Altered Fractionation Schedules Research Articles

Evidence-based organ-sparing radiotherapy in head and neck cancer

Intensification of radiotherapy treatment for locally advanced head and neck cancer by use of altered fractionation schedules or concomitant chemotherapy has resulted in substantially improved locoregional control and survival. However, these improvements have come at the cost of increased acute, and late, toxic effects. The application of technological advances, such as intensity-modulated radiotherapy, is expected to further improve the therapeutic index of radiotherapy for head and neck cancer, by limiting toxicity and possibly by increasing locoregional control. However, the organ-sparing potential of such highly conformal radiotherapy techniques relies heavily on the appropriate selection and accurate delineation of the crucial organs at risk, with the application of rigorous dose constraints during planning. Because xerostomia and dysphagia are the main causes of decreased quality of life after radiotherapy for head and neck cancer, the prevention of these two complications will form the focus of this review.

The role of amifostine in the treatment of head and neck cancer with cisplatin-radiotherapy

Although head and neck cancer is not one of the most common cancers, it is a debilitating disease with poor prognosis and considerable post-treatment normal tissue toxicity. The unremitting search to increase the therapeutic ratio between tumour control and late normal tissue injury led to the adoption of altered fractionation schedules. While the increase in acute toxicity can be managed with appropriate medical support, damage produced to late responding tissues is usually irreversible, therefore clinically unacceptable. By altering the conventionally fractionated radiotherapy both loco-regional control and overall survival are increased. Moreover, phase III randomized trials indicated that the combined administration of cisplatin and radiotherapy further improves treatment outcome. Although the uptake of cisplatin in normal cells is not amplified by the combined modality treatment, cisplatin, by itself is a highly cytotoxic agent. Therefore, the need for normal tissue protection has arisen. Amifostine is a selective, radio-protective drug used in both radiotherapy and chemotherapy to reduce normal tissue toxicity. This paper provides an overview of clinical trials employing cisplatin-radiotherapy treatment for advanced head and neck cancer with specific focus on normal tissue toxicity. The emerging role of radioprotectors and furthermore, the effectiveness of amifostine in combined cisplatin-radiotherapy trials are presented.

Radiobiological modeling of interplay between accelerated repopulation and altered fractionation schedules in head and neck cancer

Head and neck cancer represents a challenge for radiation oncologists due to accelerated repopulation of cancer cells during treatment. This study aims to simulate, using Monte Carlo methods, the response of a virtual head and neck tumor to both conventional and altered fractionation schedules in radiotherapy when accelerated repopulation is considered. Although clinical trials are indispensable for evaluation of novel therapeutic techniques, they are time-consuming processes which involve many complex and variable factors for success. Models can overcome some of the limitations encountered by trials as they are able to simulate in less complex environment tumor cell kinetics and dynamics, interaction processes between cells and ionizing radiation and their outcome. Conventional, hyperfractionated and accelerated treatment schedules have been implemented in a previously developed tumor growth model which also incorporates tumor repopulation during treatment. This study focuses on the influence of three main treatment-related parameters, dose per fraction, inter fraction interval and length of treatment gap and gap timing based on RTOG trial data on head and neck cancer, on tumor control. The model has shown that conventionally fractionated radiotherapy is not able to eradicate the stem population of the tumor. Therefore, new techniques such as hyperfractionated/ accelerated radiotherapy schedules should be employed. Furthermore, the correct selection of schedule-related parameters (dose per fraction, time between fractions, treatment gap scheduling) is crucial in overcoming accelerated repopulation. Modeling of treatment regimens and their input parameters can offer better understanding of the radiobiological interactions and also treatment outcome.

Defining the margins in the radical radiotherapy of non-small cell lung cancer (NSCLC) with active breathing control (ABC) and the effect on physical lung parameters

Background The effectiveness of ABC has been traditionally measured as the reduction in internal margin (IM) within the planning target volume (PTV). Not to overestimate the benefit of ABC, the effect of patient movement during treatment also needs to be taken into account. We determined the IM and set-up error with ABC and the effect on physical lung parameters compared to standard margins used with free breathing. We also assessed interfraction oesophageal movement to determine a planning organ at risk volume (PRV). Materials and methods Two sequential studies were performed using ABC in NSCLC patients suitable for radical radiotherapy (RT). Twelve out of 14 patients in Study 1 had tumours visible fluoroscopically and had intrafraction tumour movement assessed with and without ABC. Sixteen patients were recruited to Study 2 and had interfraction tumour movement measured using ABC in a moderate deep inspiration breath-hold, of these 7 patients also had interfraction oesophageal movement recorded. Interfraction movement was assessed by CT scan prior to and in the middle and final week of RT. Displacement of the tumour centre of mass and oesophageal borders relative to the first scan provided a measure of movement. Set-up error was measured in 9 patients treated with an in-house lung board adapted for the ABC device. Combining movement and set-up errors determined PTV and PRV margins with ABC. The effect of ABC on mean lung dose (MLD), lung V 20 and V 13 was calculated. Results ABC in a moderate deep inspiration breath-hold was tolerated in 25 out of 30 patients (83%) in Study 1 and 2. The random contribution of periodic tumour motion was reduced by 90% in the y direction with ABC compared to free-breathing. The magnitude of motion reduction was less in the x and z direction. Combining the systematic and random set-up error in quadrature with the systematic and random intrafraction and interfraction tumour variations with ABC results in a PTV margin of 8.3 mm in the x direction, 12.0 mm in the y direction and 9.8 mm in the z direction. There was a relative mean reduction in MLD, lung V 20 and V 13 of 25%, 21% and 18% with the ABC PTV compared to a free-breathing PTV. Oesophageal movement combined with set-up error resulted in an isotropic PRV of 4.7 mm. Conclusions The reduction in PTV size with ABC resulted in an 18–25% relative reduction in physical lung parameters. PTV margin reduction has the potential to spare normal lung and allow dose-escalation if coupled with image-guided RT. The oesophageal PRV needs to be considered when irradiating central disease and is of increasing importance with altered RT fractionation and concomitant chemoradiation schedules. Further reductions in PTV and PRV may be possible if patient set-up error was minimised, confirming that attention to patient immobilisation is as important as attempts to control tumour motion.

Accelerated partial breast irradiation: An advanced form of hypofractionation

Altered fractionation schedules are being increasingly investigated in the treatment of breast cancer. Two such schedules that are frequently compared are hypofractionated external beam radiation therapy (HERT) and accelerated partial breast irradiation (APBI). Though these two modalities are considered separately, APBI is an actually an advanced form of hypofractionation, where acceleration of the treatment is possible due to the smaller volume being irradiated. HERT as well as APBI are investigational at present and are being tested in randomized trials. This article looks at the advantages of APBI as a hypofractionation schedule.

Pretreatment Quality of Life Predicts for Locoregional Control in Head and Neck Cancer Patients: A Radiation Therapy Oncology Group Analysis

To analyze the prospectively collected health-related quality-of-life (HRQOL) data from patients enrolled in two Radiation Therapy Oncology Group randomized Phase III head and neck cancer trials (90-03 and 91-11) to assess their value as an independent prognostic factor for locoregional control (LRC) and/or overall survival (OS). HRQOL questionnaires, using a validated instrument, the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N), version 2, were completed by patients before the start of treatment. OS and LRC were the outcome measures analyzed using a multivariate Cox proportional hazard model. Baseline FACT-H&N data were available for 1,093 patients and missing for 417 patients. No significant difference in outcome was found between the patients with and without baseline FACT-H&N data (p = 0.58). The median follow-up time was 27.2 months for all patients and 49 months for surviving patients. Multivariate analyses were performed for both OS and LRC. Beyond tumor and nodal stage, Karnofsky performance status, primary site, cigarette use, use of concurrent chemotherapy, and altered fractionation schedules, the FACT-H&N score was independently predictive of LRC (but not OS), with p = 0.0038. The functional well-being component of the FACT-H&N predicted most significantly for LRC (p = 0.0004). This study represents, to our knowledge, the largest analysis of HRQOL as a prognostic factor in locally advanced head and neck cancer patients. The results of this study have demonstrated the importance of baseline HRQOL as a significant and independent predictor of LRC in patients with locally advanced head and neck cancer.

Risk, Outcomes, and Costs of Radiation-Induced Oral Mucositis Among Patients With Head-and-Neck Malignancies

To study the risk, outcomes, and costs of radiation-induced oral mucositis (OM) among patients receiving radiotherapy (RT) to head and neck primary cancers. A retrospective cohort consisting of 204 consecutive head-and-neck cancer patients who received RT with or without chemotherapy during 2002 was formed; their records were reviewed for clinical and resource use information. Patients who had received prior therapy, had second primary cancers, or received palliative radiation therapy were excluded. The risk of OM was analyzed by multiple variable logistic regression. The cost of care was computed from the provider's perspective in 2006 U.S. dollars and compared among patients with and without OM. Oral mucositis occurred in 91% of patients; in 66% it was severe (Grade 3-4). Oral mucositis was more common among patients with oral cavity or oropharynx primaries (odds ratio [OR], 44.5; 95% confidence interval [CI], 5.2 to >100; p < 0.001), those who received chemotherapy (OR = 7.8; 95% CI, 1.5-41.6; p = 0.02), and those who were treated with altered fractionation schedules (OR = 6.3; 95% CI, 1.1-35.1; p = 0.03). Patients with OM were significantly more likely to have severe pain (54% vs. 6%; p < 0.001) and a weight loss of > or =5% (60% vs. 17%; p < 0.001). Oral mucositis was associated with an incremental cost of $1700-$6000, depending on the grade. Head-and-neck RT causes OM in virtually all patients. Oral mucositis is associated with severe pain, significant weight loss, increased resource use, and excess cost. Preventive strategies are needed.

Early Reactions as Dose-Limiting Factors in Radiotherapy.

Early side effects of radiation therapy are generally the result of mitotic-linked cell death in rapidly renewing tissues and secondary impaired tissue function. Various types of acute normal tissue reactions are briefly summarized in this article. In general, with conventionally fractionated radiation treatment, the acute normal tissue reactions are within acceptable limits. However, new radiotherapy strategies, such as hyperfractionation and accelerated fractionation, induce more severe acute toxicity. Particularly, with most altered fractionation schedules, the mucosal reaction of the upper aerodigestive tract is elevated to the upper limit of tolerance. Early mucosal reactions may also become dose limiting when radiation is combined with chemotherapy as, for instance, for the treatment of head and neck cancer or pelvic neoplasms. Bone marrow is the critical organ for combination of chemotherapy and wide field irradiation. There is an increasing body of evidence that iatrogenic acute normal tissue toxicity has become a major obstacle for treatment intensification for a variety of cancers. Therefore, effective measures to ameliorate these side effects are essential for further development of cancer therapy. Methods to reduce the severity of acute toxicity are being investigated.

188 Radiobiological modelling of the interplay between accelerated repopulation and altered fractionation schedules in head and neck cancers

188 Radiobiological modelling of the interplay between accelerated repopulation and altered fractionation schedules in head and neck cancers

Improving the morbidity of anorectal injury from pelvic radiotherapy

Radiation anorectal injury due to pelvic radiotherapy for non intestinal cancer is a significant cause of morbidity which may limit the treatment dose required. Conservative treatment options are of limited value and surgery is reserved only for the most severe complications. This review addresses radioprotection of the anorectum and aims to increase awareness amongst surgeons of the strategies that have been in practice in order to minimize the side-effects of radiotherapy while preserving its therapeutic efficacy. This review is based on a literature search (Medline and NLM PubMed) with manual cross-referencing of all articles related to anorectal radiation injury. Optimization of radiation dose, the use of radioprotective agents and improvement in radiation delivery are the main areas of development. There are few data on the potential of altered fractionation schedules in reducing anorectal injury. A few phase I and II studies suggest that the pharmacological agents amifostine and misoprostol could be beneficial in limiting radiation damage but larger phase III studies are awaited. The introduction of 3-dimensional conformal radiation therapy and intensity modulated radiation therapy has been the most significant advance in reducing radiation morbidity.

The Role of Altered Fractionation in Head and Neck Cancers.

At the present time, the only rigorously demonstrated therapeutic gain from altered fractionation in the treatment of head and neck cancer is in patients with intermediate stage oropharyngeal cancer treated with hyperfractionation in the Phase III EORTC Trial 2279 I.’ Nevertheless, there is a compelling radiobiological rationale and abundant suggestive evidence from a number of other clinical studies that a therapeutic gain may be realized more generally when conventional fractionation is modified by either reduction in size of dose per fraction, reduction in overall duration of the treatment, or both. This article will briefly review the background radiobiology of altered fractionation schedules and the clinical results that have been reported. The term “altered fractionation” is a relative one, because from the earliest days of radiotherapy there has been lack of agreement as to what constitutes the “norm.” Regimens regarded as conventional differ widely in different parts of the world. For example, in the Manchester school, radical (ie, definitive) treatments for head and neck cancer are dispensed in 16 fractions over 3 weeks while in the United States, most definitive treatments are administered in 35 to 40 fractions over 7 to 8 weeks. Many other variations exist in what is considered conventional therapy. To a large extent, the evolution of “conventional” dose fractionation schedules reflects logistic and financial considerations and the availability of equipment and staff as much as any serious effort to determine which fractionation schedule maximizes the therapeutic advantage. 2,3 Many schedules now considered unconventional have had their proponents in the past, but only recently has sufficient information been available to assess the merits of different fractionation schedules on a radiobiologic basis.

New Approaches to Postoperative Radiotherapy for Cancer of the Head and Neck

Historically, patients with resectable stage III and IV tumors were treated with combined surgery and radiation. Early attempts at improving results by incorporating chemotherapy in the postoperative setting have been largely unsuccessful or inconsistent. However, longer follow-up of recent landmark trials exploring concurrent chemotherapy and radiotherapy have clarified the issue, supporting concurrent cisplatin based chemotherapy for high risk patients. The survival benefit seen in the concurrent chemoradiotherapy trials appears to stem from improved locoregional control, as no reduction in systemic failure has been observed. Another evolving approach to post-operative head and neck radiotherapy is the use of altered fractionation schedules. There are several recent studies exploring either hyperfractionated or accelerated radiotherapy, as a response to the issue of accelerated tumor repopulation, providing evidence that such treatment is beneficial in selected patients. There are several questions worthy of further clinical research, and these will likely continue to follow the lead of nonsurgically managed head and neck cancer. Preliminary data suggests that IMRT can be tailored to postoperative patients, and target volumes defined such that morbidity can be minimized without jeopardizing tumor control. Biological modifiers of radiotherapy may allow selective radiosensitization without the morbidity of concurrent chemotherapy.

Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects?

Improving the outcome for patients with locally advanced head and neck carcinomas (HNC) by rational modification of radiation fractionation regimens or combinations of radiation with chemotherapy has been the subject of intensive clinical investigations for more than three decades. The two prototypes of biologically sound-altered radiation fractionation regimens are hyperfractionation and accelerated fractionation. Hyperfractionation was based on preferential sparing of late-responding tissues when the radiation dose per fraction is reduced. Accelerated fractionation regimens emerged through the recognition that tumor clonogen proliferation occurring during radiotherapy has a detrimental effect on outcome. Results of large randomized trials addressing the optimization of radiation fractionation collectively show that a number of biologically sound altered fractionation schedules improve the locoregional (LR) control rate on the order of 10% to 15%, but have only a modest impact on overall survival. Although several altered fractionation regimens consistently induce more severe acute mucositis than standard 7-week radiotherapy, the general consensus is that late toxicities are not appreciably increased. Scores of clinical trials testing combined-modality therapy have also been published. Meta-analyses of studies completed before 1995 reveal that cytotoxic agents given before or after surgery or radiation do not significantly improve the therapeutic outcome over LR treatment alone. In contrast, chemotherapy given concurrently with radiation improves 2and 5-year overall survival rates by 8%. Although a variety of cytotoxic agents have been studied, cisplatin is the most extensively investigated, and will be the emphasis of this commentary. The data from four recent trials using standard radiation fractionation, with or without high-dose single-agent cisplatin given every 3 weeks, in the treatment of locally advanced non-nasopharyngeal HNC have been reported in the last 2 years. All four trials showed that the combined regimen was superior to radiation therapy alone in LR control or organ preservation; two trials also showed improvement in overall survival. A common finding, however, is that 100 mg/m of cisplatin given every 3 weeks during the course of radiotherapy substantially increases the severity of mucositis, apparently more so than altered fractionation regimens without chemotherapy. In addition, cisplatin induces systemic toxicity requiring intensive premedication and supportive care. Unfortunately, recording and reporting of the late morbidity of combined radiation-chemotherapy have not been sufficiently consistent and systematic. A thorough report of the long-term results of a French cooperative group (French Head and Neck Oncology and Radiotherapy Group [GORTEC]) trial revealed that the late complication rate of the combination of radiation with concurrent carboplatin and fluorouracil was significantly higher than that of radiation alone. Due to a lack of adequate reporting, there is controversy as to whether the late toxicity of the combination of standard radiation with 100 mg/m of cisplatin every 3 weeks might also be higher than radiation alone. Hopefully, longer and more complete follow-up data on late morbidities will be reported in the future. Although the collective data are strong in establishing the superiority of the combination of radiation with concurrent chemotherapy relative to standard radiation fractionation alone in the management of locally advanced HNC, there is variability of clinical trials in patient selection and regimens, leading to continuing debate as to which combined regimen should be considered standard. Furthermore, many questions remain to be answered, including whether the cisplatin dose can be altered to reduce acute JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004

Radiation therapy for early-stage carcinoma of the oropharynx

Purpose To evaluate the outcomes of radiation therapy treatment of patients with Stage I and II squamous cell carcinoma (SCC) of the oropharynx and discover adverse prognostic factors that may help select a subgroup of patients for a different management approach. Methods and materials A search of the database maintained by the Department of Radiation Oncology of The University of Texas M. D. Anderson Cancer Center for patients with Stage I or II SCC of the oropharynx was performed. This search identified 175 patients treated between 1970 and 1998 who met the inclusion criteria for this retrospective study. Distribution of primary sites was: tonsillar fossa/pillar, 60 patients; soft palate, 55 patients; base of tongue, 40 patients; and pharyngeal wall, 20 patients. Twenty-five patients were stage T1, 124 were T2, and 26 were Tx. All patients were treated with fractionated radiation to a median dose of 66 Gy. Eighty-five patients were treated with conventionally fractionated radiation, 73 were treated with the concomitant boost fractionation schedule, and the remaining 17 were treated with other altered fractionation schedules or with intraoral or interstitial boosts. Results The median follow-up for all patients was 76 months (range, 2–302 months). The actuarial 5-year local control (LC), regional control, locoregional control (LRC), and disease-free survival (DFS) rates were 85%, 93%, 81%, and 77%, respectively. Only 7 patients (5%) with LC developed nodal metastases, and 10 patients (7%) with LRC developed distant metastases. Eleven patients (32%) with locoregional recurrence were rendered without evidence of disease after a surgical salvage procedure, resulting in a 5- year ultimate LRC rate of 87%. T-stage classification was statistically significant ( p = 0.03) in univariate analysis for actuarial 5-year LRC, 88% for Stage I vs. 72% for Stage II. The 5- and 10-year disease-specific survival rates were 85% and 79%, respectively, while the actuarial 5- and 10-year overall survival rates were 70% and 43%, respectively. Fifty-one patients (29%) developed second primary tumors, 86% of which were cancers of the upper aerodigestive tract (UADT). Heavy alcohol consumption was associated with both an increased risk of disease recurrence and development of a second cancer of the UADT. Conclusions Patients with early-stage oropharynx cancer have high rates of disease control when treated with radiation. Lymphatic and hematogenous metastases are uncommon. Surgical salvage of disease recurrence is successful in approximately one-third of patients. As the majority of recurrences occur within the first 2 years from treatment, close observation during this time period is important. The development of second primary tumors of the UADT adversely impacts survival in these patients to as great a degree as the index cancer.

Can concomitant-boost accelerated radiotherapy be adopted as routine treatment for head-and-neck cancers? a 10-year single-institution experience

Purpose Accelerated schedules are effective in overcoming repopulation during radiotherapy (RT) for head-and-neck cancers, but their feasibility is compromised by increased toxicity. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the 10-year experience of a single institution in the routine use of concomitant boost RT as standard radical treatment in all but the most favorable stage patients. Methods and materials Between February 1991 and June 2001, 296 patients (mean age, 59 years) were treated with concomitant boost RT either alone (67%) or combined with cisplatin-based chemotherapy (33%), with a median tumor dose of 69.9 Gy. Tumors were located in the oropharynx in 52%, hypopharynx in 20%, larynx in 15%, nasopharynx in 7%, and oral cavity in 6%. International Union Against Cancer Stage III-IV disease represented 77% of tumors. The median follow-up for surviving patients was 55 months (range, 10–138 months). Results The RT schedule was completed to the prescribed dose in all but 1 patient. Twenty patients (7%) had a treatment interruption (median, 5 days; range, 2–35 days). Grade 3-4 Radiation Therapy Oncology Group acute toxicity was observed in 77% of patients, and nutritional support was required in 110 patients (37%). For all patients, the 5-year actuarial locoregional control and disease-free survival rate was 72% and 61%, respectively. In a multivariate analysis, only T and N stage was significantly associated with locoregional control and disease-free survival. Grade 3-4 late toxicity occurred in 14%, mostly bone and cartilage necrosis. Conclusions The present, moderately accelerated, concomitant boost regimen is logistically feasible, causing minimal inconvenience to the technical staff and yielding a high rate of patient compliance. Concomitant chemotherapy administration is feasible provided that patients are carefully selected and supportive care is introduced in a timely fashion. Considering the manageable toxicity and the satisfactory tumor control obtained, this regimen represents a good choice when considering implementation of an altered RT fractionation schedule as standard treatment for head-and-neck cancers.

Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules

Purpose:To investigate whether a predictive estimate can be obtained for a ‘tolerance level’ of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data. Materials and methods:Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1–3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd 1+ d α/β − Ln2 T−T k αT p (see text for parameters). Results: A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of ‘intolerable’ or ‘tolerable’. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a ‘tolerance zone of uncertainty’ could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2–10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced by up to roughly 3–5 Gy10 in BED, with a request for further evidence. Conclusions:It is suggested that total BED should be used, as specified above. Parameters of α=0.35 Gy− 1, α/β=10 Gy, Tk=7 days and Tp=2.5 days are suggested. The ‘acute/ tolerance zone’ then turns out to be 59–61 Gy10 for radiation-only treatments. Further information about the decrement caused by concurrent head-and-neck cancer chemoradiotherapy, possibly 3–5 Gy10, is required.

Accelerated hyperfractionated irradiation for advanced head and neck cancer: effect of shortening the median treatment duration by 13 days.

Optimal treatment duration of altered fractionation schedules in head and neck cancer is still undefined. A retrospective study on local tumor control, survival, and complications of accelerated hyperfractionated irradiation in head and neck cancer was undertaken to investigate whether there was an advantage in further shortening overall time from 6.5 weeks. Four hundred nineteen consecutive male patients treated with radiation alone for cure 1987-1998 were analyzed. Patients with stage I, or treated also with brachytherapy implants or chemotherapy, were excluded. Treatment with accelerated hyperfractionation was performed twice daily, at a median of 1.6 Gy/fraction, to a total median dose of 68 Gy in 39 days. The patient population was divided into two groups: those with < or =39 days overall treatment time (group A, n = 227; median, 33 days) and those with >39 days (group B, n = 192; median, 46 days). Group A received a significant median tumor dose reduction of 7% compared with group B. The 7-year actuarial local control (LC) rates were 59% and 48% for groups A and B, respectively (p =.02). The actuarial LC rates for T1-2 patients were 79% and 74% at 7 years for groups A and B, respectively (p = NS). Similarly, for T3-4 patients, they were 47% and 35% (p =.02), respectively. The 7-year actuarial disease-free survival (DFS) rates for groups A and B were 39% and 26% (p =.01), respectively. For stage II patients, DFS was 62% and 60% at 7 years (p = NS) for groups A and B, respectively. And similarly, for stage III-IV patients, DFS was 33% and 20% (p =.04), respectively, at 7 years. LC and DFS rates at 7 years for T4 and stage IV patients, respectively, were significantly improved in group A. Cox regression analyses for LC showed that both T stage and overall time were significant prognostic factors. Similarly, UICC clinical stage and overall time were significant prognostic factors for DFS. There was no difference in acute morbidity between the two groups: 3% of patients in both groups required tube or parenteral feeding. The 7-year actuarial probability of RTOG/EORTC grades 3-5 late effects was 15% and 13%, respectively, for each group (p = NS). This study, with the limitations of a retrospective study, has shown a significant improvement in local tumor control and disease-free survival, in patients treated with shorter overall treatment times (median, 33 days) with an accelerated hyperfractionated irradiation schedule compared with those treated with a median duration of 46 days. No significant enhancement of acute reactions and late morbidity were observed with the shorter schedule.

Relationship between tumor radioresistance and cell kinetics in fractionated radiotherapy

The biological basis for altered fractionation radiotherapy is reviewed in this study. The clinical application of hyperfractionation is based on evidence that late-responding normal tissues are spared more radiation damage than early-responding tissues or tumors when the dose per fraction is decreased to less than 2 Gy. Evidence has also accumulated to indicate that prolonged treatment is detrimental to control tumors due to accelerated repopulation of surviving tumor cells, which is the basis for accelerated fractionation. Recent clinical trials on altered fractionation schedules are also discussed.

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers

Background and purpose: Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery. In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications, such as altered fractionation schedules and combination with chemotherapy. Patients and methods: From October 1990 to December 1997, 239 patients with squamous cell cancers originating in the head and neck region were randomized to one of three treatment options. Standard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions (CF). The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days (V-CHART). The third study arm had identical fractionation and dose as the above accelerated treatment, with the additional administration of 20 mg/m 2 mitomycin C (MMC) on day 5 of treatment (V-CHART+MMC). Results: Main toxicity resulted from accelerated fractionation in confluent mucositis (Grade 3–4 in 95%) requiring nasogastral tube feeding, analgetics and antiphlogistics in the majority of cases. Haematological toxicity Grade 3–4 was seen after MMC administration in 18%. MMC administration did not influence mucosal reaction. Overall duration of mucositis was not different in the three treatment groups. Loco-regional tumour control was 31% after CF, 32% after V-CHART and 48% after V-CHART+MMC, respectively ( P<0.05). Overall crude survival was 24% after CF, 31% following V-CHART and 41% after V-CHART+MMC, respectively ( P<0.05). Median follow up was 48 months (assessment performed in February 1999). Conclusion: Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical. A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment.

Altered fractionation in definitive irradiation of squamous cell carcinoma of the head and neck.

The likelihood of local control after radiation therapy may be improved by increasing total dose or decreasing overall time. The probability of late complications increases with dose per fraction. Altered fractionation techniques usually employ two or more fractions per day using a dose per fraction that is similar or less than that employed in conventional fractionation. Altered fractionation may be broadly classified as hyperfractionation or accelerated fractionation. Data suggest that altered fractionation schedules may improve local control (and to a lesser extent, survival) compared with conventional irradiation.