A modelled comparison of prostate cancer control rates after high-dose-rate brachytherapy (3145 multicentre patients) combined with, or in contrast to, external-beam radiotherapy.

BACKGROUND AND PURPOSE: To analyse biochemical relapse-free-survival results for prostate cancer patients receiving combined external beam and high-dose-rate brachytherapy, in comparison with expected results using projections based on dose/fractionation/response parameter values deduced from a previous external-beam-alone 5969-patient multicentre dataset. MATERIAL AND METHODS: Results on a total of 3145 prostate cancer patients receiving brachytherapy (BT) as part or all of their treatment were collected from 10 institutions, and subjected to linear-quadratic (LQ) modelling of dose response and fractionation parameters. RESULTS: Treatments with BT components of less than 25Gy, 3-4 BT fractions, doses per BT fraction up to 6Gy, and treatment times of 3-7weeks, all gave outcomes expected from LQ projections of the external-beam-alone data (α/ß=1.42Gy). However, BT doses higher than 30Gy, 1-2 fractions, 9 fractions (BT alone), doses per fraction of 9-15Gy, and treatment in only 1week (one example), gave local control levels lower than the expected levels by up to ∼35%. CONCLUSIONS: There are various potential causes of the lower-than-projected control levels for some schedules of brachytherapy: it seems plausible that cold spots in the brachytherapy dose distribution may be contributory, and the applicability of the LQ model at high doses per fraction remains somewhat uncertain. The results of further trials may help elucidate the true benefit of hypofractionated high-dose-rate brachytherapy.

What would be the most appropriate α/ß ratio in the setting of stereotactic body radiation therapy for early stage non-small cell lung cancer.

We hypothesize that the correlation between the radiation dose expressed as the biologically effective dose (BED) and the clinical endpoints will correlate better as the value of the α/ß ratio is increased to >10 Gy, which theoretically minimizes the overestimation of the dose potency associated with the linear quadratic (LQ) formula in the setting of stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). A search was conducted in the PubMed electronic databases in August 2011. In the studies analyzed, increasing the α/ß ratio is associated with an increase in the strength of the correlation between isocenter BED and local control, especially in the studies with median followup of ≥24 months, for which Spearman's correlation coefficients of 0.74-0.76 were achieved for α/ß of 20 Gy, 30 Gy, and 50 Gy (P = 0.007-0.008). A trend toward statistical significance was observed for the correlation of isocenter BED and the 2-year overall survival when an α/ß of 20 Gy was used approached statistical significance (P = 0.073). Our results suggest that an α/ß > 10 Gy may be more appropriate for the prediction of dose response in the setting of lung SBRT.

Is the α/ß ratio for prostate tumours really low and does it vary with the level of risk at diagnosis?

AIM: To answer the questions: Is the α/ß ratio (radiosensitivity to size of dose-per-fraction) really low enough to justify using a few large dose fractions instead of the traditional many small doses? Does this parameter vary with prognostic risk factors? METHODS AND MATERIALS: Three large statistical overviews are critiqued, with results for 5,000, 6,000 and 14,000 patients with prostate carcinoma, respectively. RESULTS: These major analyses agree in finding the average α/ß ratio to be less than 2 Gy: 1.55, (95% confidence interval=0.46-4.52), 1.4 (0.9-2.2), and the third analysis 1.7 (1.4-2.2) by the ASTRO and 1.6 (1.2-2.2) by Phoenix criteria. All agree that α/ß values do not vary significantly with the low, intermediate, high and "all-included" risk factors. CONCLUSION: The high sensitivity to dose-per-fraction is an intrinsic property of prostate carcinomas and this supports the use of hypo-fractionation to increase the therapeutic gain for these tumours with dose-volume modelling to reduce the risk of late complications in rectum and bladder.

Revising the radiobiological model of synchronous chemotherapy in head-and-neck cancer: a new analysis examining reduced weighting of accelerated repopulation.

PURPOSE: Previous studies of synchronous chemoradiation therapy have modeled the additional effect of chemotherapy as additional radiation therapy biologically effective dose (BED). Recent trials of accelerated versus conventional fractionation chemoradiation have cast doubt on such modeling. The purpose of this study was to identify alternative models. METHODS AND MATERIALS: Nine trials of platinum-based chemoradiation were identified. In radiation therapy-alone arms, the radiation therapy BED for tumor was calculated using standard parameters. In chemoradiation arms, 3 methods were used to calculate tumor BED (tBED): additional BED, addition of 9.3 Gy BED for tumor to the radiation therapy BED; zero repopulation, BED with no correction for repopulation; variable t(p) (the average doubling time during accelerated repopulation), values of t(p) 3-10 were used to examine a partial suppression of repopulation. The correlations between the calculated percentage change in tBED for each method and observed percentage change in local control were assessed using the Pearson product moment correlation. RESULTS: Significant correlations were obtained for all 3 methods but were stronger with zero repopulation (P=.0002) and variable tp (t(p) = 10) (P=.0005) than additional BED (P=.02). CONCLUSIONS: Radiobiological models using modified parameters for accelerated repopulation seem to correlate strongly with outcome in chemoradiation studies. The variable tp method shows strong correlation for outcome in local control and is potentially a more suitable model in the chemoradiation setting. However, a lack of trials with an overall treatment time of more than 46 days inhibits further differentiation of the optimal model.

Effect of fractionation in stereotactic body radiation therapy using the linear quadratic model.

PURPOSE: To examine the fractionation effect of stereotactic body radiation therapy with a heterogeneous dose distribution. METHODS: Derived from the linear quadratic formula with measurements from a hypothetical 2-cm radiosurgical tumor, the threshold percentage was defined as (α/ß(tissue)/α/ß(tumor)), the balance α/ß ratio was defined as (prescription dose/tissue tolerance*α/ß(tumor)), and the balance dose was defined as (tissue tolerance/threshold percentage). RESULTS: With increasing fractions and equivalent peripheral dose to the target, the biological equivalent dose of "hot spots" in a target decreases. The relative biological equivalent doses of serial organs decrease only when the relative percentage of its dose to the prescription dose is above the threshold percentage. The volume of parallel organs at risk decreases only when the tumor's α/ß ratio is above the balance α/ß ratio and the prescription dose is lower than balance dose. CONCLUSIONS: The potential benefits of fractionation in stereotactic body radiation therapy depend on the complex interplay between the total dose, α/ß ratios, and dose differences between the target and the surrounding normal tissues.

Reirradiation human spinal cord tolerance for stereotactic body radiotherapy.

PURPOSE: We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1-5 fractions of stereotactic body radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM). METHODS AND MATERIALS: Spinal cord dose-volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P(max)), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/ß = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy(2/2)). RESULTS: The initial conventional radiotherapy nBED ranged from ~30 to 50 Gy(2/2) (median ~40 Gy(2/2)). The SBRT reirradiation thecal sac mean P(max) nBED in the no-RM group was 20.0 Gy(2/2) (95% confidence interval [CI], 10.8-29.2), which was significantly lower than the corresponding 67.4 Gy(2/2) (95% CI, 51.0-83.9) in the RM group. The mean total P(max) nBED in the no-RM group was 62.3 Gy(2/2) (95% CI, 50.3-74.3), which was significantly lower than the corresponding 105.8 Gy(2/2) (95% CI, 84.3-127.4) in the RM group. The fraction of the total P(max) nBED accounted for by the SBRT P(max) nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53. CONCLUSIONS: SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P(max) nBED of 20-25 Gy(2/2) appears to be safe provided the total P(max) nBED does not exceed approximately 70 Gy(2/2), and the SBRT thecal sac P(max) nBED comprises no more than approximately 50% of the total nBED.

Later outcomes and alpha/beta estimate from hypofractionated conformal three-dimensional radiotherapy versus standard fractionation for localized prostate cancer.

PURPOSE: Now that the follow-up time has exceeded 5 years, an estimate of the α/ß ratio can be presented. The additional late outcomes in patients treated with three-dimensional conformal external beam radiotherapy for localized prostate cancer using a hypofractionated vs. a standard fractionation regimen are reported from this prospective nonrandomized contemporary comparison. METHODS AND MATERIALS: A total of 114 nonrandomized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy (mean 3.06 Gy) for localized prostate cancer within a median overall time of 32 days (range, 29-49) using four fractions weekly. A total of 160 comparable patients were contemporarily treated within a median of 55 days (range 49-66). The median follow-up was 66 months (range, 24-95) for the hypofractionated arm and 63 months (range, 36-92) for the standard arm. The percentage of patients in the low-, medium-, and high-risk groups was 36%, 46%, and 18% in the hypofractionated arm and 44%, 50%, and 6% in standard arm (2 Gy), respectively. RESULTS: The 5-year actuarial biochemical absence of disease (prostate-specific antigen nadir + 2 ng/mL) and disease-free survival rate was the same at 89% in both arms, making the α/ß calculation unambiguous. The point ratio of α/ß was 1.86 (95% confidence interval, 0.7-5.1 Gy). The 95% confidence interval was determined entirely by the binomial confidence limits in the numbers of patients. Rectal reactions of grade 3 and 4 occurred in 1 of 114 (hypofractionated) and 2 of 160 (standard) patients. CONCLUSIONS: The presented three-dimensional conformal regimen was acceptable, and the α/ß value was 1.8, in agreement with other very recent low meta-analyses (reviewed in the "Discussion" section).

A Comment on Qi et al.: An Estimation of Radiobiological Parameters for Head-and-Neck and the Clinical Implications. Cancers, 2012, 4, 566-580.

Important results were shown as cell survival points in the two panels of the figure which is reproduced in this Comment letter. A curve was fitted assuming the mono-exponential recovery half-time of 17 ± 21 minutes. The wide error limits indicate that this fit is not very good, but the notable feature of both panels is that the last four points are clearly continuing to rise, above the "fitted" curve. This indicates that there is a second, slower, component of repair or recovery and this Comment explores constructively the implications of that additional discovery.

Hypofractionated versus conventionally fractionated radiotherapy for prostate carcinoma: final results of phase III randomized trial.

PURPOSE: To evaluate the long-term efficacy and toxicity of a hypofractionated (55 Gy in 20 fractions within 4 weeks) vs. a conventionally fractionated (64 Gy in 32 fractions within 6.5 weeks) dose schedule for radiotherapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS: A total of 217 patients were randomized to either the hypofractionated (n=108) or the conventional (n=109) dose schedule. Most patients (n=156) underwent RT planning and RT using a two-dimensional computed tomography method. Efficacy using the clinical, radiologic, and prostate-specific antigen data in each patient was evaluated before RT and at predetermined intervals after RT until death. Gastrointestinal and genitourinary toxicity using the modified Late Effect in Normal Tissue-Subjective Objective Management Analytic (LENT-SOMA) scales was also evaluated before and at intervals after RT to 60 months. RESULTS: The whole group has now been followed for a median of 90 months (range, 3-138). Of the 217 patients, 85 developed biochemical relapse (nadir prostate-specific antigen level+2 µg/L), 36 in the hypofractionated and 49 in the conventional group. The biochemical relapse-free, but not overall, survival at 90 months was significantly better with the hypofractionated (53%) than with the conventional (34%) schedule. Gastrointestinal and genitourinary toxicity persisted 60 months after RT and did not differ between the two dose schedules. Multivariate analyses revealed that the conventional schedule was of independent prognostic significance, not only for biochemical failure, but also for an increased risk of worse genitourinary symptoms at 4 years. CONCLUSIONS: A therapeutic advantage of the hypofractionated compared with the conventional dose schedule for RT of prostate cancer was evident at 90 months in the present study.

Stereotactic body radiation therapy in non-small-cell lung cancer: linking radiobiological modeling and clinical outcome.

For patients with peripheral, early-stage non-small-cell lung cancer, it has been found feasible to deliver 5 or fewer fractions of large doses through stereotactic body radiation therapy (SBRT) without causing severe early or late injury and with impressive tumor control. In this review, we employ radiobiological modeling with the linear quadratic formulation to explore the adequacy of various dose schedules used for tumor control in the lung as supported by clinical evidence, the influence of dose distribution and delivery time on local control, and how to decrease the likelihood of severe toxicity following SBRT. Furthermore, the validity of the linear quadratic formalism in the high dose range of SBRT for lung cancer is explored.

Acute and late toxicity in a randomized trial of conventional versus hypofractionated three-dimensional conformal radiotherapy for prostate cancer.

PURPOSE: To compare the toxicity between hypofractionation vs. conventional fractionation schedules in patients with high-risk prostate cancer. METHODS AND MATERIALS: Between January 2003 and December 2007, 168 patients were randomized to receive either hypofractionated (62 Gy in 20 fractions within 5 weeks, 4 fractions/wk) or conventionally fractionated (80 Gy in 40 fractions within 8 weeks) three-dimensional conformal radiotherapy to the prostate and seminal vesicles. All patients had undergone a 9-month course of total androgen deprivation, with radiotherapy starting 2 months after initiation of the total androgen deprivation. RESULTS: The median follow-up was 32 and 35 months in the hypofractionation and conventional fractionation arms, respectively. For the patients developing acute toxicity, no difference between the two fractionation groups was found in either severity or duration of gastrointestinal or genitourinary toxicity. Also, no difference was found in the incidence and severity of late gastrointestinal and genitourinary toxicity between the two treatment schedules, with a 3-year rate of Grade 2 or greater toxicity of 17% and 16% for the hypofractionation arm and 14% and 11% for the conventional fractionation arm, respectively. A statistically significant correlation between acute and late gastrointestinal toxicity was found only in the conventional fractionation group. CONCLUSION: Our findings suggest that the hypofractionation regimen used in our study is safe, with only a slight, nonsignificant increase in tolerable and temporary acute toxicity compared with the conventional fractionation schedule. The severity and frequency of late complications was equivalent between the two treatment groups.

Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy.

PURPOSE: This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction. MATERIALS AND METHODS: Patients, treated in prospective trials of concomitant chemo-IMRT with 2.17 Gy, 2.25 Gy and 2.4 Gy per fraction and identical dose of cisplatin, were included in this study. Acute toxicity was recorded prospectively using the CTCAE v2.0. We describe the incidence and prevalence of grade 3 oral mucositis and dysphagia over time and report the influence of overall treatment time (OTT). The association between the lengths of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) and grade 3 dysphagia was tested. RESULTS: The incidence and the peak prevalence of grade 3 dysphagia were significantly higher in patients receiving 2.4 Gy per fraction. The peak prevalence of grade 3 dysphagia was higher and the recovery was slower in patients with lower OTT (median 38 days vs. 42 days) treatment. There was a significant correlation between L50, L60 and grade 3 dysphagia. A L50 and L60 greater than 8 cm resulted in greater than 60% and 70% incidence of grade 3 dysphagia, respectively. CONCLUSION: The length of pharyngeal mucosa receiving doses close to the prescription dose correlates with grade 3 dysphagia. It was observed that incidence of grade 3 dysphagia was lower and recovery from it was quicker in patients with greater OTT.

A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117.

PURPOSE: In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer. METHODS AND MATERIALS: Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m(2), and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions. RESULTS: The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade >or=3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients). CONCLUSIONS: The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.

Red shell: defining a high-risk zone of normal tissue damage in stereotactic body radiation therapy.

PURPOSE: To define a volume of tissue just outside of the clinical target volume (CTV) or planning target volume (PTV) in stereotactic body radiation therapy (SBRT) that receives doses appreciably above the tolerance level and in which other critical tissue structures must be avoided. METHODS AND MATERIALS: We define the tissue between the borders of the CTV and PTV as the Inner Red Shell. The tissue surrounding the PTV that receives higher than the local tissue tolerance is defined as the Outer Red Shell. Contributing factors to the volume of the Red Shell include the prescription dose, dose gradient and PTV size, together with the type of tissue and its tolerance are discussed. An illustrative example and two clinical cases are reported. RESULTS: The volume of Red Shell increases with higher prescription dose, slower dose fall-off, larger PTV volume, and higher tissue radiosensitivity. Avoidance of proximal critical serial organs may alter the volume and shape of the Red Shell after repeated, detailed treatment planning. CONCLUSION: Rather than defining tolerance and toxicity as simply a dose level received by the tissues, the volume of tissue receiving risk levels above tolerance can be quantified as the "cost" of SBRT. This concept may be adopted in other techniques offering ablative and high-dose gradients. Further consideration should be given to collecting clinical data for refining the choice of constraint doses, especially in parts of the brain, lung, liver, and kidney.

Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117.

PURPOSE: Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non-small-cell lung cancer (NSCLC). Phase II results are reported here. PATIENTS AND METHODS Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m(2) and carboplatin at area under the curve 2 mg/m(2). The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be or= 3 lung toxicity (two patients had grade 5 lung toxicity). CONCLUSION: The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.