CHART revisited: a conservative approach for advanced head and neck cancer.

AIMS: To evaluate the long-term late adverse effects and treatment outcome in patients treated for advanced squamous cell carcinomas of the head and neck with continuous, hyperfractionated, accelerated radiation therapy (CHART). MATERIALS AND METHODS: One hundred and twenty-six consecutive patients were entered into a non-randomised study of CHART alone with salvage treatment reserved for locoregional recurrence. The primary end points were locoregional control and late treatment-related morbidity. Time-incidence curves and statistical comparisons were obtained by computing actuarial event-free intervals using the product-limit (Kaplan-Meier) method. The prevalence rate of adverse effects was calculated using yearly intervals. Patients have been followed over a 15-year period. RESULTS: The actuarial 12-year locoregional recurrence-free rate after radiotherapy alone was 46%, which was increased by 15% with the use of salvage treatment (hazard ratio for recurrence with CHART alone 1.23, confidence interval 1.017-1.494; P=0.033). Actuarial estimates of severe adverse effects at this time were: dysphagia 12% (grade 4); subcutaneous fibrosis 3%; xerostomia 15%. Ulcers of mucous membranes were observed in 18% of patients. As expected, the prevalence of events was lower than that calculated by the life-table method. CONCLUSIONS: Few, if any, studies have documented and reported on long-term adverse effects and treatment outcomes as in this pilot trial of CHART (median follow-up time of those alive at 5 years or more is 11 years and the maximum follow-up time is 18 years). The low level of moderate to severe long-term morbidity together with a good and maintained level of locoregional tumour control indicates that CHART achieves a therapeutic benefit in patients with advanced squamous cell carcinoma of the head and neck.

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.

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.

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.

bcl-2 expression in head and neck cancer: an enigmatic prognostic marker.

PURPOSE: The role of bcl-2 overexpression in cancer presents a paradox. In some tumor types, it is associated with favorable outcome, whereas in others the reverse is true. The purpose of this study was to explore the influence of bcl-2 in a large series of head and neck cancer patients treated in the CHART randomized trial. METHODS AND MATERIALS: Histologic material was obtained from 400 patients; bcl-2 expression was assessed by immunohistochemistry as either positive or negative cytoplasmic staining. RESULTS: Positivity of bcl-2 was recorded in 12.8% (9.5-16.5%, 95% confidence limits) of tumors. There were significant differences in positive tumors within different sites with nasopharynx showing the highest incidence (46.2%). A multivariate logistic regression analysis showed that bcl-2 was strongly associated with histologic dedifferentiation, as well as increasing N stage and female gender. In univariate analyses, bcl-2 positive patients had a lower locoregional relapse rate (RR 0.57, p = 0.02) and improved survival (RR 0.49, p = 0.004) compared to bcl-2 negative patients; this became more significant in multivariate analysis. CONCLUSION: These data demonstrate that bcl-2 overexpression is a marker of what is considered to be more advanced and aggressive disease yet it is associated with a more favorable outcome irrespective of the treatment schedule.

Translational Research--a new entity?

The term 'Translational Research' has been increasingly used during the past decade. Julie Denekamp defines the term as 'involved with the detailed assessment of the factors influencing tumour specificity of action in order to achieve the successful implementation of a laboratory concept into a clinical protocol'. Translational research needs laboratory and clinical research units with dedicated staff who can work together. Only the careful planning and performance of clinical trials gathering all the data that may relate to the response of tumour and to that of normal tissues will allow advances in knowledge and lead to improvement in the care of patients with cancer.

Morbidity related to axillary irradiation in the treatment of breast cancer.

Some of the most debilitating morbidity after surgery and radiotherapy for breast cancer is related to treatment of the axilla. This includes persistent arm lymphoedema, impaired shoulder mobility and brachial plexopathy. Considerable research efforts have been carried out on the radiation pathogenesis and the clinical radiobiology of these clinical endpoints, which has enabled their severity and incidence to be minimized. It is clear that the radiation dose-response relationships for these late endpoints are very steep. In other words, even small changes in the exact dose fractionation and physical dose distribution can cause major changes in toxicity. In particular, in many treatment schedules dose fractions larger than 2 Gy have been used without a sufficient reduction in total dose to avoid increased late effects. This is important, as much of the available literature reports side effects after suboptimal dose-fractionation schedules and inferior radiotherapy techniques. Such reports are not representative of what can be achieved using modern radiotherapy. An interesting parallelism to the problems encountered in reviewing historical experience is found in the British breast litigation, the current status of which is presented in this article. Furthermore, morbidity after radiotherapy is strongly influenced by concomitant surgery and/or chemotherapy, and this should be allowed for when designing the overall treatment. Apart from other therapeutic modalities, it has been suggested that other exogenous factors have an influence on the risk of radiotherapy-related morbidity. However, patients' age and, in the case of lymphoedema, also obesity are the only factors that have been established with some certainty. Routine adjustment of radiotherapy dose in these cases is not recommended. Two current developments may strengthen the role of radiotherapy in the treatment of breast cancer. Sentinel node biopsy may allow nodal staging without major surgical excision of axillary nodes and this opens the possibility for a more optimal combination of radiotherapy and surgery in the management of the axilla. With more cancers now being detected by systematic screening programmes, this will also increase the possibilities for conservative management, which in most cases involves radiotherapy. In conclusion, the improved understanding of the clinical radiobiology of late sequelae after radiotherapy allows treatment schedules and techniques to be devised that are therapeutically effective while maintaining a minimal risk of serious, late morbidity.

Sweat gland function as a measure of radiation change.

BACKGROUND: Radiotherapy may result in dryness of the skin even when no other change can be detected. We describe a system for recording the electrical conductance of skin as a measure of sweat gland function. PATIENTS AND METHODS: In 22 normal volunteers close agreement was obtained between measurements obtained from comparable sites on both sides of the chest. Measurements were subsequently made in 38 patients treated by radiotherapy to one side of the chest for tumours of the breast or lung using one of five different fractionation schedules. Simultaneous readings were obtained from both sides of the chest with the non irradiated side acting as a control. RESULTS: A dose response relationship was demonstrated: five patients who received the equivalent total dose of 15 Gy in 2-Gy fractions showed no change in conductance. Sixteen out of 23 who received an equivalent total dose of 42-46 Gy in 2-Gy fractions had a greater than 22% reduction in mean skin conductance compared with that of the control areas despite the skin appearing normal in the large majority. Marked changes in skin conductance were seen after higher total doses. In a prospective study 18 women receiving breast irradiation underwent weekly readings during treatment. A mean reduction of 40% in skin conductance was noted by the end of the second week of treatment prior to any clinical evidence of radiation change. Skin conductance returned to normal in 44% of patients by 6 months. In the remainder, those patients who showed the greatest reduction in skin conductance during treatment demonstrated the least recovery. CONCLUSIONS: Changes in sweat gland function can be detected and quantified in skin which may otherwise appear normal. Differences may so be demonstrated between areas treated using different fractionation schedules and the method may be applied to the detection during radiotherapy of unusually sensitive patient.

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 5 mm, 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 49.5 Gy and 54 Gy. 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.

Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee.

BACKGROUND AND METHOD: A randomised controlled trial in locally advanced non-small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of 563 patients were entered between April 1990 and April 1995. This report is based upon the data updated to 1 April 1998. RESULTS: The analysis of the mature data shows that the benefits previously reported have been maintained. Overall there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (P = 0.008) and a 21% reduction in the relative risk of local progression (P = 0.033). In the large subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P = 0.0007) and a 27% reduction in the relative risk of local progression (P = 0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P = 0.025) and 24% reduction in the relative risk of metastasis (P = 0.043). There was no evidence that CHART gave more or less benefit in any other subgroup. CONCLUSION: This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC. This demonstrates the importance of cellular repopulation as a cause of failure in the radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that improved local tumour control, even in lung cancer, can reduce the incidence of metastasis. This trial shows that control of local tumour can lead to an improvement in long term survival.

Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy.

PURPOSE: Late radiation-induced skin effects were studied in a multicenter project using our new sensitive noninvasive viscoelasticity skin analyzer (VESA). METHODS AND MATERIALS: Skin viscoelasticity and anisotropy were examined quantitatively in symmetric areas of both breasts in healthy women and in 110 breast cancer patients who underwent lumpectomy and radiotherapy. These parameters were evaluated by the VESA measurement of the speed of elastic wave propagation in the skin; higher VESA readings correspond to higher skin stiffness. Effect of radiation was estimated by comparison of the data recorded in the irradiated versus nonirradiated breast of the same patient. RESULTS: Skin viscoelasticity and anisotropy were similar in contralateral areas of the breasts in healthy controls as well as in the nonirradiated breasts of the patients. With age, skin viscoelasticity decreased and anisotropy increased similarly in both breasts. Radiotherapy, by a total radiation dose in the range of 45-50 Gy given with 1.8 Gy/fraction (fx) resulted in a similar minor, but still statistically significant, increase of skin stiffness relative to control. The effect was more pronounced when a dose of 50 Gy was given in a higher dose/fraction of 2.5 Gy. CONCLUSION: We found that the increase in dose of radiation per fraction had much more impact on the development of late skin effects than elevation in the total dose given.

Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide.

BACKGROUND: In animal models carbogen (normobaric 95% oxygen, 5% carbon dioxide) provides significant enhancement of local tumor control with fractionated radiotherapy. This approach to radiosensitization has been evaluated in the treatment of patients with bladder carcinoma using radical radiotherapy. METHODS: Sixty-one patients with locally advanced bladder carcinoma were treated using a Phase II trial delivering radiotherapy to the bladder (50-55 Grays in 20 daily fractions over 4 weeks) with inhalation of carbogen alone in 30 patients and the addition of oral nicotinamide (80 mg/kg) prior to radiotherapy with carbogen in 31 patients. The results from these 61 patients were compared with those from two earlier attempts at hypoxic sensitization: the second Medical Research Council (MRC) hyperbaric oxygen trial in patients with bladder carcinoma and a Phase III trial of misonidazole with radiotherapy in patients with bladder carcinoma performed at Mount Vernon Hospital. RESULTS: Although there was no difference between the hyperbaric oxygen and misonidazole trials, when compared with the two earlier series there was a large, statistically significant difference in favor of those patients receiving carbogen with or without nicotinamide for local control (P = 0.00001), progression free survival (P = 0.001), and overall survival (P = 0.04). CONCLUSIONS: Although the advantage for the carbogen group may be explained in part by changes in radiotherapy practice over the period of the three studies the improvement in local control is sufficiently great to support the hypothesis that hypoxia is important in modifying the control of bladder carcinoma using radiation therapy. Further evaluation of accelerated radiotherapy, carbogen, and nicotinamide in patients with bladder carcinoma is needed in a Phase III trial.

The CHART regimen and morbidity.

In 1984, when the CHART regime was devised, it was predicted that acute reactions in skin and mucosae would be more severe but that there would be a considerable reduction of late effects in normal tissues. The findings from the pilot study conducted from 1985 to 1990 and from the randomized trials, which entered cases from 1990 to 1995, are reviewed. With CHART, it was found that acute mucosal reactions were more severe but tolerable and recoverable. Unexpectedly, acute skin reactions were reduced rather than increased. Late reactions in the central nervous system have led to a dose restriction of 40 Gy. Effects in other normal tissues were significantly reduced but the sparing effect was less than that predicted. This can perhaps be explained by a half-time of repair of sublethal injury in human tissues in excess of 4 h.

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

PURPOSE: The 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. MATERIALS AND METHODS: Data 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. RESULTS: From 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). CONCLUSIONS: The 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.