Standard Fractionation Schedule Research Articles

Radioterapija raka dojke - promjene u shemama frakcioniranja kroz desetljeća

Traditionally, as a standard dose fractionation schedule, adjuvant radiotherapy for breast cancer has been performed using prescribed doses of 46–50 Gy divided into daily fractions of 1.8–2 Gy. Overall, radiotherapy treatment took 5 weeks. In the 1990s, schedules using higher daily doses (2.5–3 Gy), a smaller number of fractions (hypofractionation), and a reduced overall prescribed dose started in the context of clinical trials. First results revealed an equivalent cosmetic effect of hypofractionated protocols compared to standard fractionation, and after longer follow-up, hypofractionation was connected with better control of the disease. Hypofractionation started to be considered the new treatment standard. Results of newer clinical trials confirm the efficacy and safety of adjuvant breast cancer radiotherapy lasting 5 working days using daily fractions of 5.2 Gy in certain subgroups of breast cancer patients.

Similar long-term swallowing outcomes for accelerated, mildly-hypofractionated radiotherapy compared to conventional fractionation in oropharyngeal cancer: A multi-centre study

Background and purposeThere is renewed interest in hypofractionated radiotherapy, but limited data and a lack of consensus to support use for head and neck cancer. In this multicentre analysis we compared outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with conventional and accelerated, mildly hypofractionated radiotherapy without chemotherapy. Materials and methodsA multi-centre, observational study of consecutive OPSCCs treated between 2015 and 2018. Patients underwent curative-intent radiotherapy (oropharyngeal and bilateral neck) using conventionally fractionated (70 Gy in 35 fractions over 7 weeks, n = 97) or accelerated, mildly hypofractionated (65–66 Gy in 30 fractions over 6 weeks, n = 136) radiotherapy without chemotherapy. Locoregional control (LRC) and overall survival (OS) were compared. Patients alive and cancer-free at a minimum of 2 years post-radiotherapy (n = 151, 65%) were sent an MD Anderson Dysphagia Inventory (MDADI) questionnaire to assess swallow function. ResultsLRC and OS were similar across schedules (p = 0.78 and 0.95 respectively, log-rank test). Enteral feeding rates during radiotherapy appeared higher in the 7-week group though this did not reach statistical significance (59% vs 48%, p = 0.08). Feeding rates were similar at 1 year post radiotherapy for both groups (10% vs 6%, p = 0.27). 107 patients returned MDADI questionnaires (71%); there were no differences between the 6- and 7-week groups for median global (60.0 vs 60.0, p = 0.99) and composite (65.8 vs 64.2, p = 0.44) MDADI scores. ConclusionPatients with OPSCC treated with radiotherapy alone have similar swallowing outcomes, LRC and OS following accelerated, mild hypofractionation and standard fractionation schedules, supporting its use as a standard-of-care option for patients unsuitable for concurrent chemotherapy.

A Palliative Radiation Oncology Consult Service Reduces Total Costs During Hospitalization

ContextPalliative radiation therapy (PRT) is a highly effective treatment in alleviating symptoms from bone metastases; however, currently used standard fractionation schedules can lead to costly care, especially when patients are treated in an inpatient setting. The Palliative Radiation Oncology Consult (PROC) service was developed in 2013 to improve appropriateness, timeliness, and care value from PRT. ObjectivesOur primary objective was to compare total costs among two cohorts of inpatients with bone metastases treated with PRT before, or after, PROC establishment. Secondarily, we evaluated drivers of cost savings including hospital length of stay, utilization of specialty-care palliative services, and PRT schedules. MethodsPatients were included in our observational cohort study if they received PRT for bone metastases at a single tertiary care hospital from 2010 to 2016. We compared total costs and length of stay using propensity score-adjusted analyses. Palliative care utilization and PRT schedules were compared by χ2 and Mann-Whitney U tests. ResultsWe identified 181 inpatients, 76 treated before and 105 treated after PROC. Median total hospitalization cost was $76,792 (range $6380–$346,296) for patients treated before PROC and $50,582 (range $7585–$620,943) for patients treated after PROC. This amounted to an average savings of $20,719 in total hospitalization costs (95% CI [$3687, $37,750]). In addition, PROC was associated with shorter PRT schedules, increased palliative care utilization, and an 8.5 days reduction in hospital stay (95% CI [3.2,14]). ConclusionThe PROC service, a radiation oncology model integrating palliative care practice, was associated with cost-savings, shorter treatment courses and hospitalizations, and increased palliative care.

276P Once-weekly high dose rate interstitial brachytherapy for carcinoma cervix is convenient, effective & well-tolerated

Aim/Background: Interstitial brachytherapy (ISBT) in cervical cancer is used for post-operative gross residual disease and unoperated cases with poor anatomy/or bulky disease precluding intracavitary insertion. There is no standard dose fractionation schedule for ISBT. This study describes a logistically convenient schedule. Methods: The study included 35 patients of advanced non-metastatic carcinoma cervix (squamous cell carcinoma & adenocarcinoma), 24 with bulky primary disease and 11 with vault recurrence/ residual, treated between June 2012 and December 2014. All patients underwent pelvic external beam radiotherapy (EBRT) using standard 4-field technique to a dose of 50Gy/25#/ 5 weeks; para-aortic nodes were treated if involved; concurrent chemotherapy was used wherever appropriate. Thereafter, the patients underwent 2 insertions of high dose rate (HDR) ISBT using the Syed-Neblett perineal template with titanium needles inserted percutaneously under spinal anaesthesia; ISBT was done once weekly as a daycare procedure; all patients underwent computerized tomography (CT) planning on the Brachyvision treatment planning software using volume optimization to achieve standard combined (ie EBRT+ ISBT) dose-volume constraints for 2cc of urinary bladder (EQD2 75Gy) & rectum (EQD2 70Gy) [EQD2= equivalent dose delivered at 2Gy per fraction]; prescribed dose was 9Gy /# to the high-risk clinical target volume. Results: Thirty two patients (91.4%) achieved complete response and 3 achieved partial response. At a median follow-up of 20 months, 30 patients (85.7%) continue to be in remission. No patient had significant post-operative local pain/ bleeding; 4 patients had post-spinal headache persisting beyond 1 day; no patient had local skin/mucosal infection. There were 3 cases of grade 3 late rectal toxicity (8.57%) and none of grade 3 cystitis. Conclusions: Once weekly HDR ISBT for carcinoma cervix is well-tolerated, convenient and effective. The difficulties of continuously retaining the perineal template over several days of continuous therapy, including pain, discomfort and local infection are easily avoided by this protocol. Disclosure: All authors have declared no conflicts of interest.

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundPatient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.MethodsThe CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b–T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.Findings2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4–64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.InterpretationThe incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Abstract OT1-4-01: HIOB trial - Hypofractionated whole-breast irradiation preceded by intraoperative radiotherapy with electrons as anticipated boost

Abstract ClinicalTrials.gov Identifier: NCT01343459 Brief background discussion: The commonly accepted standard fractionation schedule for whole breast irradiation (WBI) consists of 25fractionations with single fractional doses of 2 Gy, resulting in cumulative doses of 50 Gy to the whole breast. Hypofractionation trials from UK and Canada demonstrated a similar outcome in local control and cosmesis compared to conventional fractionation. The combination of IOERT boost and hypofractionation was not yet evaluated. Trial design: Prospective one-armed multi-center trial - ISIORT 01 Eligible patients are treated with hypofractionated whole breast irradiation (WBI) of 40.5 Gy in 2.7 Gy per fraction for 15 days, preceded by an intraoperative electron boost (IOERT) to the tumor bed of 10 Gy (90% isodose) during breast conserving surgery. Eligibility criteria: Inclusion criteria: Invasive breast cancer Age 35 years and older T1/T2, N1/N2, G1 - G3 Hormone receptor and Her 2 status: no limitations Exclusion criteria: Non-invasive breast cancer Age less than 35 years T3/T4, N2/N3 Neoadjuvant chemotherapy Aim of the study: To assess the effectiveness of IOERT in combination with hypofractionated WBI in terms of in-breast tumor control and cosmetic outcome, by matching or exceeding the best published results for annual LR rates in 3 different age groups in reference to an upper limit (exceeding = inferiority) and a lower limit (undershooting = superiority) which were estimated on the basis of the existing literature as follows: Age 35 – 40 years: Upper limit (best published evidence): 1.2 % (EORTC 22881- Boost trial) Lower limit (commonly expected dimension): 0.72 % (CONSORT trial) Age 41 – 50 years: Upper limit (best published evidence): 1.2 % (EORTC 22881- Boost trial) Lower limit (commonly expected dimension): 0.72 % (CONSORT trial) Age over 50 years: Upper limit (best published evidence): 0.7 % (EORTC 22881- Boost trial) Lower limit (commonly expected dimension): 0.4 % (START B trial) Primary endpoint: Proof of superiority or iso-effectiveness. Secondary endpoints: Acute toxicity (CTC- toxicity scoring system) and late toxicity (LENT SOMA scoring system), cosmetic results (Van Limbergen - Score), DFS, OS. Statistical methods: Sequential Probability Ratio Test (SPRT): As a consequence of best published analyses for this patient selection, stopping rules for annual local recurrence rates are defined as follows: Age group 35-40: H0: p1 &amp;lt;= 0.72% vs H1: p1 &amp;gt; 0.72% with p2 = 4.0% Age group 41-50: H0: p1 &amp;lt;= 0.72% vs H1: p1 &amp;gt; 0.72% with p2 = 2.4% Age group 51+: H0: p1 &amp;lt;= 0.4% vs H1: p1 &amp;gt; 0.4% with p2 = 1.4% H0-Hypothesis means no superiority to standard regimen. H1-Hypothesis means superiority of HIOB against best published evidence. Present accrual and target accrual: Start date: January 2011 Estimated enrollment: 1500 patients 542 patients recruited by March 2014 10 international institutions recruiting. Citation Format: Roland Reitsamer, Gerd Fastner, Michael Kopp, Felix Sedlmayer. HIOB trial - Hypofractionated whole-breast irradiation preceded by intraoperative radiotherapy with electrons as anticipated boost [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-4-01.

Safety and efficacy of intensity-modulated stereotactic body radiotherapy using helical tomotherapy for lung cancer and lung metastasis.

Stereotactic body radiotherapy (SBRT) proved to be an effective treatment with acceptable toxicity for lung tumors. However, the use of helical intensity-modulated (IM) SBRT is controversial. We investigated the outcome of lung tumor patients treated by IMSBRT using helical tomotherapy with a Japanese standard fractionation schedule of 48 Gy in 4 fractions (n = 37) or modified protocols of 50–60 Gy in 5–8 fractions (n = 35). Median patient's age was 76 years and median follow-up period for living patients was 20 months (range, 6–46). The median PTV was 6.9 cc in the 4-fraction group and 14 cc in the 5- to 8-fraction group (P = 0.001). Grade 2 radiation pneumonitis was seen in 2 of 37 patients in the 4-fraction group and in 2 of 35 patients in the 5- to 8-fraction group (log-rank P = 0.92). Other major complications were not observed. The LC rates at 2 years were 87% in the 4-fraction group and 83% in the 5- to 8-fraction group. Helical IMSBRT for lung tumors is safe and effective. Patients with a high risk of developing severe complications may also be safely treated using 5–8 fractions. The results of the current study warrant further studies of helical IMSBRT.

Predicting the Risk of Secondary Lung Malignancies Associated With Whole-Breast Radiation Therapy

The risk of secondary lung malignancy (SLM) is a significant concern for women treated with whole-breast radiation therapy after breast-conserving surgery for early-stage breast cancer. In this study, a biologically based secondary malignancy model was used to quantify the risk of secondary lung malignancies (SLMs) associated with several common methods of delivering whole-breast radiation therapy (RT). Both supine and prone computed tomography simulations of 15 women with early breast cancer were used to generate standard fractionated and hypofractionated whole-breast RT treatment plans for each patient. Dose-volume histograms (DVHs) of the ipsilateral breast and lung were calculated for each patient on each plan. A model of spontaneous and radiation-induced carcinogenesis was used to determine the relative risks of SLMs for the different treatment techniques. A higher risk of SLMs was predicted for supine breast irradiation when compared with prone breast irradiation for both the standard fractionation and hypofractionation schedules (relative risk [RR] = 2.59, 95% confidence interval (CI) = 2.30-2.88, and RR = 2.68, 95% CI = 2.39-2.98, respectively). No difference in risk of SLMs was noted between standard fractionation and hypofractionation schedules in either the supine position (RR = 1.05, 95% CI = 0.97-1.14) or the prone position (RR = 1.01, 95% CI = 0.88-1.15). Compared with supine whole-breast irradiation, prone breast irradiation is associated with a significantly lower predicted risk of secondary lung malignancy. In this modeling study, fractionation schedule did not have an impact on the risk of SLMs in women treated with whole-breast RT for early breast cancer.

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.

Hypofractionation does not increase radiation pneumonitis risk with modern conformal radiation delivery techniques

Purpose. To study the interaction between radiation dose distribution and hypofractionated radiotherapy with respect to the risk of radiation pneumonitis (RP) estimated from normal tissue complication probability (NTCP) models. Material and methods. Eighteen non-small cell lung cancer patients previously treated with helical tomotherapy were selected. For each patient a 3D-conformal plan (3D-CRT) plan was produced in addition to the delivered plan. The standard fractionation schedule was set to 60 Gy in 30 fractions. Iso-efficacy comparisons with hypofractionation were performed by changing the fractionation and the physical prescription dose while keeping the equivalent tumor dose in 2 Gy fractions constant. The risk of developing RP after radiotherapy was estimated using the Mean Equivalent Lung Dose in 2-Gy fractions (MELD2) NTCP model with α/β=4 Gy for the residual lung. Overall treatment time was kept constant. Results. The mean risk of clinical RP after standard fractionation was 7.6% for Tomotherapy (range: 2.8–15.9%) and 9.2% for 3D-CRT (range 3.2–20.2%). Changing to 20 fractions, the Tomotherapy plans became slightly less toxic if the tumor α/β ratio, (α/β)T, was 7 Gy (mean RP risk 7.5%, range 2.8–16%) while the 3D-CRT plans became marginally more toxic (mean RP risk 9.8%, range 3.2–21%). If (α/β)T was 13 Gy, the mean estimated risk of RP is 7.9% for Tomotherapy (range: 2.8–17%) and 10% for 3D-CRT (range 3.2–22%). Conclusion. Modern highly conformal dose distributions are radiobiologically more forgiving with respect to hypofractionation, even for a normal tissue endpoint where α/β is lower than for the tumor in question.

Effect of radiotherapy boost and hypofractionation on outcomes in ductal carcinoma in situ

Boost radiotherapy (RT) improves outcomes for patients with invasive breast cancer, but whether this is applicable to patients with pure ductal carcinoma in situ (DCIS) is unclear. This study examined outcomes from whole breast RT, with or without a boost, and the impact of different dose-fractionation schedules in a population-based cohort of women with pure DCIS treated with breast-conserving surgery (BCS). Data was analyzed for 957 subjects diagnosed between 1985 and 1999. RT use was analyzed over time. Ten-year Kaplan-Meier local control (LC), breast cancer specific survival (BCSS), and overall survival (OS) were compared using the log-rank test. Cox regression modeling of LC was performed. Median follow-up was 9.3 years. Of the patient cohort 475 (50%) had no RT (NoRT) after BCS, 338 (35%) had RT without a partial breast boost (RTNoB), and 144 (15%) had RT with boost (RT + B). Subjects with risk factors of local recurrence were more likely to receive RT. Subjects receiving adjuvant RT had a trend toward improved LC (15-year LC: NoRT 87%; RTNoB 94%; RT + B 91%; P = .065). Multivariable analysis showed that RT with or without a boost was significantly associated with improved LC (HR, 0.29 and 0.38, respectively, compared with NoRT, P = .025), with no difference associated with a boost or different dose-fractionation schedules. Adjuvant RT improves local control in patients with DCIS treated with BCS. Hypofractionation is as effective as standard fractionation schedules. Boost RT was not associated with improved LC compared with whole breast RT alone. Cancer 2011. © 2010 American Cancer Society.

Accelerated Hypofractionated Intensity-Modulated Radiotherapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma Multiforme: A Safety and Efficacy Analysis

Despite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ). Between March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al. The median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration. The results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ.

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial

SummaryBackgroundThe international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size.MethodsBetween 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy versus 41·6 Gy or 39 Gy in 13 fractions of 3·2 Gy or 3·0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.Findings749 women were assigned to the 50 Gy group, 750 to the 41·6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5·1 years (IQR 4·4–6·0) the rate of local-regional tumour relapse at 5 years was 3·6% (95% CI 2·2–5·1) after 50 Gy, 3·5% (95% CI 2·1–4·3) after 41·6 Gy, and 5·2% (95% CI 3·5–6·9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0·2% (95% CI −1·3% to 2·6%) after 41·6 Gy and 0·9% (95% CI −0·8% to 3·7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0·69 (95% CI 0·52–0·91, p=0·01). From a planned meta-analysis with the pilot trial, the adjusted estimates of α/β value for tumour control was 4·6 Gy (95% CI 1·1–8·1) and for late change in breast appearance (photographic) was 3·4 Gy (95% CI 2·3–4·5).InterpretationThe data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41·6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin in the treatment of stage III non-small cell lung cancer.

Concurrent chemoradiotherapy is regarded as the standard care for locally advanced non-small cell lung cancer at present. This paper is designed to evaluate the efficacy and toxicity of low-dose weekly docetaxel (DTX) with concurrent chemoradiotherapy followed by consolidation chemotherapy with DTX and cisplatin for unresectable stage III non-small cell lung cancer(NSCLC). 44 previously untreated patients with stage III NSCLC were randomized into low-dose weekly DTX group and control group concomitant with radiotherapy. Both groups were treated by the standard fractionation schedule with three-dimensional conformal radiotherapy. An involved-field irradiation technique was performed. Gross tumor and metastatic lymph nodes were irradiated to a total dose of 66 Gy-70 Gy. Patients in the former group received chemotherapy with DTX 20 mg.m(-2).w(-1), and the other group patients received DTX 60 mg/m(2) on day 1 and DDP 30 mg/m(2) on day 1-3 every 21 days. All patients received consolidation chemotherapy with DP regime after chemoradiotherapy for no more than 4 cycles. The overall response rates of patients in the low-dose weekly DTX group and control group were 81.8% with 27.3% CR(complete response) and 86.4% with 27.3% CR respectively (Chi-Square=0.120, P=0.942). After a median follow-up of 20 months, the median survival time was 20 months and 17 months respectively. The 1-, 2- year survival rates of patients in low-dose weekly DTX group and control group were 69.8%, 48.1% versus 66.5%, 40.2% respectively;there was no difference between two groups. Grade 3 or 4 neutropenia and esophagitis occurred in 26.3%, 14.3% and 15.8%, 28.6% respectively (Chi-Square=0.765, P=0.382;Chi-Square=1.108, P=0.292).Grade 3 and 4 pulmonary toxicity was unusual. Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin is highly active with manageable toxicity in patients with stage III NSCLC.

Accelerated Hypofractionated Intensity Modulated Radiotherapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma Multiforme: A Safety and Efficacy Analysis

Despite multimodality treatments, the outcome of patients with glioblastoma multiforme (GBM) remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated IMRT with concomitant and adjuvant temozolomide. We report our initial experience with this novel approach. Between March 2004 and June 2006, 35 unselected patients (median age: 63 years), with histologically proven GBM, were treated. A total of 26 patients (74.3%) had RTOG RPA class 5 or 6. Nine patients underwent biopsies only, while 26 patients had partial or complete resections. The methylation status of the MGMT promoter was known in the pathological specimens of 30 patients. Of these, 20 patients had a methylated-MGMT promoter while the other 10 had an unmethylated pattern. IMRT was delivered either by a forward or inverse planning technique. Gross Tumor Volume (GTV) consisted of the contrast-enhanced area and surgical cavity on the post-operative CT/MRI images. Planning target volume (PTV) was the GTV +15 mm. Patients received 60 Gy in 20 fractions (3 Gy per fraction), over 4 weeks, prescribed to the edge of the GTV, while 40 Gy was delivered to the periphery of the PTV. Temozolomide was administered according to the Stupp regimen. The median follow-up was 12.6 months (range: 3.2–26.5). Twenty-nine patients (82.8%) completed the combined modality treatment, and 25 of them (71.4%) received adjuvant temozolomide, with a median number of 4 cycles. Median survival was 14.2 months and median disease-free survival was 6.1 months. Median survival differed significantly between patients who underwent a biopsy versus a partial or total resection, (8.6 vs. 16.8 months, p < 0.01). Median survival was also significantly different between patients with methylated versus unmethylated MGMT promoters (17.23 vs. 7.083 months, p < 0.049). The pattern of failure was mainly central, within the initial GTV. Grade III-IV toxicity was limited to one patient with nausea and emesis during adjuvant temozolomide administration. Seven patients who relapsed received further treatment: five received temozolomide and procarbazine second-line chemotherapy, three underwent further debulking surgery, one patient underwent stereotactic radiosurgery and one patient started metronomic temozolomide. Accelerated hypofractionated IMRT with concomitant and adjuvant temozolomide is well tolerated with a useful two-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% RPA class 5–6), median survival was comparable to standard radiotherapy fractionation schedules plus temozolomide.

A REVIEW OF IMAGE-GUIDED INTENSITY-MODULATED RADIOTHERAPY FOR SPINAL TUMORS

A new paradigm for the radiotherapeutic management of paraspinal tumors has emerged. Intensity-modulated radiotherapy (IMRT) has gained wide acceptance as a way of delivering highly conformal radiation to tumors. IMRT is capable of sparing sensitive structures such as the spinal cord of high-dose radiation even if only several millimeters away from the tumor. Image-guided treatment tools such as cone beam computed tomography coupled with IMRT have reduced treatment errors associated with traditional radiotherapy, making highly accurate and conformal treatment feasible. This review discusses the physics of image-guided radiotherapy, including immobilization, the radiobiological implications of hypofractionation, as well as outcomes. Image-guided technology has improved the accuracy of IMRT to within 2 mm of error. Thus, the marriage of image guidance with IMRT (IG IMRT) has allowed the safe treatment of spinal tumors to a high dose without increasing the risk of radiation-related toxicity. With the use of near real-time image-guided verification, very-high-dose radiation has been given for tumors in standard fractionation, hypofractionated, and single fraction schedules to doses beyond levels traditionally believed safe in terms of spinal cord tolerance. Clinical results, in terms of treatment-related toxicity and tumor control, have been very favorable. With follow-up periods extending beyond 30 months, tumor control rates with single fraction IG IMRT (1800-2400 cGy) are in excess of 90%, regardless of histology, and without serious sequelae such as radiation myelopathy. Patients also report correspondingly high rates of palliation. Excellent results, both in terms of tumor control and minimal toxicity, have been consistently reported in the literature. IG IMRT represents a significant technological advance. Paraspinal IG IMRT is proof of principle, making it possible to give very-high-dose radiation within close proximity to the spinal cord. By reducing treatment-related uncertainties, margins around tumors can be shortened, thereby reducing the volume of normal tissue that must be irradiated to tumoricidal doses, reducing the likelihood of toxicity. Similarly, higher doses of radiation can be administered safely, improving the likelihood of eradication. Dose escalation can be done to increase the likelihood of tumor cell kill without increasing the dose given to nearby sensitive structures.

MO‐D‐BRA‐01: Hypofractionated RT: Biological Basis and Clinical Application in the Prostate and Lung

Hypo‐fractionation, the delivery of radiation therapy with a dose per fraction &gt;2.0 Gy, was introduced in curative radiotherapy in many centers all over the World in the period from WWII to the mid‐1970's, mainly for health economics reasons. Clinical studies published in the late 70's and early 80's showed that these schedules were often associated with excessive late toxicity compared to standard fractionation schedules, and hypo‐fractionation was abandoned in most centers. In hindsight, this negative experience largely resulted from the over‐estimation of tolerance doses in hypo‐fractionated schedules arising from the Ellis NSD formula. Logically, this historical clinical experience does not exclude that hypo‐fractionation can be acceptable or even advantageous under certain defined circumstances.The current status of the linear‐quadratic bio‐effect model in clinical practice is reviewed. Two clinical settings, where hypo‐fractionation is considered, are presented and discussed: (1) definitive radiotherapy for nonsmall cell lung cancer (NSCLC); (2) definitive radiotherapy for prostate cancer.For both NSCLC and prostate cancer the current interest in the development and clinical testing of safe hypo‐fractionation regimens springs partly from the improved physical dose distribution achievable with 3D conformal radiotherapy or IMRT. This provides a window of opportunity for escalating dose per fraction. But there is also a biological rationale for hypo‐fractionation in these two tumor types — and a slightly different one in the two cases! For NSCLC there is strong evidence that shortening the overall treatment time creates a favorable efficacy:toxicity ratio with respect to late toxicity: hypo‐fractionation is a convenient way of delivering accelerated radiotherapy. In other words, we are trading in time for dose per fraction. For prostate cancer, there are no good reasons to believe that there is a strong time factor. However, there is increasingly convincing evidence that the α/β ratio for this tumor type is low, perhaps even lower than for the dose‐limiting rectal side‐effects. This alone creates a case for exploring hypo‐fractionation in this disease.Hypo‐fractionation schedules are being tested in controlled clinical trials in several tumor types at the moment. These schedules should not be introduced in the clinic without appropriate evidence that they are safe and effective. However, based on our improved knowledge of clinical radiobiology, it appears that hypo‐fractionation schedules may yield a beneficial therapeutic ratio and/or a superior cost‐effectiveness in some clinical indications.Learning objectives:After this session the participants should be able to:1. Recognize the limitations of the traditional linear‐quadratic model.2. Summarize the changes in biological understanding of dose fractionation that have occurred over the last 10–15 years.3. Explain the rationale behind the current interest in hypo‐fractionation in NSCLC and prostate cancer.

Evaluation of results of radiotherapy alone vs combined surgery and postoperative radiotherapy in carcinoma external auditory canal—10 years review

Forty-one patients of external auditory canal (EAC) cancer attended the Department of Radiotherapy (RT), Medical College Hospital, Kolkata during the period from 1987 to 1996. Majority were above 50 years of age with slight female preponderance. Out of 41 patients 36 patients completed the full course of treatment of which 12 patients underwent combined modality treatment (RT 50-55 Gy plus surgery) and 24 patients received primary RT alone (55-60 Gy). Radiation therapy was given in standard fractionation schedule. Retrospective analysis revealed complete response in 8/12 (66.7%) in combined modality treatment group and in 3/24 (12.5%) in RT alone group. The actuarial 2 year survival was 19%. following RT alone, 85% following combined modality, 70% in early lesions and 18% in advanced lesions. The study suggests, surgical resection followed by postoperative irradiation is an effective method and better treatment option than RT alone as primary treatment modality for carcinoma of EAC.

Reducing the Overall Treatment Time for Radiotherapy of Metastatic Spinal Cord Compression (MSCC): 3-Year Results of a Prospective Observational Multi-Center Study

This prospective multi-center study investigates a reduction of the overall treatment time for radiotherapy of MSCC, which is important for these mostly disabled patients. Two standard fractionation schedules, 30 Gy/10 fractions/2 weeks (n = 71) and 40 Gy/20 fractions/4 weeks (n = 65) were compared for functional outcome and ambulatory status. Motor function was graded using an 8-point-scale before RT, at the end and at 6, 12 and 24 weeks after RT. A multi-variate analysis was performed for functional outcome. Included variables were the fractionation schedule and the three relevant prognostic factors. These factors are the type of primary tumor, the time of developing motor deficits before RT and the pre-treatment ambulatory status. The ambulatory rates were 49% in the 30 Gy group and 52% in the 40 Gy group before RT (P = 0.888), and 56% and 60% after RT (P = 0.888). Improvement of motor function occurred in 45% of the 30 Gy group and 40% of the 40 Gy group (P = 0.752). The relevant prognostic factors were comparably distributed in both groups. According to the multivariate analysis, a slower development of motor deficits (P < 0.001), a favorable histology (P = 0.040) and being ambulatory (P = 0.045) were associated with better functional outcome, whereas the fractionation schedule had no significant impact (P = 0.311). The data suggest both schedules to be comparably effective for functional outcome. Thus, 30 Gy/10 fractions/2 weeks should be applied instead of 40 Gy/20 fractions/4 weeks. The reduction of the overall treatment time from 4 to 2 weeks means less discomfort for the paraparetic or paraplegic patient.