Radiation Fractionation Schedules Research Articles

Abstract 2721: MEHD7945A, dual specific antibody against EGFR and HER3, augments radiation response in head and neck squamous cell carcinoma

Abstract The HER receptor family members (EGFR, HER2, HER3 and HER4) play an important role in tumorigenesis. High EGFR expression levels correlate with poor prognosis and resistance to therapy for many epithelial tumors. Combining EGFR inhibition with radiation has been extensively studied in head and neck squamous cell carcinoma (HNSCC). Increasing evidence implicates HER3 as a key mediator of response and resistance to EGFR targeted therapies. We therefore examined the capacity of a dual specific antibody MEHD7945A, that can simultaneously target EGFR and HER3, to modulate radiation response in HNSCC. We characterized 10 HNSCC cell lines for their EGFR and HER3 expression. Immunoblot analysis confirmed that MEHD7945A significantly inhibited basal and radiation-induced EGFR and HER3 phosphorylation and downstream MAPK and AKT signaling. MEHD7945A consistently inhibited tumor cell growth in culture ranging from 30∼80%. The growth inhibitory effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibody alone. Using clonogenic survival assay, we found that MEHD7945A significantly enhanced radiosensitivity in HNSCC cells. Once again, this effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibodies. Treatment with MEHD7945A and radiation induced cell cycle arrest in G1 and G2 phases. Tumor cells eventually processed to apoptosis without successful DNA damage repair, as reflected by increased apoptotic populations detected by AnnexinV/PI staining. In addition, an increase of nuclear γ-H2AX foci was observed in cells receiving combination MEHD7945A and radiation. We administered MEHD7945A systemically to athymic mice bearing human tumor xenografts. Using single dose and fractionated radiation schedules, we observed that combined MEHD7945A and radiation was significantly more potent than single modality treatment to induce HNSCC tumor growth inhibition. These in vitro and in vivo results indicate that MEHD7945A can sensitize cells to radiation and inhibit HNSCC tumor growth, suggesting the potential of MEHD7945A as a radiation sensitizer for future clinical investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2721. doi:1538-7445.AM2012-2721

Australian & New Zealand Faculty of Radiation Oncology Genito‐Urinary Group: 2011 consensus guidelines for curative radiotherapy for urothelial carcinoma of the bladder

Curative radiotherapy, with or without concurrent chemotherapy, is recognized as a standard treatment option for muscle-invasive bladder cancer. It is commonly used for two distinct groups of patients: either for those medically unfit for surgery, or as part of a 'bladder preserving' management plan incorporating the possibility of salvage cystectomy. However, in both situations, the approach to radiotherapy varies widely around the world. The Australian and New Zealand Faculty of Radiation Oncology Genito-Urinary Group recognised a need to develop consistent, evidence-based guidelines for patient selection and radiotherapy technique in the delivery of curative radiotherapy. Following a workshop convened in May 2009, a working party collated opinions and conducted a wide literature appraisal linking each recommendation with the best available evidence. This process was subject to ongoing re-presentation to the Faculty of Radiation Oncology Genito-Urinary Group members prior to final endorsement. These Guidelines include patient selection, radiation target delineation, dose and fractionation schedules, normal tissue constraints and investigational techniques. Particular emphasis is given to the rationale for the target volumes described. These Guidelines provide a consensus-based framework for the delivery of curative radiotherapy for muscle-invasive bladder cancer. Widespread input from radiation oncologists treating bladder cancer ensures that these techniques are feasible in practice. We recommend these Guidelines be adopted widely in order to encourage a uniformly high standard of radiotherapy in this setting, and to allow for better comparison of outcomes.

Single fraction versus multiple fraction radiotherapy for palliation of painful vertebral bone metastases: A prospective study

Context:Metastatic bone disease is a commonly encountered problem in oncology practice. The most useful and cost effective treatment is radiotherapy (RT). Different fractionation schedule of RT can be used to treat such condition.Aims:Assessment of pain response in patients with vertebral bone metastasis after treating them with various radiation fractionations and to compare the toxicity profile in the treatment arms.Settings and Design:A prospective randomized study was designed to include total 64 patients from July 2010 to May 2011. Patients with histopathologically proven primary malignancy having symptomatic secondary deposits to vertebra were selected for the study. Patients were randomized to two arms receiving multiple fraction of RT with 30 Gy in 10 fractions and 8 Gy in single fraction RT, respectively.Materials and Methods:Patients with age >75 years, Karnofsky Performance Status (KPS) <40, features of cord compression were excluded from study. Initial pain response was assessed using Visual Analogue Scale (VAS) and compared using the same scale at weekly interval up to 1 month after treatment completion.Results:Arm A comprised of 33 patients while 31 patients were enrolled in Arm B. Baseline patient characteristics were comparable. Eleven patients were lost to follow-up. Initial pain scores were 7.23 ± 0.765 and 7.51 ± 0.55 in arm A and arm B, respectively. Pain scores reduced significantly in both the arms after 1 month (4.39 ± 1.82 in arm A; 5.25 ± 2.39 in arm B). Time of initiation of pain response was earlier in arm A (P = 0.0281), statistically significant. Mild G-I toxicity was noted in both the arms but differences in two arms were not statistically significant (P = 0.49), no interruption of treatment was required because of side effects.Conclusions:Different fractionation of radiation has same response and toxicity in treatment of vertebral bone metastasis. Single fraction RT may be safely used to treat these cases as this is more cost effective and less time consuming. Studies may be conducted to find out particular subgroup of patients to be benefitted more by either fractionation schedule; however, our study cannot comment on that issue.

Impact of Total Thoracic Radiation Dose and Dose Fractionation on Overall Survival in Limited-Disease Small Cell Lung Cancer: A Retrospective Study on 456 Patients

Impact of Total Thoracic Radiation Dose and Dose Fractionation on Overall Survival in Limited-Disease Small Cell Lung Cancer: A Retrospective Study on 456 Patients

Radiotherapy for Steroid-Resistant Laryngeal Rosai–Dorfman Disease

Rosai-Dorfman disease is a rare lymphoproliferative disorder that can have nodal and extranodal manifestations. In the absence of established guidelines for the management of this condition, various therapeutic modalities are used, including radiotherapy. Radiation dosages and fractionation schedules have not been reported in all instances. We present a case in which glottic and subglottic Rosai-Dorfman lesions causing airway obstruction in a frail steroid-refractory patient were put into complete remission using radiotherapy. The lesions responded transiently to a course of prednisone, but responded completely to external-beam radiation, with minimal side effects to the patient.

IsoBED: a tool for automatic calculation of biologically equivalent fractionation schedules in radiotherapy using IMRT with a simultaneous integrated boost (SIB) technique

BackgroundAn advantage of the Intensity Modulated Radiotherapy (IMRT) technique is the feasibility to deliver different therapeutic dose levels to PTVs in a single treatment session using the Simultaneous Integrated Boost (SIB) technique. The paper aims to describe an automated tool to calculate the dose to be delivered with the SIB-IMRT technique in different anatomical regions that have the same Biological Equivalent Dose (BED), i.e. IsoBED, compared to the standard fractionation.MethodsBased on the Linear Quadratic Model (LQM), we developed software that allows treatment schedules, biologically equivalent to standard fractionations, to be calculated. The main radiobiological parameters from literature are included in a database inside the software, which can be updated according to the clinical experience of each Institute. In particular, the BED to each target volume will be computed based on the alpha/beta ratio, total dose and the dose per fraction (generally 2 Gy for a standard fractionation). Then, after selecting the reference target, i.e. the PTV that controls the fractionation, a new total dose and dose per fraction providing the same isoBED will be calculated for each target volume.ResultsThe IsoBED Software developed allows: 1) the calculation of new IsoBED treatment schedules derived from standard prescriptions and based on LQM, 2) the conversion of the dose-volume histograms (DVHs) for each Target and OAR to a nominal standard dose at 2Gy per fraction in order to be shown together with the DV-constraints from literature, based on the LQM and radiobiological parameters, and 3) the calculation of Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) curve versus the prescribed dose to the reference target.

Impact of average weekly dose of radiation during radiotherapy alone or chemoradiotherapy in head and neck cancer

Altered fractionated radiotherapy (RT) has been shown to improve locoregional control (LRC) and overall survival (OS) in squamous cell cancer of the head and neck (SCCHN). We investigated patient outcomes using a new parameter: the average weekly dose (AWD). The medical records of 601 patients who received definitive RT for SCCHN were reviewed. AWD was calculated by dividing the total dose in Gray (Gy) by overall treatment time in weeks, and assessed for predictive value. Various standard RT fractionation schedules were used. An AWD >10.0 Gy was associated with improved LRC at 2 years for patients treated with RT alone (80.9% vs 60.9%; p = .006), but not for those treated with concurrent chemoradiation (75.3% vs 77.3%; p = .77). Nonsignificant increases in late dysphagia were seen with AWD >10.0 Gy. An AWD of >10 Gy was found to be beneficial for RT alone regimens but not chemoradiotherapy regimens.

Comparison of Radiation-Induced Fatigue using 3 Fractionation Schedules in Breast Radiotherapy

Radiation-induced fatigue is a common side effect of breast cancer radiotherapy. Treatment regimens such as partial breast irradiation and hypofractionation presume to cause less fatigue in treatment compared to standard fractionation schedules. The purpose of this study is to compare the induction and persistence of radiation-induced fatigue in 3 different fractionation schedules in breast cancer radiotherapy.

Comparison of Three Treatment Schemes for Lung SBRT

The optimal stereotactic body radiation therapy (SBRT) dose and fractionation schedule for lung cancer treatment is unknown. We evaluated local control and overall survival in a large institutional cohort treated with one of three regimens.

The BJR and progress in radiobiological modelling

Exactly 21 years ago this journal published an extensive article by Professor Jack Fowler [1], which examined the role of the linear-quadratic (LQ) radiobiological model in stratifying radiotherapy fractionation schedules. At that time the LQ model was already well-established, but its fuller and more practical usefulness was still unfolding. Fowler's 1989 paper introduced the concept of biologically effective dose (BED) as an overall “one-number” measure of the biological effectiveness of a radiotherapy schedule on a given tissue. With BED, Fowler extended the earlier concept of extrapolated response dose (ERD) [2] (in particular, by introducing allowance for tumour repopulation effects during treatment). He used it to demonstrate the value of modelling in making choices between different radiotherapy treatments. This article has been particularly well cited. In this edition of the BJR, Fowler revisits the role of BED and, in a wide-ranging review [3] (which includes many references to the role played by the BJR) examines how quantitative radiobiology has helped progress the design and analysis of new schedules. This includes those that do not involve conventional low-LET external beam delivery. In particular, Fowler identifies how even simple modelling has proved capable of separating out the relative influence of the factors that govern radiotherapy in a wide variety of clinical circumstances. Two points are especially noteworthy. Firstly, the interval between the two articles serves as a reminder that useful scientific developments frequently have a long lead-in time before they become widely accepted. That some progress is being made can be seen in the fact that Part I FRCR examinations in clinical oncology now routinely include LQ-related questions. Secondly, as Fowler pointed out in 1989 and does so again here, although the LQ model itself remains an over-simplified description of the events which govern radiotherapy response, its strength stems from its ability to identify potentially dangerous treatments that are best avoided. Given the complexity of many modern radiotherapy techniques and how rapidly advances are being made, this is a particularly valuable asset. While it may appear that radiobiological modelling is in a healthy state, there are some concerns. One worry is that BED, instead of being considered as the fulcrum measure of the radiobiological impact of any given schedule, is sometimes confused with EQD2, the “equivalent total dose which, when delivered in 2 Gy fractions of photon irradiation, produces the same biological effect”. This confusion between “biologically effective” and “biologically equivalent” doses is easy to understand, given the similarity between the names and the fact that both are expressed in physical dose units (Gy). However, frequent misuse of BED has the capacity to create new problems and to undermine progress [4]. For some of the newer radiotherapy techniques, for example those using technologically advanced beam delivery patterns, high LET radiations or biologically targeted radionuclides, it is perhaps questionable whether the concept of “2 Gy photon equivalence” has much relevance in these areas. If this is the case, the argument for judging all schedules in terms of “biological doses” (BEDs) is strengthened. On account of this, Fowler [3] proposes that consideration be given to introducing a unit that is unique to BED. Such an idea was first put forward in embryonic form in 2009 [5], the suggestion then being made specifically by the nuclear medicine community to help establish easier comparison between the results of targeted radionuclide therapy with those seen with conventional external beam therapy. But, as Fowler points out [3], the establishment of a dedicated unit for BED would have wider benefit and impact, not least because it would help to remove some wider confusion. The suggested name for the BED unit is the barendsen (symbol Bd), in recognition of the seminal work of Professor GW Barendsen [3–5]. The process of considering a unit for expressing deterministic effects in radiation oncology is likely to be a protracted process (it will require international agreement on concepts, quantities and units), but the need has been established. The message emerging from Fowler's latest article is that properly applied radiobiological principles can positively guide the introduction of technological and fractionation advances in radiotherapy. However, it is also noteworthy that Fowler reflects on the fact that only in retirement did he have the time to give this topic his full attention. Given Fowler's eminence in the field, this must surely be the strongest of indications that this important and expanding field now justifies the serious attention of a new generation of oncologists and scientists who can contribute ideas and advance them. This is something the BJR wishes to continue to encourage and support.

Prospective randomized trial comparing postoperative adjuvant concurrent versus sequential hormonal and different radiation fractionation schedule in breast cancer patients.

544 Background: To evaluate the optimal sequencing of tamoxifen (T) and radiation therapy (RT) after surgery (S) in breast cancer (BC) patients regarding pulmonary fibrosis (PF), breast cosmesis (BC) and tt outcome and to compare the acute, late toxicity and tt outcome resulting from two different fractionation schedules. Methods: This prospective randomized study included 308 female patients who underwent S followed by chemotherapy if indicated, subsequently randomized to receive p/o conventional fractionation (CF) (50 Gy in 25 fractions over 35 days - 200 cGy/fraction) concomitant or sequentialwith T or to receivehypofractionated protocol (HF) (40 Gy in 15 fractions over 3 weeks - 267 cGy /fraction) concomitantor sequentially with T (Patients with conservative surgery less than 50 years received boost to tumor bed 1600 cGy in 8 fractions over 1.5 weeks). Results: There was no statistical significant difference between the early, late skin reactions, BC grades,and symptomatic cough among the concurrent and sequential T treatment sub-groups. CT lung fibrosis at 1 year increased from 13.6% to 22.7% in the concurrent T (p = 0.039). The sequence of T did not influence 4year OS (concurrent 82.4%; sequential 81.7%; p = 0.831),or that of locoregional DFS (concurrent 94.8%; sequential 96.2%; p = 0.555), as well as distant-free survival (concurrent 73.4%; sequential 72.4%; p = 0.911). There was statistical significant difference between early skin reactions of the two different fractionation groups. The maximum early skin reactions, in CR occurred during the fifth week of tt, while in HF occurred during the second and third week of tt. There was no difference between the 2 groups regarding late skin toxicity, cosmetic grades, occurrence of cough and PF as proved by CT.The different fractionation schedules did not influence 4year OS (CF 79.2%; HF 84.8%; p = 0.408), or locoregional DFS (CF 94.1%;HF 97%; p = 0.265) and DFS (CF 70.2%; HF 75.7%; p = 0.248). Conclusions: The use of T concurrently with RT does not compromise the early or late skin reactions, BC, local control or OS however the incidence of PF was increased. HF appear to be as favorable as the standard CF. No significant financial relationships to disclose.

Stochastic modelling of the role of cisplatin in altered fractionation schedules for head and neck cancer

Advanced head and neck cancers are one of the most challenging cancers facing the oncologists due to their aggressiveness attributable to the high hypoxic content and the tumour's ability to repopulate during radiotherapy. Alterations of radiotherapy fractionation schedules are possible ways to improve tumour control. Clinical trials have shown that both hyperfractionated radiotherapy (multiple fractions a day, over the same treatment time), and accelerated radiotherapy (higher doses per fraction, six days a week, over 5 weeks or less) are more effective than conventional radiotherapy in the management of head and neck cancer. However, the treatment choice between hyperfractionated and accelerated radiotherapy is still debated, due to very similar results obtained regarding tumour control. Furthermore, while radiotherapy alone has an impact on the short-term prognosis of advanced head and neck cancer, the long-term benefits have been moderate. Cisplatin is a chemotherapeutic agent which combined with conventional radiotherapy has shown to improve patient survival. The present paper employs a Monte Carlo modelling approach in assessing the effect of combined cisplatin-altered fractionation schedule on tumour response. The growth of a head and neck carcinoma has been modelled using probabilistic functions sampled by computer generated random number sequences, maintaining the biological constitution of a tumour. The tumour growth model has been built to simulate the in vivo processes taking place before and after radiotherapy/chemotherapy. The model has shown that adding cisplatin to radiotherapy improves tumour control in both hyperfractionated and accelerated radiotherapy.

A multinomial model of tumor growth treated by radiotherapy

A main challenge in radiotherapy is to personalize the treatment by adapting the dose fractionation scheme to the patient. One way is to model the treatment effect on the tumor growth. In this study, we propose a new multinomial model based on a discrete-time Markov chain, able to take into account both of cell repair and cell damage heterogeneity. The proposed model relies on the ‘Hit’ theory in Radiobiology and assumes that a cancer cell contains m targets which must be all deactivated to produce cell death. The malignant cell population is then split up into m categories to incorporate the variation of cancer cell radio-sensitivity according to their states. This work gives also a new formulation of the tumor control probability (TCP) suited to the perspective of dynamic fractionation schedules in radiotherapy.

A Comparison Study of Radiotherapy Toxicity between Conventional and Hypofractionated Whole Breast Radiotherapy

The aim is to compare the acute skin toxicity between two different fractionation schedules of adjuvant whole breast radiotherapy, conventional fractionation radiotherapy and hypofractionated radiotherapy. This is a prospective study of breast cancer patients referred for adjuvant radiation therapy. Radiation therapy was given either as conventional fractionation radiotherapy (5000 cGy/ 25 fractions / 5 weeks) or hypofractionated radiotherapy (4005 cGy/15 fractions / 3 weeks). Acute RT toxicity was evaluated using the Radiation Therapy Oncology Group toxicity grading system; the incidence of radiation therapy toxicity was compared. Seventy-eight patients were accrued in the study, 58% had breast conservative surgery and 42% had modified radical mastectomy. 54% were treated with hypofractionated radiotherapy and 46% with conventional fractionation radiotherapy, while 64% had Grade 0-II radiation therapy toxicity and 36% had Grade III-IV toxicity. On univariate analysis, the incidence of radiation therapy toxicity was (52.8%) in conventional fractionation radiotherapy group as compared to 21.4% in hypofractionated radiotherapy group (p = 0.004); other variables were not statistically significant. On multivariate analysis radiotherapy fractionation was the only factor of statistical significance regarding the incidence of radiation reaction (p = 0.03). This study showed fewer incidences of acute radiation reactions in hypofractionated arm as compared to conventional fractionated arm in the adjuvant whole breast radiotherapy.

Phase I Trial Using Patupilone (Epothilone B) and Concurrent Radiotherapy for Central Nervous System Malignancies

Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicity requiring hospitalization, occurred during treatment. Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m(2), 4 at 2.0 mg/m(2), 4 at 2.5 mg/m(2), and 1 at 4 mg/m(2). Of 18 patients, 7 were treated in the 6-mg/m(2) group, 6 in the 8-mg/m(2) group, and 5 in the 10-mg/m(2) group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m(2) every 3 weeks. At the subsequent dose level (10 mg/m(2)), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m(2) every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m(2) every 3 weeks.

Validation of Lysyl Oxidase As a Prognostic Marker for Metastasis and Survival in Head and Neck Squamous Cell Carcinoma: Radiation Therapy Oncology Group Trial 90-03

To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial. We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS). LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile. AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.

A Comparison of Two Stereotactic Body Radiation Fractionation Schedules for Medically Inoperable Stage I Non-small Cell Lung Cancer: The Cleveland Clinic Experience

To assess the impact of fractionation upon tumor control and toxicity in medically inoperable early stage lung cancer patients treated with stereotactic body radiotherapy. We reviewed 94 consecutive stereotactic body radiotherapy treatments (86 patients) with medically inoperable stage I non-small cell lung cancer receiving either 50 Gy in five fractions (n = 56) or 60 Gy in three fractions (n = 38) from October 2003 to August 2007. Institutional practice was 10 Gy x 5 before March 1, 2006, when it changed to 20 Gy x 3 to conform to Radiation Therapy Oncology Group 0236 unless otherwise dictated clinically. Median age was 73 years and median Karnofsky performance status 80. A total of 69 lesions were T1, 24 were T2 lung cancer. Median follow-up was 15.3 months. For the 50- and 60-Gy cohorts at 1 year, local control was 97.3% versus 100%, nodal failure 7.3% versus 3.4%, distant metastasis rate 21.8% versus 29.5%, and overall survival 83.1% versus 76.9% (p = 0.68, 0.54, 0.56, and 0.54, respectively). There was no difference in overall survival for patients with histologic (n = 61) compared with radiographic (n = 33) diagnosis. There was no impact of fractionation in the subset of T2 tumors. We observed two cases (2.2%) of clinical grade 2 pneumonitis. Mild late chest wall toxicity (grade 1 or 2) was seen in nine patients (10%) at a median of 8.4 months after treatment and was more common in the 60-Gy group (7 of 38 [18%] versus 2 of 56 [4%], p = 0.028). Local control, overall survival, nodal failure, and distant failure were not affected by fractionation. Chest wall toxicity was more common with 60-Gy group.

A phase I trial using patupilone (epothilone B) and concurrent radiotherapy for CNS malignancies

e14504 Background: Based on pre-clinical data indicating the radiosensitizing potential of Epothilone B, this study was designed to evaluate the toxicity and response rate of patupilone (EPO906), an anti-microtubule stabilizing agent, with concurrent radiotherapy in the treatment of patients with CNS malignancies. Methods: This phase I study evaluated the toxicities associated with patupilone in combination with radiotherapy for the treatment of CNS malignancies in order to establish maximum tolerated dose (MTD). Eligible patients had recurrent gliomas (10), primary (5), or metastatic (17) brain tumors. Dose escalation occurred if no dose limiting toxicities (DLT) defined as any Grade 4–5 toxicity or Grade 3 toxicity requiring hospitalization or interruption of radiation therapy. Results: A total of 32 patients were enrolled. Five patients were treated with weekly patupilone at 1.5 mg/m2, 4 patients at 2.0 mg/m2, 4 patients at 2.5 mg/m2 and one patient at 4mg/m2. Based on sponsor recommendations, the protocol was changed to a q-3 week dosing schedule with a starting dose of 6 mg/m2. Seven patients were treated in the 6 mg/m2 group, 6 patients in the 8 mg/m2 cohort and 5 patients in the 10 mg/m2 group. Radiation treatment was determined by the patient's diagnosis. Primary CNS malignancies received a median dose of 60 Gy in 1.8–2.0 Gy fractions. CNS metastases received whole brain radiation with a median dose of 37.4 Gy in 1.8–2.5 Gy fractions and patients with recurrent gliomas received stereotactic radiotherapy with a median dose of 37.5 Gy in 2.0–3.5 Gy fractions. No DLTs were observed in patients who received weekly patupilone or in the 6 mg/m2 q3wk cohort. One DLT (pneumonia/infection without neutropenia) was observed at the 8 mg/m2 q3wk group. In the subsequent dose level (10 mg/m2), two grade 4 DLTs occurred (renal failure and pulmonary hemorrhage) making 8 mg/m2 q3wk the MTD and recommended phase II dose. Median overall survival was 12 months for recurrent gliomas, 15 months for primary brain tumors and 4 months for CNS metastasis. Conclusions: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone is well tolerated and safe with a MTD of 8 mg/m2 q3wk. A phase II study to characterize efficacy should be considered. No significant financial relationships to disclose.

Radiothérapie : quelles orientations thérapeutiques contre les séquelles digestives ?

Despite constant progress in radiotherapy techniques such as tumour imaging and cartography, techniques of radiation delivery or fractionation schedules, damage to normal gastro-intestinal tissues is inevitably associated with radiation therapy of pelvic tumours. Acute radiation enteritis concerns 80% of patients. It is related to stem cell loss, default in epithelial regenerating capacity and inflammation-induced mucosal dystrophy and ulceration. Chronic injury may develop in 5 to 10% of patients and is characterized by intestinal wall fibrosis resulting from an exaggerated scarring process, chronic inflammation and tissue necrosis. Research in mechanistic processes of normal tissue damage paved the way for new therapeutic approaches to emerge. These new targets include mucosal regeneration, reduction of vascular activation, inflammation and thrombosis, and fight against mesenchymal cells sustained activation. Effective strategies are multiple on preclinical models, but numerous efforts have to be made to achieve the complicated goal of protection of normal tissues from the side effects of radiation therapy.

Shorter fractionation schedules in breast cancer radiotherapy: Clinical and economic implications

An accumulating body of level I evidence from randomised trials of adjuvant radiotherapy in early breast cancer supports the safety and efficacy of giving a lower total dose in fewer larger fractions (hypofractionation) than the historical standard of 50 Gy in 25 fractions of 2.0 Gy over 5 weeks. 1 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008; 371: 1098-1107 Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar , 2 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008; 9: 331-341 Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar , 3 Owen J.R. Ashton A. Bliss J.M. et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006; 7: 467-471 Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar , 4 Whelan T. MacKenzie R. Julian J. et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002; 94: 1143-1150 Crossref PubMed Scopus (554) Google Scholar The published phase 3 trials relate to patients prescribed whole breast radiotherapy, but the principle is being extended to trials evaluating partial breast irradiation restricted to the tumour bed. 5 Orecchia R. Ciocca M. Lazzari R. et al. Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer. Breast. 2003; 12: 483-490 Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar , 6 Vaidya JS, Baum M, Tobias JS, Houghton J. Lancet. Targeted intraoperative radiotherapy; 1999. <http://www.thelancet.com/journals/lancet/misc/protocol/99PRT-47>. Google Scholar , 7 Strnad V, Polgar C. On behalf of the European Brachytherapy Breast Cancer GEC-ESTRO Working Group. GEC-ESTRO APBI Trial: interstitial brachytherapy alone versus external beam radiation therapy after breast conserving surgery for low risk invasive carcinoma and low risk duct carcinoma in-situ (DCIS) of the female breast; 2006. <http://www.apbi.uni-erlangen.de/outline/outline.html>. Google Scholar , 8 Wolmark N, Curran WJ. Trial protocol March 13, 2007. On behalf of NSABP and RTOG of the American College of Radiology (ACR). NSABP Protocol B-39. RTOG Protocol 0413. A randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. National surgical adjuvant breast and bowel project (NSABP); 2007. p. 1–132. Google Scholar , 9 OCOG. Ontario Clinical Oncology Group (OCOG), Canadian Institutes of Health Research (CIHR), Canadian Breast Cancer Research Alliance. RAPID: Randomized Trial of Accelerated Partial Breast Irradiation; 2008. <http://clinicaltrials.gov/ct2/show/NCT00282035>. Google Scholar , 10 Yarnold J, Coles C. Trial Protocol, version 4, 19.02.2008. On behalf of the IMPORT LOW Trial Management Group: Intesity Modulated and Partial Organ Radiotherapy. Randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer. Sutton, Surrey, UK: The Institute of Cancer Research: Royal Cancer Hospital; 2008. p. 1–74. Google Scholar , 11 http://www.irmatrial.it/. Google Scholar Interest in hypofractionation is based not only on the practical advantages to patients and health services of fewer hospital visits, but also on two postulated clinical benefits. The first is that breast cancer is more sensitive to fraction size than formerly thought, so that fewer larger fractions maintain current levels of anti-tumour effect without increasing late adverse effects. The second is that shorter overall treatment times (accelerated hypofractionation) may be more effective in patients with rapidly proliferating tumours.