H. Rodney Withers

Accelerated fractionation vs hyperfractionation: Rationales for several treatments per day

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

Biologic basis for altered fractionation schemes

Conventional is commonly not universally correct, and so with dose fractionation in radiotherapy. Fractionation spares slowly responding tissues more than tissues and tumors that show an early response, suggesting that therapeutic gains may be further increased by reducing fractional doses below 1.8 to 2 Gy. The overall duration of a course of radiotherapy should not be the same for all tumors in all sites because the time of onset of regeneration after the start of radiotherapy varies from tissue to tissue and among tumors. Although growth kinetics and dose‐response characteristics are known to vary, inability to identify and quantify them prospectively frustrates rational selection of patients for individualized fractionation regimens. In general, curative radiotherapy should be delivered in as short an overall time as possible using the smallest practical dose per fraction. Although 2 Gy, 5 times per week may be a reasonable “average” treatment, greater individualization should be a research goal.

A new isoeffect curve for change in dose per fraction

A method is proposed for using survival curve parameters for calculating the change in total dose necessary to achieve an equal response in a tissue when the dose per fraction is varied. The method uses the ratio alpha/beta of the coefficients of the linear quadratic survival formula and accounts only for the effect of repair of cellular injury. Absolute values for alpha and beta are not required. The isoeffect curves vary for different tissues. A dose adjustment to account for differences in the regeneration of surviving cells that might result from changing a treatment regimen must be made separately and will also vary from tissue to tissue. Examples of the use of the curves are given. At present, the curves, particularly those for late effects, are uncertain and caution should be observed in using them until they are defined more accurately with additional data.

Induction of acute phase gene expression by brain irradiation.

PURPOSE To investigate the in vivo acute phase molecular response of the brain to ionizing radiation. METHODS AND MATERIALS C3Hf/Sed/Kam mice were given midbrain or whole-body irradiation. Cerebral expression of interleukins (IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6), interferon (IFN-gamma), tumor necrosis factors (TNF-alpha and TNF-beta), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthetase (iNOS), von Willebrand factor (vWF), alpha 1-antichymotrypsin (EB22/5.3), and glial fibrillary acidic protein (GFAP) was measured at various times after various radiation doses by ribonuclease (RNase) protection assay. The effects of dexamethasone or pentoxifylline treatment of mice on radiation-induced gene expression were also examined. RESULTS Levels of TNF-alpha, IL-1 beta, ICAM-1, EB22/5.3 and to a lesser extent IL-1 alpha and GFAP, messenger RNA were increased in the brain after irradiation, whether the dose was delivered to the whole body or only to the midbrain. Responses were radiation dose dependent, but were not found below 7 Gy; the exception being ICAM-1, which was increased by doses as low as 2 Gy. Most responses were rapid, peaking within 4-8 h, but antichymotrypsin and GFAP responses were delayed and still elevated at 24 h, by which time the others had subsided. Pretreatment of mice with dexamethasone or pentoxifylline suppressed radiation-induced gene expression, either partially or completely. Dexamethasone was more inhibitory than pentoxifylline at the doses chosen. CONCLUSIONS The initial response of the brain to irradiation involves expression of inflammatory gene products, which are probably responsible for clinically observed early symptoms of brain radiotherapy. This mechanism explains the beneficial effects of the clinical use of steroids in such circumstances.

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

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

Quality of life after surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer

The primary treatments for clinically localized prostate cancer confer equivalent cancer control for most patients but disparate side effects. In the current study, the authors sought to compare health‐related quality of life (HRQOL) outcomes after the most commonly used treatments.

Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions

PURPOSE To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per days extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each days extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil: Patterns of fractionation study of radiobiology

PURPOSE To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil. METHODS AND MATERIALS A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed. RESULTS With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa. CONCLUSION The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

DOSE FRACTIONATION AND REGENERATION IN RADIOTHERAPY FOR CANCER OF THE ORAL CAVITY AND OROPHARYNX. PART 2. NORMAL TISSUE RESPONSES: ACUTE AND LATE EFFECTS

The early responses of normal tissues of the oral cavity and oropharynx in 498 patients, and the slowly-developing responses in 268 patients who survived a minimum of 18 months after radiotherapy for squamous cell carcinoma were analyzed. The severity of acute responses correlated with dose intensity. The incidence of severe late responses increased with increase in dose per fraction and was characterized by a low alpha/beta ratio. Severe late responses were significantly associated with severe acute responses independently of dose per fraction and total dose, and were also ameliorated slightly by protraction of treatment time suggesting that some late effects were, at least partly, a consequence of acute injury. Probability of local tumor control correlated with severity of acute response, suggesting that excessive protraction of overall treatment time to minimize acute toxicity may compromise local control of the tumor. There was no demonstrable correlation between the volume of tissue irradiated and the severity of acute or late response.

Keynote address—the problem: Tumor radioresistance in clinical radiotherapy

Abstract Tumor radioresistance in clinical radiotherapy implies failure to achieve loco-regional disease control with radiation doses producing an acceptable degree of morbidity. Such radioresistance may be a result of many different causes (biological and technical) which are reviewed in terms of possible remedial actions. Dose response relationships for human cancers suggest that in many sites, tumors are heterogenous with respect to their cure-limiting characteristics. The case is developed that unless the predominant cure-limiting factor can be predicted, little benefit may be seen in trials of new treatment strategies using heterogeneous tumor populations. The fundamental problem of clinical radioresistance is therefore perceived as the inability to predictively identify its cause in the individual patient.