Hyperfractionated Group Research Articles

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Hyperfractionation versus Conventional Fractionation of Preoperative Intensity-Modulated Radiotherapy with Oral Capecitabine in Locally Advanced Mid-Low Rectal Cancer: A Propensity Score Matching Study.

Purpose In theory, the hyperfractionated radiotherapy can enhance biological effect dose against tumor and alleviate normal tissue toxicity. This study is to assess the efficacy and safety of preoperative hyperfractionated intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced rectal cancer (LARC). Methods We retrospectively screened patients with LARC from January 2015 to June 2016. Patients that received hyperfractionated IMRT or conventional fractionated IMRT were eligible in the hyperfractionation (HF) group or conventional fractionation (CF) group, respectively. The primary outcome was the complete response rate. Secondary outcomes included toxicity, postoperative complications, anus-reservation operation rate, local recurrence and distant metastases rate, overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Results 335 patients were included in the analysis. The complete response rate for the hyperfractionated and conventional fractionated IMRT was 20.41% vs. 23.47% (P = 0.583). The anus-reservation operation rate was 68.37% vs. 65.31% (P = 0.649). There were no cases of grade 4 toxicity during radiotherapy; the rate of grade 3 toxicity and postoperative complications was both comparable between groups. However, in the CF group, more patients had a second operation due to complications (0.0% vs. 5.68%, P = 0.011). The cumulative local regional recurrence and distant metastases rates of the HF group and CF group were 5.10% vs. 9.18% (P = 0.267) and 22.45% vs. 24.49% (P = 0.736), respectively. The 5-year OS, CSS, and DFS in the HF group and CF group were 86.45% vs. 73.30% (P = 0.503), 87.34% vs. 75.23% (P = 0.634), and 70.80% vs. 68.11% (P = 0.891), respectively. Conclusions The preoperative hyperfractionated IMRT with oral capecitabine, with an acceptable toxicity and favorable response and survival, could reduce the rate of secondary surgery.

UNCONVENTIONAL FRACTIONATION RADIOTHERAPY REGIMENS IN TREATMENT OF INOPERABLE LUNG CANCER

The purpose of the study was to compare the efficacy and toxicity of hypofractionated versus hyperfractionated radiotherapy in patients with inoperable lung cancer.Material and Methods. Patients with inoperable lung cancer, who were treated between 2014 and 2017, were assigned to undergo radiotherapy in two arms: accelerated hypofractionated conformal radiotherapy arm with 70 patients (60 Gy in 25 fractions, with 2.4 Gy per fraction) and accelerated hyperfractionated radiotherapy with 49 patients (60–70 Gy with 1–1.5 Gy per fraction). At the same time, platinum-based chemotherapy was applied.Results. The rates of partial response, complete response, stable disease and progressive disease were 44.3, 7.2, 38.5 and 10.0 %, respectively in patients with hypofractionated conformal radiotherapy arm. The corresponding values were 71.4, 6.1, 16.4 and 6.1 %, respectively in patients with hyperfractionated radiotherapy arm. The 2-year overall survival rate was 62.8 % for the hypofractionated group and 58.1 % for the hyperfractionated group. Esophagitis III grade was observed in 4 (5.7 %) patients of the hypofractionated group and in 3 (6.5 %) patients of the hypofractionated group. Pneumonitis III grade was reported in 2 (2.9 %) patients in the hypofractionated radiotherapy arm and in 4 (8.7 %) patients in the hyperfractionated radiotherapy arm.Conclusion. Results of the study showed that 3D-conformal hypofractionated radiotherapy combined with concurrent chemotherapy resulted no in severe radiation-induced complications, and demonstrated satisfactory short-and long-term treatment outcomes.

Efficacy and safety of hyperfractionated versus conventionally fractionated chemoradiotherapy for limited-stage small-cell lung cancer: a meta-analysis

Objective To systematically evaluate the differences in efficacy and safety between hyperfractionated and conventionally fractionated radiotherapy for limited-stage small-cell lung cancer (LS-SCLC). Methods A computerized search was performed in PubMed, Embase, Cochrane Library, Web of Science, CBM, Wanfang Data, CNKI, and VIP to collect controlled clinical trials of hyperfractionated versus conventionally fractionated chemoradiotherapy in the treatment of LS-SCLC. The RevMan 5.3 software was used to perform meta-analyses of short-term outcomes, survival data, and adverse events. Results Eight controlled clinical trials involving 1361 patients were enrolled in this study. The results of meta-analysis showed that there were no significant differences in objective response rate or 2-and 5-year overall survival rates between the hyperfractionation group and the conventional fractionation group (odds ratio[OR]=1.31, 95% confidence interval[CI]: 0.64-2.69, P=0.46; risk ratio[RR]=1.10, 95%CI: 0.98-1.24, P=0.12; RR=1.13, 95%CI: 0.75-1.69, P=0.56). Compared with the conventional fractionation group, the hyperfractionation group had a significantly higher incidence of grade ≥2 radiation esophagitis (RR=1.74, 95%CI: 1.39-2.17, P 3 hematological toxicity between the two groups (RR=0.73, 95%CI: 0.24-2.24, P=0.58; RR=1.18, 95%CI: 0.99-1.39, P=0.06). Conclusions In the treatment of LS-SCLC, two fractionation modes show similar short-term efficacy and survival benefits. However, hyperfractionated radiotherapy causes a higher incidence of radiation esophagitis than conventionally fractionated radiotherapy. Given that hyperfractionated radiotherapy is not superior to conventionally fractionated radiotherapy, conventionally fractionated radiotherapy is recommended for treating LS-SCLC. Key words: Carcinoma, small cell lung/radiotherapy; Radiotherapy, hyperfractionated; Radiotherapy, conventionally fractionated; Meta-analysis

Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis

The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8). This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. Institut National du Cancer; and Ligue Nationale Contre le Cancer.

Radiotherapy for diffuse brainstem glioma in children and young adults.

Diffuse brainstem glioma is a devastating disease with very poor prognosis. The most commonly used radiological treatment is conventional fractionated radiation. So far, there is no meta-analysis or systematic review available that assesses the benefits or harms of radiation in people with diffuse brainstem glioma. To assess the effects of conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, and EMBASE to 19 August 2015. We scanned conference proceedings from the International Society for Paediatric Oncology (SIOP), International Symposium on Paediatric Neuro-Oncology (ISPNO), Society of Neuro-Oncology (SNO), and European Association of Neuro-Oncology (EANO) from 1 January 2010 to 19 August 2015. We searched trial registers including the International Standard Randomised Controlled Trial Number (ISRCTN) Register, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the register of the National Institutes of Health to 19 August 2015. We imposed no language restrictions. All randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) that compared conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem glioma in children and young adults aged 0 to 21 years. Two review authors independently screened studies for inclusion, extracted data, assessed the risk of bias in each eligible trial, and conducted GRADE assessment of included studies. We resolved disagreements through discussion. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified two RCTs that fulfilled our inclusion criteria. The two trials tested different comparisons.One multi-institutional RCT included 130 participants and compared hyperfractionated radiotherapy (six-week course with twice a day treatment of 117 cGy per fraction to a total dose of 7020 cGy) with conventional radiotherapy (six-week course with once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy). The median time overall survival (OS) was 8.5 months in the conventional group and 8.0 months in the hyperfractionated group. We detected no clear evidence of effect on OS or event-free survival (EFS) in participants receiving hyperfractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.75 to 1.53; EFS: HR 1.26, 95% CI 0.83 to 1.90). Radiological response (risk ratio (RR) 0.94, 95% CI 0.54 to 1.63) and various types of toxicities were similar in the two groups. There was no information on other outcomes. According to the GRADE approach, we judged the quality of evidence to be low (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e. we are very uncertain about the estimate) for radiological response and toxicities.The second RCT included 71 participants and compared hypofractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy per fraction) with conventional radiotherapy (54 Gy in 30 fractions over six weeks, 1.8 Gy per fraction). This trial reported a median OS of 7.8 months for the hypofractionated group and 9.5 months for the conventional group. It reported a progression-free survival (PFS) of 6.3 months for the hypofractionated group and 7.3 months for the conventional group. We found no clear evidence of effect on OS (HR 1.03, 95% CI 0.53 to 2.01) or PFS (HR 1.19, 95% CI 0.63 to 2.22) in participants receiving hypofractionated radiotherapy when compared with participants receiving conventional radiotherapy. The mainly observed adverse effect was local erythema and dry desquamation especially behind the auricles. There were some other toxicities, but there was no statistically significant difference between treatment groups. There was no information on other outcomes. We judged the quality of evidence to be moderate (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) for OS, and low for PFS and toxicities. It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical power for a clinically relevant outcome. We could make no definitive conclusions from this review based on the currently available evidence. Further research is needed to establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults. Future RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration. Moreover, international multicentre collaboration is encouraged. Considering the potential advantage of hypofractionated radiotherapy to decrease the treatment burden and increase the quality of remaining life, we suggest that more attention should be paid to hypofractionated radiotherapy.

Effects of Preoperative Conventional and Hyperfractionated Radiotherapy on the Healing of Rat Colonic Anastomoses

Background: One problem associated with end to end anastomoses after preoperative radiotherapy is leakage. The strength of the anastomoses is very important. Fractionation schedules are widely under investigation to achieve higher doses with less toxicity and high curative potential. The aim of this study was to compare preoperative conventional and hyperfractionated radiotherapy effects on anastomoses. Materials and Methods: Sixty Wistar albino rats were divided into 3 groups: control, conventional radiotherapy (2 Gy/fraction, total 44 Gy), and hyperfractionated radiotherapy (1.2 Gy/fraction, total 52.8 Gy). 5 weeks after completion of the treatment, the rats underwent end to end anastomoses to the rectum. Following the surgery, the bursting pressure of the anastomoses and the hydroxyproline levels were measured on days 3 and 7. Results: The bursting pressure was lower in both radiotherapy groups on the 3rd day. On day 7, the results of the conventional radiotherapy arm matched those of the control group, but the results of the hyperfractionated group did not (p = 0.001). On day 3, hydroxyproline levels were significantly lower in both radiotherapy groups than in the control group (p = 0.001). On the 7th day, the statistical difference disappeared within the radiotherapy groups. However, the hydroxyproline levels of the 2 radiotherapy arms were still lower than those of the control group (p = 0.001). Conclusion: Hyperfractionation strongly inhibits collagen synthesis and is associated with protracted healing.

喉頭癌放射線治療に伴う疼痛の検討

Radiation therapy in those with head and neck malignancies often triggers painful mucositis poorly controlled by nonsteroidal antiinflammatory drugs (NSAIDs). To better understand how radiation-induced pain develops over time, we studied the numerical rating scale (NRS 0-5) pain scores from 32 persons undergoing radiation therapy of 60-72 Gy for newly diagnosed laryngeal cancer. The degree of mucositis was evaluated using Common Terminology Criteria for Adverse Events version3.0 (CTCAE v3.0). We divided the 32 into a conventional fractionation (CF) group of 14 and a hyperfractionation (HF) group of 18, and further divided laryngeal cancer into a small-field group of 23 and a large-field group of 9. The mucositis pain course was similar in CF and HF, but mucositis pain was severer in the HF group, which also required more NSAIDs. Those in the large-field group had severer pain and mucositis and required more NSAIDs than those in the small-field group. We therefore concluded that small/large-field radiation therapy, rather fractionation type, was related to the incidence of radiation-induced mucositis pain.

The effect of pre-operative conventional and hyperfractionated radiotherapy schedules on wound healing and tensile strength in rats: an experimental study

We examined the effects of pre-operative conventional and hyperfractionated radiotherapy schedules on wound healing and tensile strength in 90 female Wistar rats weighing between 182 and 240 g. The animals were randomized into three groups ( n = 30 each). Group I was sham-irradiated. Group II (conventional) received 20 daily fractions of 200 cGy, to a total dose of 4000 cGy. Group III (hyperfractionated) received 40 fractions of 120 cGy, twice daily, to a total dose of 4800 cGy. Four weeks after radiotherapy, incision and primary repair with simple suturing was performed on one side of the neck. Twenty-one days after wounding, all the rats were sacrificed. Non-parametric Kruskal–Wallis and Mann–Whitney U-tests were used for the statistical analysis of wound tensile strength. The chi-squared test was used for the statistical analysis of the histopathologic findings. The hyperfractionated group had a significantly lower tensile strength than that of the control group ( P = 0.03, z=–2.18). According to the histopathologic findings, fibrosis was increased significantly in the hyperfractionated group as compared to the other groups ( P = 0.038, χ 2 = 6.52). Hyperfractionated radiotherapy significantly reduced the wound tensile strength in the early evaluation period as compared to the control group.

Different risks of symptomatic brain necrosis in NPC patients treated with different altered fractionated radiotherapy techniques

Purpose: To report our observation of excessive temporal lobe necrosis in nasopharyngeal carcinoma (NPC) patients treated with 160 cGy b.i.d. radiotherapy technique. During the same period, patients treated with 120 cGy b.i.d. have not shown a similar tendency. Our experience may be useful for designing unconventional radiotherapy regimens for NPC patients.Methods and Materials: During the period from October 1991 to January 1998, 81 M0, previously untreated NPC patients completed altered fractionated radiotherapy. Seventy patients were treated with the hyperfractionated technique, and 11 were treated using the accelerated-hyperfractionated scheme. Hyperfractionated radiotherapy was delivered using 120 cGy b.i.d. separated by 6-h intervals throughout the course. A minimum tumor dose of 8000 cGy was the standard dose over an 8-week period. With the accelerated-hyperfractionated scheme, 160 cGy was given twice daily, also with an interval of 6 h. The minimum tumor dose ranged between 6840 and 7640 cGy, with 7 of the 11 patients receiving 7000 cGy. The arrangement of portals was the same for both regimens. The follow-up period for patients alive was from 32 to 102 months with a median of 61 months for the hyperfractionated patients. For the accelerated-hyperfractionated group, it ranged from 67 to 82 months with a median of 72 months. No patient was lost to follow-up.Results: At the time of analysis, 49 of the 70 patients in the hyperfractionated group were alive. In the accelerated group, 8 of the 11 patients were alive. The estimated radiation dose to the temporal lobe for the hyperfractionated group was 6000–7440 cGy with a median of 7080 cGy. For the accelerated-hyperfractionated group, the dose range was 4480–6700 cGy with a median of 6400 cGy. Of the 70 patients treated with hyperfractionated radiotherapy, none developed symptomatic brain necrosis, despite the higher total dose to the temporal lobe in general. In contrast, 3 of the 11 (27%) patients irradiated using the accelerated-hyperfractionated regimen suffered from temporal lobe necrosis at 16, 19, and 40 months after completion of radiotherapy.Conclusion: An excessive incidence of temporal lobe necrosis was noted when an accelerated-hyperfractionated regimen with 160 cGy b.i.d. was used in NPC patients with a median brain dose of 6400 cGy. There has been no such event in patients treated using a hyperfractionated regimen with 120 cGy and a median brain dose of 7000 cGy. The real causes of this discrepancy are not known. However, a high sensitivity of the human brain to a change in fraction size may play a role.

Hyperfractionation in carcinoma of the cervix: tumor control and late bowel complications

Purpose: Hyperfractionation has been advocated to improve local tumor control by increasing radiation dose without increasing late normal tissue complications. The aim of this study was to determine if hyperfractionation decreased late bowel complications. Methods and Materials: Thirty patients with Stage II and III cervical cancer were randomized to receive either hyperfractionation or conventional fractionation. Patients were followed for 5 years and monitored for tumor control, recurrence, and bowel complications. The relative risks of tumor control and bowel complications were computed at 1 year and 5 years of follow-up. Kaplan-Meier survival curves were plotted to determine probabilities of being tumor-free and bowel complication–free. Results: There were 15 patients in each group. At 1 year of follow-up, 2 patients in the hyperfractionation group (13%) and 7 patients in the conventional treatment group (45%) had tumor (relative risk [RR] 0.3; 95% confidence interval [CI] 0.1, 1.1; p = 0.054). Delayed bowel complications were seen in 8 patients in the hyperfractionation group and 1 patient in the conventional treatment group (RR 7.5; 95% CI 1.1, 52; p = 0.014). At 5 years, 2 patients in the hyperfractionation group and 8 patients in the conventional treatment group had tumor (RR 0.3; 95% CI 0.1, 1.1; p = 0.04). Delayed bowel complications (Grades 2 and 3) occurred in 9 women in the hyperfractionation group and 2 patients in the conventional group (RR 5.4; 95% CI 1.5, 19.5; p = 0.0006). Kaplan-Meier analysis showed that the hyperfractionation group had significantly more bowel complications over the 5 years of follow-up ( p = 0.024). Conclusion: Hyperfractionation may result in better tumor control both at 1 year and at 5 years following treatment of cervical cancer. However, hyperfractionation could lead to increased late bowel complications and must be used judiciously in the treatment of cervical cancer.

Late course accelerated fractionation in radiotherapy of esophageal carcinoma

Purpose: To evaluate the efficacy of adding accelerated fractionation after completing two thirds of routine fractionated radiotherapy in esophageal carcinoma.Methods and materials: From April 1988 to April 1990, 85 patients with histologically confirmed carcinoma of the esophagus were randomized into two groups. (1) The conventional fractionation (CF) group, received 1.8 Gy per day five times a week to a total dose of 68.4 Gy in 7–8 weeks, and (2) the late course accelerated hyperfractionated (LCAF) group which received the same schedule as the CF group during the first two thirds of the course of radiotherapy to a dose of 41.4 Gy/23 fx/4 to 5 weeks. This was then followed by accelerated hyperfractionation using reduced fields. In the LCAF portion of the radiotherapeutic course, the irradiation schedule was changed to 1.5 Gy twice a day, with an interval of 4 h between fractions, to a dose of 27 Gy/18 fx. Thus the total dose was also 68.4 Gy, the same as the CF group, but the course of radiotherapy was shorter, being only 6.4 weeks. The same Cobalt 60 teletherapy unit was used to treat all the cases.Results: The 5 year actuarial survival and disease-free survival rates in the LCAF group were 34% and 42%, as compared to 15% and 15% respectively in the CF group, all statistically significant. Better local control was seen in the LCAF group than in the CF group, the 5 year control rates being 55% versus 21% (P=0.003). The acute reactions were increased but acceptable in the LCAF patients, the radiation treatments could be completed without any breaks. The late reactions as observed after 5 years were not increased in comparison with the CF patients.Conclusions: The results from this study show that the late course accelerated hyperfractionated radiotherapy regime can improve results in esophageal carcinoma, with acceptable acute reactions as compared to conventional radiotherapy.

Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood.

The purpose of this study was to investigate autonomic regulation of neurocardiac function in survivors of acute lymphoblastic leukemia (ALL) in childhood, through power spectral and time domain analyses of the heart rate variability signal. Studies were conducted on 34 unselected patients and 34 age matched controls. Patients were in remission, off therapy for at least 20 months and from high risk (HR, n=21) and standard risk (SR, n=13) groups as described by Dana-Farber Cancer Institute protocols 87-01 and 91-01. Twenty-nine patients had received cranial irradiation, 7 on a hyperfractionated schedule. Power spectral analysis of the heart rate (PS/HRV) was performed on 30 min heart rate time series and time domain statistics were computed from 24 h Holter recordings. Left ventricular function was assessed by measuring ejection and shortening fractions on echocardiography. All such measures were normal. Analysis of PS/HRV revealed that the supine low frequency: high frequency (LF:HF) area ratio was elevated in patients compared to controls. Changes in the LF and HF power on standing were attenuated in the patients compared to controls. Circadian analysis revealed a depressed diurnal rhythm of heart rate in the patients. Those from the SR group showed greater reduction of the LF power response to orthostatic stress and a reduced circadian rhythm of the heart rate compared to those with HR ALL. Patients from the HR group showed reductions in both HF and LF power responses to orthostasis compared to controls. Elevated supine LF power and depressed circadian variation in the HF power band were evident only in female subjects. Patients who received standard cranial irradiation had higher LF:HF area ratio and diminished LF and HF power responses to orthostatic stress than did subjects in the hyperfractionated group. These findings suggest that the autonomic nervous regulation of the heart is compromised in patients treated for ALL in childhood even when resting echocardiographic measures provide no evidence of cardiac decompensation. The extent of neurocardiac dysfunction is influenced by risk status, gender and schedule of cranial irradiation.

Hyperfractionation in advanced carcinoma of the uterine cervix: A preliminary report

Experience with twice-a-day radiation therapy program for carcinoma of the uterine cervix (FIGO Stages IIB, IIIA & IIIB) is presented. The program consists of delivering 120 cGy per fraction, two fractions a day with 6 hours between fractions. A total of 6000 cGy was delivered in 50 fractions over 5 weeks. A control group was given conventional fractionation 5000 cGy in 25 fractions, 200 cGy per fraction over 5 weeks. This feasibility study enrolled 30 patients, 15 in each group. Normal tissue reactions in skin, mucosa and bowel were recorded. The acute normal tissue reactions were enhanced in the hyperfractionation group. This was significant with regard to the bowel complications. The tumor control rate did not show any significant difference between the two groups. A short follow-up period has revealed complete healing of all acute normal tissue reactions. This study shows that further dose escalation is feasible and a study with large sample size and longer follow-up is required to reach definite conclusions.

194 Hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: A radiation therapy oncology group study

Hepatocellular carcinoma is known to have a doubling time of approximately 41 days. This rapid cell division suggested that hyperfractionated radiation and chemotherapy might add an advantage in gaining remission of this malignancy. One hundred and thirty-five patients (70% with metastasis and/or previous treatment) were prospectively treated with single daily fractions to the liver (3.0 Gy external beam radiation, total dose 21.0 Gy), and chemotherapy for hepatocellular carcinoma. The low dose chemotherapy used in conjunction with the radiation was 2 hr before treatment on days 1, 3, 5, and 7 and consisted of Adriamycin, 15 mg IV and 5-FU, 500 mg IV. These patients were compared to a second group of 59 patients (80% with metastases and/or previous treatment) treated using the same chemotherapy regimen but using hyperfractionated whole liver external beam irradiation (1.2 Gy twice daily, 4 hr between treatments, 5 days per week to 24.0 Gy, 10 MV photons). Response was determined by CT scan tumor volumetric analysis. The response rate for the single daily fraction patient group was 22% and for the new hyperfractionated group, 18% ( p = 0.68). Toxicity was evaluated by RTOG criteria. The grade 4 hematologic toxicity noted in the daily fraction patient group was 6%. Among 59 patients treated with the hyperfractionated liver irradiation, 2% experienced grade 4 hematologic toxicity. Esophagitis occurred in 1% of patients in the standard fractionation group and 19% in the hyperfractionated group ( p = 0.0001). Grade 1–4 thrombocytopenia occurred in 49% of patients in the conventional group and 68% in the hyperfractionated group ( p = 0.03). Normal liver volume changes with treatment were measured with CT scan tumor volumetric analysis. The hyperfractionated group experienced a median of 11 cc increase in liver volume and the conventional group a 46 cc decrease, but the difference was not significant. Hyperfractionated radiation did not demonstrate a significant benefit over standard daily radiation, but acute toxicity appeared to be higher.