer. The trial accrued 918 patients from March 1990 to April 1995. Several early morbidity items were evaluated weekly for the first 8 weeks after the start of treatment. Weekly evaluation was continued in patients with early reactions extending beyond 8 weeks. Linear regression was used to analyze the time with reactions in individual patients. Polychotomous ordinal response regression was used to analyze the peak grade of early reactions in individual patients. Results: The main findings of this analysis were as follows. (1) The incidence and peak prevalence of confluent mucositis was higher after CHART than after conventional radiotherapy. Therefore, the average time spent with confluent mucositis per patient treated was significantly longer after CHART than after conventional fractionation. (2) In patients who actually developed confluent mucositis, the average duration of this grade of reaction was not significantly different after CHART compared with conventional radiotherapy. (3) Confluent mucositis developed earlier after the start of treatment (2.9 vs. 4.9 weeks) but also started to improve sooner (5.4 vs. 7.5 weeks after the start of treatment) after CHART than after conventional radiotherapy. (4) The dose recovered per 1-day protraction of overall treatment time, D prolif, was estimated at 0.80 Gy with 95% confidence limits 0.7 and 1.1 Gy/day for human mucosa. (5) For human skin erythema, the estimate of D prolif was 0.12 Gy/day with 95% confidence limits -0.12 and 0.22 Gy/day. (6) Highly significant relationships were found between the grade of morphological mucositis on one hand and dysphagia, pain on swallowing and prescribed analgesics on the other. Patients with confluent mucositis had fewer functional problems if this was confined to the larynx as compared with other subsites in the head and neck. (7) Although the incidence of confluent mucositis was higher in the oral cavity and oropharynx than in the hypopharynx and larynx, the radiobiological properties of mucosal reactions did not show significant variation among the various subsites within the head and neck region. (8) For a given dose and overall treatment time, a highly significant increase in incidence and severity of both mucositis and erythema was seen with increasing field size. Thus, a significant dose–volume or dose–area effect exists for both of these tissues. (9) Patients’ age had no significant influence on the incidence and severity of mucositis or erythema. Conclusions: This study provides quantitative estimates of the dose–time and dose–volume relationships for human skin and normal mucosa in the head and neck region based on an analysis of data from 918 patients entered into a randomized-controlled trial of altered dose fractionation in radiotherapy.

High-dose-rate brachytherapy may be radiobiologically superior to low-dose rate due to slow repair of late-responding normal tissue cells

Background and Purpose: Recent analysis of morbidity for patients treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen demonstrates that repair half-times for late-reacting normal tissue cells are of the order of 4–5 h, which is considerably longer than previously believed. This would reduce repair of these tissue cells during a course of low-dose rate (LDR) brachytherapy, but have no effect at high-dose-rate (HDR), where there is no repair during, and full repair between fractions, regardless of repair half-time. The effect this has upon radiobiologic comparison of LDR and HDR is the topic of this paper. Materials and Methods: The linear–quadratic (L–Q) model is used to compare late-effect biologically effective doses (BEDs) of LDR and HDR, for constant BED (tumor). The effects of dose rate (for LDR), fractionation (for HDR), and geometrical sparing of normal tissues are all considered. Repair half-times observed in the CHART study are used to investigate the potential impact of long repair times on the comparison of LDR and HDR. Results: It is demonstrated that, for a repair half-time of 1.5 h for tumor cells, if the half-time for repair of late-reacting normal tissue cells exceeds about 2.5 h, LDR becomes radiobiologically inferior to HDR. Even with the least HDR-favorable combinations of parameters, HDR at over about 5 Gy/fraction ought to be radiobiologically superior to LDR at 0.5 Gy/h, so long as the time between HDR fractions is long compared to the repair half time. It is also shown that any geometrical sparing of normal tissues will benefit HDR more than LDR. Conclusion: The previously held belief that LDR must be inherently superior radiobiologically to HDR is wrong if the long repair times demonstrated in the recent CHART study are applicable to other late-reacting normal tissues. This could explain why HDR has been so successful in clinical practice, especially for the treatment of cervical cancer, despite previous convictions of radiobiologic inferiority of this modality.

A Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer

A Phase II pilot study of continuous hyperfractionated accelerated radiotherapy (CHART)/CHART weekend less (CHARTWEL) was carried out in the postoperative treatment of patients with squamous cell carcinoma of the head and neck.Twenty-four patients (17 male, seven female) with a median age of 64 years (range 34–80) were treated with postoperative radiotherapy between 1991 and 1999. All patients presented with primary squamous cell carcinoma, which, at surgery, had shown adverse pathological factors for recurrence. Intermediate risk was determined by the presence of two of the following factors: margins 5mm, Stage T3/T4, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, and more than four positive lymph nodes. High-risk factors included the presence of extracapsular spread and/or incomplete resection margins, or the presence of four of the factors defining intermediate risk. The patients were treated using a CHART (n = 11) or a CHARTWEL (n = 13) schedule, administering a dose between 49.5Gy and 54Gy.High-risk factors were present in 18/24 patients. Treatment was commenced from a median time of 6.9 weeks (range 4.4–16.6) after radical surgery. All patients completed treatment. A confluent radiation mucositis occurred in 20/23 evaluable patients, which settled in 4–10 weeks after commencing radiotherapy. Moderate dysphagia was observed in 13 patients. Mild subcutaneus oedema was noted in 11 patients from 12 weeks after treatment. No significant late toxicity has been observed. Over a median follow up-period of 17 months, local control has been maintained in 17 patients (71%). Seven patients have relapsed and died of disease. A mean survival of 24 months (range 1–84) has been observed.This pilot study demonstrates acceptable morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy versus conventional fractionation for the radical postoperative treatment of primary head and neck cancer is currently in preparation.