Conventional Fractionation Regimens Research Articles

RADT-48. RADIATION MYELOPATHY AFTER STANDARD DOSE RADIATION: POTENTIAL RADIATION SENSITIZING EFFECTS OF SYSTEMIC THERAPY

Abstract Radiation myelopathy is an uncommon adverse effect of spinal irradiation. It is especially rare following conventional palliative fractionation regimens for vertebral metastasis. We present two cases of delayed thoracic radiation myelopathy in patients with breast cancer. In both cases, palliative radiation of 30 Gy in ten fractions was administered to thoracic spinal metastases. Neither patient received concurrent systemic therapy. One began trastuzumab emtansine nine days after finishing radiation and the other started palbociclib three months afterwards, which was switched to capecitabine at disease progression. Each patient developed progressive leg weakness and numbness, ten months following radiation and eleven months following radiation (four weeks following capecitabine), respectively. MRI showed edema and focal contrast enhancement within the radiation field in each. Both were treated with high-dose corticosteroid, vitamin E, and pentoxifylline. Neither patient returned to their neurologic baseline and remain with significant deficits, requiring assistance with ambulation. Serial MRIs revealed eventual reduction in cord enhancement and edema, followed by cord atrophy in one case. The cumulative radiation dose of 30 Gy is typically within the safety tolerance of the spinal cord, so it is speculative if post-radiation systemic therapy played a role in the development of myelopathy. The timing is particularly convincing in the patient who developed symptoms within four weeks of starting capecitabine. These cases are similar to recently reported instances of radiation myelopathy after standard dose spinal radiation followed by chemotherapy or immunotherapy. Recognition of the potential radiation sensitizing effects of systemic therapy should lead clinicians to consider radiation myelopathy early if spinal cord symptoms develop and to consider the timing of initiation of potential sensitizing drugs when spinal radiation has been given.

Hypofractionated Whole-Breast Irradiation Focus on Coronary Arteries and Cardiac Toxicity-A Narrative Review.

Breast cancer is the most common cancer among women worldwide, which is often treated with radiotherapy. Whole breast irradiation (WBI) is one of the most common types of irradiation. Hypo-fractionated WBI (HF-WBI) reduces the treatment time from 5 to 3 weeks. Recent radiobiological and clinical evidence recommended the use of HF-WBI regardless of the age or stage of disease, and it is proven that hypo-fractionation is non-inferior to conventional fractionation regimen irradiation. However, some studies report an increased incidence of heart-related deaths in the case of breast irradiation by hypo-fractionation, especially in patients with pre-existing cardiac risk factors at the time of treatment. Due to the new technical possibilities of radiotherapy techniques, HF-WBI can reduce the risk of cardiac toxicity by controlling the doses received both by the heart and by the anatomical structures of the heart. The radiobiological “double trouble”, in particular “treble trouble”, for hypo-fractionated regimen scan be avoided by improving the methods of heart sparing based on image-guided irradiation (IGRT) and by using respiration control techniques so that late cardiac toxicity is expected to be limited. However, long-term follow-up of patients treated with HF-WBI with modern radiotherapy techniques is necessary considering the progress of systemic therapy, which is associated with long-term survival, and also the cardiac toxicity of new oncological treatments. The still unknown effects of small doses spread in large volumes on lung tissue may increase the risk of second malignancy, but they can also be indirectly involved in the later development of a heart disease. It is also necessary to develop multivariable radiobiological models that include histological, molecular, clinical, and therapeutic parameters to identify risk groups and dosimetric tolerance in order to limit the incidence of late cardiac events. MR-LINAC will be able to offer a new standard for reducing cardiac toxicity in the future, especially in neoadjuvant settings for small tumors.

Improving Outcomes in NSCLC: Optimum Dose Fractionation in Radical Radiotherapy Matters

IntroductionWe analyzed a comprehensive national radiotherapy data set to compare outcomes of the most frequently used moderate hypofractionation regimen (55 Gy in 20 fractions) and conventional fractionation regimen (60–66 Gy in 30–33 fractions). MethodsA total of 169,863 cases of NSCLC registered in England from January 2012 to December 2016 obtained from the Public Health England were divided into cohort 1 (training set) diagnosed in 2012 to 2013 and cohort 2 (validation set) diagnosed in 2014 to 2016. Radiotherapy data were obtained from the National Radiotherapy Dataset and linked by National Health Service number to survival data from the Office of National Statistics and Hospital Episode Statistics, from which surgical data and Charlson comorbidity index were obtained. Of 73,186 patients with stages I to III NSCLC, 12,898 received radical fractionated radiotherapy (cohort 1—4894; cohort 2—8004). The proportional hazards model was used to investigate overall survival from time of diagnosis. Survival was adjusted for the prognostic factors of age, sex, stage of disease, comorbidity, other radical treatments, and adjuvant chemotherapy, and the difference between the treatment schedules was summarized by hazard ratio (HR) and 95% confidence interval. The significance of any difference was evaluated by the log likelihood test. ResultsOf patients with stages I to III NSCLC, 17% to 18% received radical fractionated radiotherapy. After adjustment for independent prognostic factors of age, stage, comorbidity, and other radical and adjuvant treatments, patients in cohort 1 treated with the 2.75 Gy per fraction regimen had a median survival of 25 months compared with 29 months for patients treated with the 2 Gy per fraction regimen (HR = 1.16, p = 0.001). Similarly, in cohort 2, the respective median survival values were 25 and 28 months (HR = 1.10, p = 0.02). ConclusionsBig data analysis of a comprehensive national cohort of patients with NSCLC treated in England suggests that compared with a 4-week regimen of 55 Gy in 20 fractions, a 6-week regimen of conventional daily fractionation to a dose of 60 to 66 Gy at 2 Gy per fraction is associated with a survival benefit. Within the limitations of the retrospective big data analysis with potential selection bias and in the absence of randomized trials, the results suggest that conventional fractionation regimens should remain the standard of care.

The Association Between Use of Hypofractionated Radiation Therapy for the Treatment of Prostate Cancer and Treatment Completion

While hypofractionated (HF) radiation therapy (RT) is recognized as a suitable treatment for low and intermediate risk prostate cancer, it is not yet the standard of care. As HF RT requires the patient to attend fewer appointments, it is potentially easier for patients to complete than conventional fractionation (CF) RT. Since noncompletion of RT has been shown to lead to inferior outcomes, use of HF RT may be a way to increase treatment adherence. This study examines whether there is a difference in treatment completion rates for HF RT versus CF RT in the context of prostate cancer.Radiation therapy order data from a prior authorization program and health plan claims data were extracted. The data related to patients belonging to commercial and Medicare Advantage health plans from a national organization. The patients included had early-stage prostate cancer, had not had prostatectomy, were not receiving palliative care, had no prior prostate cancer RT orders, and received their order for RT between July 1st, 2016 and September 30th, 2019. Orders were categorized as HF if they were authorized for 5 to 28 fractions of RT, and CF if they were authorized for 29 to 48 fractions. Each RT order was assigned a target date for completion, and completion was assessed on the basis of whether the patient had received the number of fractions authorized by that date. Patients with orders for 5 fractions were considered to have completed treatment if they received 3+ fractions, as these were stereotactic body RT regimens that are adjusted based upon treatment response. A Chi-square test was used to evaluate the association between the authorized regimen and completion. A multivariate logistic regression was used to assess the same, after controlling for age, urbanicity, the median income of the patient's home ZIP code, if the order was placed at a hospital, and if the ordering facility's name suggested an academic affiliation. Finally, a multivariate logistic regression was used to assess whether any of the control variables were associated with the authorization of a HF regimen.Of the 936 orders included, 309 (33.0%) were for HF and 627 (67.0%) were for CF. The completion rate significantly (P < 0.01) differed between the groups; 64.7% (200/309) for HF orders and 55.8% (350/627) for CF orders. Multivariate analysis found HF orders were significantly associated with treatment completion, relative to CF orders; 1.49 (95% CI: 1.12-1.99) adjusted odds. None of the other covariates were significantly associated with completion. Patients had significantly higher odds of having an order for HF if they came from a < $40,000 median income ZIP code (OR: 1.40; 95% CI: 1.01-1.93), or if the site of service at which the order was placed was a hospital (OR: 1.75; 95% CI: 1.26-2.42).Patients with orders for HF regimens completed their RT more frequently than patients with orders for CF regimens. The potential for greater treatment adherence should be considered as a possible benefit of HF.

Economic evaluation of postoperative hypofractionated radiation therapy in patients with breast cancer

Breast cancer remains the most common malignant neoplasm in women. According to the current standards, radiation therapy is one of the most important components of the multi-disciplinary treatment. The efficacy of the postoperative radiotherapy in both the traditional fractionation regimen and in the hypofractionation mode is not questioned. Contrary to the conventional fractionation, hypofractionation implies an increase in the daily dose and a reduction in the total treatment time. This approach helps reduce the treatment costs in patients with breast cancer while maintaining a high treatment efficacy and quality of life.The aim of the study was to analyze the economic efficiency of the dose hypofractionation as compared to the traditional mode of dose fractionation during postoperative radiation therapy in patients with breast cancer.Materials and methods. The study included 220 patients with breast cancer who received a combined treatment. Of these, 120 patients (study group) received hypofractionated radiotherapy (40.5 Gy in 15 fractions) whereas 100 patients of the control group were treated by the conventional therapy of 50 Gy in 25 fractions. Patients of the both groups were comparable by stages of the disease, systemic treatment, age and molecular type of tumor. The cost of treatment was calculated from the price list of this research center.Results. The present economic analysis showed that the method of hypofractionation was more (30% on average) cost-efficient than the conventional regimen while both modalities produced similar rates of total and relapse-free survival. We were then able to identify the main items in the list of medical services that contributed to the estimated difference in the treatment costs. Reducing the number of examinations and the treatment duration help reduce the expenditure of this medical organization.Сonclusion. Hypofractionation of postoperative radiotherapy in patients with breast cancer allows one to reduce the treatment costs as compared to the conventional fractionation regimen. The funds saved by optimizing the costs of postoperative radiation can be directed to the development of additional means of cancer treatment.

The Role of Hypofractionated Radiation Therapy with Photons, Protons, and Heavy Ions for Treating Extracranial Lesions.

Traditionally, the ability to deliver large doses of ionizing radiation to a tumor has been limited by radiation-induced toxicity to normal surrounding tissues. This was the initial impetus for the development of conventionally fractionated radiation therapy, where large volumes of healthy tissue received radiation and were allowed the time to repair the radiation damage. However, advances in radiation delivery techniques and image guidance have allowed for more ablative doses of radiation to be delivered in a very accurate, conformal, and safe manner with shortened fractionation schemes. Hypofractionated regimens with photons have already transformed how certain tumor types are treated with radiation therapy. Additionally, hypofractionation is able to deliver a complete course of ablative radiation therapy over a shorter period of time compared to conventional fractionation regimens making treatment more convenient to the patient and potentially more cost-effective. Recently, there has been an increased interest in proton therapy because of the potential further improvement in dose distributions achievable due to their unique physical characteristics. Furthermore, with heavier ions the dose conformality is increased and, in addition, there is potentially a higher biological effectiveness compared to protons and photons. Due to the properties mentioned above, charged particle therapy has already become an attractive modality to further investigate the role of hypofractionation in the treatment of various tumors. This review will discuss the rationale and evolution of hypofractionated radiation therapy, the reported clinical success with initially photon and then charged particle modalities, and further potential implementation into treatment regimens going forward.

SU-E-T-313: In Vivo Studies On the Pulsed Low-Dose Hyper-Radiosensitivity in Prostate Cancer

Purpose: In vitro radiation doses of below 0.5 Gy have been shown to be more effective than higher doses per unit dose in killing clonogenic cells of various tumor cell lines and can lead to better biological effects than predicted by the standard linear quadratic (LQ) model. This phenomenon is known as low‐dose hyper‐radiosensitivity (LD‐HRS). To investigate the in vivo HRS effects of pulsed low‐dose radiotherapy (PLDR) for prostate cancer treatment, we developed a human prostate PC3 cancer cell model in nude mice. Methods: We developed an orthotopic murine model of human prostate tumor and evaluated the in vivo treatment efficacy using MRI. PC3 cells were implanted in the prostates of nude mice. The mice with tumor are randomly allocated into a PLDR group, a conventional fractionation (CF) group, and a control group. The mice in the PLDR and CF groups were both treated with 4Gy radiation dose, which was divided into two fractions of 2Gy treatments with a seven‐day interval. For PLDR treatment, the fractional 2Gy dose was further divided into ten 0.2Gy pulses with an inter‐pulse interval of 3 minutes. Results: We have monitored the tumor growth on a weekly basis. Sizable delay of the tumor growth after the treatments have been observed, with the PLDR group showing better tumor control than the CF group. For example, the average relative tumor volumes are 1.33, 1.70, and 1.82 at one week after treatment, and 2.06, 2.19, and 3.40 at two weeks after the last treatment, for the PLDR, CF, and control groups, respectively. Conclusion: According to our preliminary results, the PLDR could be more efficacious than the CF regimen for prostate cancer treatment.

Stereotactic Body Radiotherapy for Primary Management of Early-Stage, Low- to Intermediate-Risk Prostate Cancer: Report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee

Stereotactic Body Radiotherapy for Primary Management of Early-Stage, Low- to Intermediate-Risk Prostate Cancer: Report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee

Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma

The role of radiotherapy for nodal metastases from malignant melanoma is controversial. In patients with features that indicate high risk of recurrence of nodal disease, adjuvant irradiation lowers recurrence rates. High-risk features include extranodal spread of melanoma, more than two positive lymph nodes, large nodal size, or recurrent disease in previously dissected nodal basin. Data from randomised trials that confirm a benefit of adjuvant radiotherapy in patients with nodal disease at high risk of recurrence are unavailable. However, the use of adjuvant radiotherapy for high-risk nodal disease is increasingly widespread. Recurrence rates and risk of complications differ with anatomic location of the nodal basin involved, and treatment decisions should be made accordingly. Whether to use hypofractionated radiotherapy or conventional fractionation regimens for adjuvant irradiation to nodal basins is also a matter of debate. Hypofractionation is the accepted approach when radiotherapy is recommended. Technical issues have to be considered when hypofractionated regimens are given because survival might be long and the potential for normal tissue toxicity is high. Overall survival remains poor for patients with macroscopic nodal metastases from malignant melanoma. Until advances in systemic treatment are available, regional nodal control is an important endpoint for patients with this disease.

Ductal Carcinoma in situ of the Breast in Israeli Women Treated by Breast-Conserving Surgery Followed by Radiation Therapy

Background: Lumpectomy followed by radiation therapy (RT) has become an accepted local management strategy for patients with small, mammographically detected ductal carcinoma in situ (DCIS) of the breast. The aim of this analysis is to describe control rates and patterns of relapse in a cohort of Israeli women with mammographically detected DCIS treated at a single medical center. Patients and Methods: The files of 107 consecutive patients with DCIS were retrieved from the cancer registry of the unit of RT. All women underwent lumpectomy followed by definitive RT, administered in conventional dose fractionation regimens. Oral tamoxifen, 20 mg/ day, was prescribed to all but 2 patients with positive receptors. Results: Within a median follow-up time of 52 months, no local recurrence of any breast tumor was found. There was no correlation between event-free survival and tumor size, focality, grading, hormone receptor status, administration of adjuvant hormonal therapy, timing of RT, and RT boost delivery. The 8-year overall survival, disease-free-survival, and event-free survival were 100, 100, and 87%, respectively. Conclusions: The results reported herein are consistent with short-term and intermediate-term outcomes that are better than the reported benchmarks from prospective randomized trials. Although this could reflect selection factors at a single institution, it is also plausible that a genetically distinct disease is present in this local population.

SU-GG-T-408: Computational Analysis of the Dose and Dose-Rate Dependence of DNA Double-Strand Break Repairs

Purpose: Computational quantification of the dose and dose‐rate dependence of radiation‐induced DNA double‐strand break (DSB) repair, and the significance of high dose and high dose‐rate limits pertinent to stereotactic body radiation therapy(SBRT) fractionation regimens. Method and Materials: The mass‐action biochemical kinetics approach was used to describe the binding of repair enzymes to DSBs through the formation of intermediate repair complexes which lead to DNA rejoining. To quantify the formation of intermediate repair complexes, coupled non‐linear ordinary differential equations (ODEs) which govern the dynamics of DNADSB non‐homologous end‐joining (NHEJ) repair were used. Biochemical kinetics parameters for human fibroblast cells were used and the ODEs were numerically solved to predict the number of DSB complexes for doses in the range of 2–30 Gy and dose‐rates in the range of 1–100 Gy/h. Results: Our computational analysis predicts that the number of DSB repair complexes formed in the high dose and high dose‐rate limit can be several orders of magnitude higher than those in the low dose and low dose‐rate limit. Conclusion: This work indicates that SBRT can lead to significantly higher therapeutic ratios in radiation therapy, if normal tissue toxicity can be maintained at levels comparable to those of conventional fractionation regimens. Since our computational analysis directly incorporates the quantification of cellular biochemical processes, its predictions are considerably more tractable in the high dose and high dose‐rate regime than models such as the linear‐quadratic model. Contributors: Ramin M. Abolfath, Ph.D., Robert D. Timmerman, M.D., Timothy D. Solberg, Ph.D., Debabrata Saha, Ph.D., Michael Story, Ph.D., Paul Derose, M.D., Homayoun Hamidian, Ph.D.

Hypofractionated radiation therapy in the treatment of epidemic Kaposi sarcoma – A prospective randomized trial

Purpose To compare a conventional fractionation regimen with a hypofractionated regimen in the treatment of Epidemic Kaposi sarcoma with radiation therapy. Materials and methods Sixty patients were randomized to receive a standard regimen of 24 Gy in 12 fractions (ARM A) or the study regimen of 20 Gy in five fractions (ARM B). Radiation technique was individualized. Treatment response, local control and toxicity were recorded. Results Thirty five sites were treated in ARM A and 30 sites in ARM B. Treatment arms were similar for gender, ECOG performance score, treated site, antiretroviral therapy usage, T stage, I stage and S stage. The overall survival using the Kaplan Meier method was 37% at 1 year. Complete responses were recorded at 28 sites (13 Arm A, 15 Arm B), partial responses at 19 sites (8 Arm A, 11 Arm B) and stable disease at three sites (2 Arm A, 1 Arm B). The mean time to maximum objective response was 3 months (range: 1–14 months). Response rates and local control were equal in the two arms ( p = 0.73 and 0.77, respectively, log rank test). Acute skin toxicity ( p = 0.77) and late skin toxicity ( p = 0.24) were equal in the two arms. Conclusion The two treatment regimens produced equivalent results for treatment response, local recurrence-free survival and toxicity.

TU‐EE‐A2‐02: Fractionated Grid Therapy in Treating Cervical Cancers: Hypo‐Fractionation Or Conventional Fractionation?

Purpose: To evaluate the hypo‐fractionated and conventionally fractionated grid therapy in treating cervical cancers. Material and methods: A Monte Carlo technique was employed to calculate dose distribution of a commercially available grid. Based on the previously validated Monte Carlo technique, our new study has considered the divergence of all holes and thus improved the accuracy of grid geometry description in the simulations. The linear‐quadratic (LQ) model is used to evaluate the therapeutic outcome of both the hypo‐fractionated (fewer fractions and higher dose/fraction, herein 15 Gy/fraction) and conventionally fractionated (2Gy/fraction) regimens using grid therapy to treat cervical tumors that were represented by different radio‐biological responses. Results: The dose profiles and 2D dose distributions at dmax (d=1.5 cm) and 5 cm depths in water were obtained. An excellent agreement of dose profiles between calculated and measured was confirmed. The tumor cell and normal tissue survival statistics of grid therapy for two types of treatment regimens were calculated using the 2‐D dose distributions at the depth of 5 cm, and the therapeutic ratios and equivalent open field doses were obtained. Conclusions: The consideration of the divergence of grid holes has improved the Monte Carlo simulation results. In both the hypo‐fractionated and conventionally fractionated regimens, the therapeutic ratio depends not only on the single α/β value, but also on the individual α and β values. There is a significant therapeutic advantage of grid therapy for treating the studied cervical cancer cells because of their large α/β values, and the normal tissue sparing effect for the hypo‐fractionation regimen with few fractions is comparable to the conventional fractionation regimen with many fractions. For the radiosensitive normal tissues, both regimens give almost the same results, but for the radio‐resistant normal tissue the conventional fractionation regimen is preferred to spare them.

Outcome of hyperfractionated radiotherapy in chemotherapy-resistant non-Hodgkin’s lymphoma

Patients with chemotherapy-resistant lymphoma have rapidly progressive disease and a poor prognosis. Local symptoms are treated with radiotherapy (RT) for local control. We have reviewed local control and toxicity in patients treated with hyperfractionated accelerated RT. A total of 34 patients received hyperfractionated RT between 1997 and 2003. The radiation dose was 39.9-40.5 Gy in 30 fractions. The median treatment time was 22 days with twice-daily involved-field RT. The median follow-up was 4.4 years. Response was assessed <3 months after RT and was classified as a complete response, a complete response-unconfirmed, a partial response, or no response. Local control was defined as maintenance of local complete response, complete response-unconfirmed, or lack of local progression with a partial response. Recurrence or progression outside the RT volume was regarded as distant disease. The median age was 53 years; 20 patients were men and 14 were women. The initial diagnosis was Stage I-II in 56% and Stage III-IV in 44%. The disease bulk was > or =10 cm in 35% (n = 12). The histologic features at diagnosis were follicular in 11 (Grade 1 in 4, Grade 2 in 3, and Grade 3 in 4), diffuse large B-cell in 14, peripheral T-cell lymphoma in 2, Burkitt-like in 1, mantle cell in 2, natural killer cell in 2, plasmacytoma/lymphoma in 1, and T-cell lymphoblastic in 1. The initial treatment was chemotherapy in 32 patients (94%); 71% were refractory to initial chemotherapy and 29% developed a relapse after an initial response. The RT response was complete in 24% (n = 8), complete, unconfirmed in 26% (n = 9), partial in 47% (n = 16), and none in 3% (n = 1). The local control rate was 73% at 1, 2, and 3 years. Grade 1 dermatitis was the most common side effect. Hyperfractionated RT provided good local control and was well tolerated. This encouraging result requires additional study with comparison to conventional fractionation regimens.

Outcome of hyperfractionated radiotherapy in chemotherapy-resistant non-Hodgkin’s lymphoma

Lymphoma patients exhibiting chemotherapy-resistant disease not amenable to further intensive chemotherapy (CT) approaches often have rapidly progressive disease and a poor prognosis. Those with predominant local symptoms are often referred for palliative radiation therapy (RT). Accelerated RT may have a higher biologic effect for such rapidly proliferating tumors. This effect may offer improved local control compared to conventional fractionation. We have selectively treated patients with chemotherapy-resistant Non-Hodgkin’s Lymphoma (NHL) with a hyperfractionated accelerated radiation regimen (40 Gy in 30 fractions, given twice daily over 3 weeks). Their clinical outcome is retrospectively reviewed, focusing on tolerability and local control. There were 34 patients treated with the accelerated RT regimen from 1997 to 2003. Total dose ranged from 3990 cGy to 4050 cGy in 30 fractions, over a median overall treatment time of 22 days (range 5–29 days), given twice daily (BID) to the involved field. Two patients did not complete the treatment as planned but were included in the outcome analysis. Involved field (IF) nodal irradiation was given in 74% (n = 25), and extranodal IF radiation was given to 26% (n = 9). Treatment sites were: neck (n = 7), axilla (n = 9), neck and axilla (n = 2), mediastinum (n = 3), other supradiaphragmatic (n = 7), infradiaphragmatic (n = 6). The median follow-up was 4.41 years. Response was assessed within 3 months of completing RT, and classified as CR (includes unconfirmed CR), PR, and no response (NR). Local control was defined as maintenance of local CR, or lack of progression of the local disease in the PR patients. Failure outside of the RT volume was regarded as distant disease. The median age was 50 years and there were 20 male (59%) and 14 female (41%) patients. At initial diagnosis, 56% (n = 19) were stage I or II, and 44% (n = 15) were stage III or IV. Bulky disease (≥ 10cm) was present in 35% (n = 12). The histology at diagnosis was: follicular: 11, (grade I: 4, grade II: 3, grade III: 4), diffuse large B-cell: 14, PTCL: 2, Burkitt-like: 1, mantle cell: 2, NK cell: 2, plasmacytoma/lymphoma: 1, and T-lymphoblastic: 1. HIV status was positive in 2 patients. CT was given as initial treatment in 32 patients (94%); most commonly CHOP (81%, n = 26). RT alone was given to 2 patients initially, followed by CT as a secondary modality upon relapse of disease. The majority of patients (71%, n = 24) were refractory to initial CT; the remaining patients had relapse of disease after initial treatment. Prior to receiving accelerated RT, 3 patients failed one CT regimen, 15 failed 2 regimens, and 16 failed ≥3 regimens. Stem-cell transplant was received by 15% (n = 5) as part of their salvage treatment prior to accelerated RT. Following accelerated RT, CR was obtained in 32% (n = 11), PR in 65% (n = 22), and 3% (n = 1) had no response (NR). Local control was obtained in 73% of patients. The overall survival was 24%, 15%, and 9% at 1, 2, and 3 years, respectively. Progression of disease was present in 82% of patients at 1 year, and 85% had progression at 2 and 3 years. Disease was locally progressive in 27% of patients. Distant progression of disease was present in 73% of patients at 1 year, and in 76% of patients at 2 and 3 years. The accelerated RT regimen was well tolerated. Grade 1 dermatitis was the most commonly reported side-effect (32%, n = 9). Grade 2 dermatitis, mucositis, esophagitis and dysphagia were reported in one patient each. There were two grade 3 toxicity, dermatitis: 1 and mucositis: 1. Toxicity was not reported/documented in 9 patients. Accelerated hyperfractionated RT for chemotherapy-resistant lymphoma provided local control in 73% of patients, and was well tolerated therefore providing excellent palliation in this group of patients. This result is encouraging and deserves further study with a comparison to conventional fractionation regimens

A simple analytic derivation suggests that prostate cancer α/β ratio is low

Since the publication of Brenner and Hall’s recent paper (1) suggesting that the a/b ratio for prostate cancer is 1.5 Gy, a debate has been propagated through the radiotherapy community (2–5). This surprisingly low value carries implications of more efficient (and perhaps less costly) regimens of external beam radiotherapy (i.e., hypofractionated schedules) and optimal forms of brachytherapy (i.e., high dose rate). Should it prove to be true, such a low ratio would negate the therapeutic advantage of conventional fractionation regimens and call out for clinical trials. There is certainly indirect evidence for a low a/b ratio. The very small proportion of proliferating cells (6, 7), the very long observed doubling times (8, 9), the slow response to irradiation, and the recent interim results of high-dose-rate brachytherapy of varying fractionation (10) are all are consistent with such a low value. The surprise is that this value is as low as, if not even lower than, normal tissue response to irradiation. Can one apply the linear-quadratic (LQ) equation to outcomes of a population of clinically localized prostate cancer after radiotherapy? The LQ equation, although purely phenomenological, has certainly proven to be of great use, both in the study of cultured tumor cells irradiated in vitro, in comparing regimens of different fractionation, and in the study of normal tissue response to radiation. Although issues of interand intratumor heterogeneity are not directly accounted for in the standard LQ formalism, these issues might not necessarily affect the a/b ratio when applied to changes in fraction size (4). Whereas the a term, a direct measure of radiosensitivity, does depend upon heterogeneity (3) and is intimately tied to the number of clonogens, the ratio a/b might not. We present a simple analytical derivation of a/b that is a logical conclusion from the observation that, for clinically localized prostate cancer, external beam and permanent brachytherapy appear to achieve equivalent outcomes. This derivation makes no assumptions and does not attempt to fit models to specific clinical data. For fractionated external-beam irradiation to a total dose De, with dose per fraction d, the LQ survival fraction of clonogens can be written as follows:

There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a pediatric oncology group phase III trial comparing conventional vs. hyperfractionated radiotherapy

Purpose: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m2 of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy.Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m2 was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2.Results: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2–15 months) and the median time to death 8.5 months (range 3–24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1–12 months) and 8 months (range 1–23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete response in 1 patient of each Rx arm, a partial response (> 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases.Conclusion: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival (p = 0.96) nor did it improve survival (p = 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome.

Curative radiotherapy for stage II-III squamous cell carcinoma of the glottic larynx.

The authors report the analysis and outcome of curative radiotherapy for stage II and III squamous cell carcinoma of the glottic larynx. Thirty-nine men with invasive, previously untreated squamous cell carcinoma of the glottic larynx were referred for curative radiotherapy from May 1976 through June 1991, to the Veterans Administration Medical Center in Minneapolis, Minnesota, U.S.A. Thirty-eight patients had T2N0 disease, and one had T2N1 disease. All patients were treated by megavoltage units (two by cobalt 60 and 37 by 4 mV-linear accelerator). The median fractional dose was 1.80 Gy, and the median total tumor dose was 70.20 Gy. Surgical salvage was reserved for irradiation failure. All patients had a minimum 5-year follow-up. The Kaplan-Meier method was used for survival analysis. The 5-year disease-free survival with voice preservation after radiotherapy was 70.2% (80% for T2a and 64% for T2b patients). The ultimate 5-year disease-free survival for all T2 patients after surgical salvage was 91%. In nine patients, ten second primary malignancies were diagnosed during follow-up. Nine of these second lesions occurred in the aerodigestive tract. Curative radiotherapy using conventional fractionation regimen with surgical salvage for irradiation failure is an efficacious modality for T2N0 and T2N1 squamous cell carcinoma of the glottic larynx. A high incidence of second malignancy was noted in our series.

Altered fractionation in radiotherapy.

Differences between late-responding (slowly proliferating) normal tissues and early-responding (rapidly proliferating) normal tissues and tumor cells and the event of tumor cell repopulation occurring during treatment have essentially led to the development of altered fractionation schemes. Altered fractionation regimens mainly refer to schedules utilising two or more (small dose) fractions per day for part of or for the entire treatment course. It must be underlined that a true standard or conventional fractionation regimen does not exist: no schedule is universally recognised as the standard of reference to be compared with. However, continental European and U.S. conventional regimens are the considered control arm with which the new experimental regimens have to be compared. For this reason they are generally recognised as the standards. The basic rationale for hyperfractionated or accelerated regimens respectively lies in the possibility (a) to deliver higher total doses reducing late-responding normal tissue damage, (b) to deliver total doses in a reduced overall treatment time to defeat tumor clonogen repopulation. Multiple fractions per day should not be delivered with interfraction intervals smaller than 6 hours. Clinical results of phase I-II and limited but convincing phase III randomised trials suggest that a therapeutic benefit can be achieved with new altered regimens.

Clinical results of unconventional fractionation radiotherapy in central nervous system tumors.

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.