Search

Objectives To assess the feasibility and safety of a repeated SHort course Accelerated RadiatiON therapy (SHARON) regimen in the palliative setting of Head and Neck (H&N) cancer in older adults. Material and Methods Patients with histological confirmed H&N cancers, age ≥ 80 years, expected survival >3 months, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 were enrolled. Patients were treated in cohorts of six patients: a total dose of 20 Gy was delivered in 2 consecutive days with a twice-daily fractionation (5 Gy per fraction) and at least 8-h interval. If no Grade 3 toxicity was registered, a second enrollment started with another cohort of six patients to whom were administered two cycles (total dose of 40 Gy). The primary endpoint was to evaluate the feasibility of the two cycles of treatment. Secondary endpoints were evaluation of symptoms control rate, symptoms-free survival (SFS), and Quality of Life (QoL) scores. Results Seventeen consecutive patients (median age: 85 years) were treated. Nine patients were treated with one cycle and 8 patients with two cycles. No G3 toxicity was reported in either cohort. With a median follow-up time of 4 months, 3-month SFS in the first and second cohorts was 83.3%, and 87.5%, respectively. The overall palliative response rate was 88%. Among 13 patients reporting pain, 8 (61.5%) showed an improvement or resolution of their pain. Conclusion Repeated short course accelerated radiotherapy in a palliative setting of H&N cancers is safe and well-tolerated in older adults.

Background: The optimal TRT dose/fraction for LD-SCLC remains debatable, and due to increasing number of population in Egypt and number of patients as well, so reducing the duration of radiation therapy is favored. This study was conducted using etoposide and cisplatin (EP) concurrently with accelerated hypofractionated TRT to evaluate the response and toxicity of this protocol in the treatment of patients with limited-disease small cell lung cancer (LD-SCLC). Patients and Methods: Thirty patients with previously untreated LD-SCLC were enrolled into this study between June 2012 and February 2015. All patients received etoposide 100 mg/m2 days 1 to 3 and cisplatin 25 mg/m2 days 1 to 3 with start of accelerated hypofractionated thoracic radiation therapy on first day of the second cycle of chemotherapy of 55 Gy, 2.5 Gy/fraction over 30 days. Chemotherapy was given 4 - 6 cycles. Prophylactic cranial irradiation 25 Gy/10 fractions were given for patients who achieved complete remission. Results: The median age was 60 years; 28 patients (93%) were men. ECOG PS was 0 in 5 (17%) patients and 1 in 12 (40%) patients. Four (13%) patients achieved a complete response (CR), 17 (57%) patients achieved a partial response (PR), while 7 patients (23%) had progressive disease (PD), and the ORR was 90%. The median survival time was 26.4 months. The median PFS was 16.7 months. Among the hematologic toxicities neutropenia was the most prevalent toxicity and it was evident as grade 3 - 4 in 12 (40%) patients. Grade 3 - 4 Asthenia was the most prevalent nonhematological toxicity, in 12 (40%) patients; esophagitis occurred in 7 (23%) patients. No treatment-related deaths (due to sepsis or bleeding) were reported in the study. Conclusion: Using etoposide and cisplatin concurrently with accelerated hypofractionated thoracic radiation therapy for the treatment of patients with LD-SCLC showed an encouraging outcome and acceptable toxicity and warrants further research.

Background To analyse the survival and late toxicities of elderly nasopharyngeal carcinoma (NPC) patients treated by intensity-modulated radiotherapy (IMRT) with the high-total- and fractionated-dose simultaneous modulated accelerated radiation therapy (SMART) boost technique and to identify the effect of concurrent chemotherapy for these patients. Methods Two hundred and fifty-four elderly patients (age ≥ 60.0) with newly diagnosed non-metastatic NPC were retrospectively analysed. Statistical analyses were performed using the SPSS software program. Results The actual mean total and fractionated doses delivered to the gross tumour volume of the nasopharynx (GTVnx) were 74.55 Gy and 2.49 Gy, respectively. The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) of the whole cohort were 93.0%, 85.7%, 83.2% and 74.1%, respectively. No grade 4 acute or late radiotherapy-induced toxicities were observed. Of 247 patients with stage II–IVb disease, 89 patients received radiotherapy (RT) alone, and 158 patients received concurrent chemoradiotherapy (CCRT), and the 5-year LRRFS, DMFS, DSS and OS of the RT-alone group vs. the CCRT group were 94.0% vs. 92.2%, 83.5% vs. 86.2%, 81.8% vs. 83.1% and 74.0% vs. 72.8% (all P > 0.05), respectively. Multivariate analyses showed that CCRT was not an independent predictor for LRRFS, DMFS, DSS and OS (all P > 0.05). Conclusion High-total- and fractionated-dose SMART boost IMRT could obtain a satisfactory long-term outcome with mild late toxicity in elderly NPC patients. The role of CCRT needs to be further studied to optimize the treatment strategy and improve the overall survival.

Background: To evaluate the toxicities and long-term outcomes of induction chemotherapy (ICT) plus simultaneous modulated accelerated radiation therapy (SMART) in non-operative hypopharyngeal and supraglottic laryngeal squamous cell carcinoma (SCCH/L).Materials and Methods: This was a prospective phase 2 study. Patients diagnosed with SCCH/L, aged from 18 to 75, staged from III to IVB in accordance with the AJCC 2010 criteria, and refusing surgery were eligible. The patients were treated with 2–3 cycles of docetaxel-cisplatin-based ICT and SMART combined with 2–3 cycles of cisplatin-based concurrent chemotherapy. The prescription dose to the primary tumor and metastatic nodes was 69 Gy in 30 fractions. Acute and late toxicities were assessed according to the established Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria, and long-term outcomes were analyzed.Results: Between February 2013 and June 2015, 55 newly diagnosed SCCH/L patients were enrolled. No grade 2 or worse acute xerostomia was noted. The incidences of grade 3 acute dermatitis, oral mucositis, and pharyngoesophagitis were 12.7, 3.6, and 12.7%, respectively. The median follow-up time was 48 months (range 5.5–74 months). The main late toxicity was hoarseness or sore throat, with an incidence of 32.7%. The 5-year functional larynx-preservation survival was 51.5%. The 3- and 5-year locoregional control and overall survival were 58.2, 51.5, 63.6, and 54.1%, respectively.Conclusions: The ICT plus SMART with a regimen of 69 Gy/30 F for the treatment of SCCH/L demonstrated acceptable severe toxicity, satisfactory long-term outcomes, and laryngeal function preservation.

Context Better locoregional control and increased overall survival by continuous hyper fractionated accelerated radiotherapy have been shown in unresectable nonsmall cell lung carcinoma (NSCLC). Dose escalation and neoadjuvant chemotherapy (NACT) along with continuous hyperfractionated accelerated radiotherapy week end-less (CHARTWEL) were also tried for improved survival. In this present study, we compared the results of NACT followed by CHARTWEL against NACT followed by conventional concurrent chemo-radiation therapy. Aims The aim of this study is to compare the locoregional control and toxicities in NSCLC Stage IIIA and B in both arms. Settings and design Randomized, prospective single-institutional study with a study population comprising all locally advanced unresectable NSCLC patients enrolled in 2014 at our institute. Subjects and methods All enrolled patients were randomized into two arms-CHARTWEL and concomitant chemo-radiotherapy (CCRT), after three weeks of the fourth cycle of NACT. In CHARTWEL arm 30 patients received two-dimensional radiotherapy (RT) 58.5 Gy/39 fr/2.5 weeks while in CCRT arm 30 received 66 Gy/33 fr/6.5 weeks. Disease response was evaluated at 6 months and toxicity assessment during and after treatment completion. Data were analyzed using tools such as percentage, mean, Chi-square test and P value. Chi-square and P value was calculated by statistical online software (http://quantpsy.org). Results 28% of patients in study arm and 20% in control arm had complete response at 6 months after RT. Locoregional disease control was observed in 44% in study arm and 32% in control arm of patients. There was no statistical difference in grades of toxicities or overall survival (OS)/disease-free survival except persistent esophagitis Grade III seen in two patients of study arm. Conclusions Study suggests that CHARTWEL in combination with NACT is an effective strategy to treat patients with locally advanced lung cancer with the advantage of a smaller dose and shorter duration. Although large multivariate studies still needed.

PurposeTo investigate the safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non-small cell lung cancer (NSCLC).Patients and methodsThe primary objectives were to define the maximally tolerable course of accelerated radiation therapy and to describe toxicities of therapy. Total radiation therapy remained at 60Gy. The number of once-daily fractions in each successive cohort was reduced as follows: cohort 1, 60Gy in 27 fractions; cohort 2, 60Gy in 24 fractions; cohort 3, 60Gy in 22 fractions; and cohort 4, 60Gy in 20 fractions. Concurrent treatment consisted of weekly carboplatin area under the curve (AUC) 2 and paclitaxel 45mg/m2. Consolidation treatment consisted of carboplatin AUC 6 and paclitaxel 200mg/m2 every weeks×2 cycles. Maximum tolerated dose: Of 6 patients/cohort, ≤2 patients experienced grade ≥3 toxicity, and ≤1 patient experienced grade ≥4 toxicity.Results22 patients were accrued; of those, 21 patients were evaluable between July 2012 and May 2014. Grade 5 toxicity occurred in 3 patients: 1 patient in cohort 2 (hemoptysis), 2 patients in cohort 3 (hemoptysis, pneumonitis). The maximum tolerated dose (MTD) was defined by cohort 2 (60Gy in 2.5Gy/fraction). Time to grade 5 toxicity was 9months, 6months, and 9months after the start of treatment. The median follow-up time was 23.0months (range, 7.6-30.6months) in living patients, the median overall survival was 19.3months (95% confidence interval [CI] 9.3-34.0months), and the median progression-free survival was 12.2months (95% CI 6.1-22.5months).ConclusionsOnly modest hypofractionation was achievable as a result of long-term toxicities. Nevertheless, the MTD of 60Gy given at 2.5Gy/fraction allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help to better define the therapeutic index.

Purpose The purpose of the study was to evaluate the feasibility and efficacy of an accelerated radiotherapy schedule using weekend boost in terms of tumor response, compliance, and acute toxicities for head and neck squamous cell carcinoma, and to report long-term clinical outcomes. Materials and Methods Twenty-six patients with stages III-IV head and neck squamous cell carcinoma receiving radical chemoradiotherapy were accrued prospectively into the study. External beam radiation therapy to a total dose of 66–70 Gy in 33–35 fractions, 1.8–2.0 Gy per fraction along with concurrent weekly cisplatin was planned. Radiation regimen included delivery of six fractions per week, with boost field delivered as the sixth fraction on the weekend. The compliance, tumor response, and toxicities were recorded. Survival curves were estimated using the Kaplan–Meier method. Results Twenty-one of 26 patients (81%) completed treatment as planned and five patients died during the course of treatment. Sixteen patients (62%) completed treatment in less than 44 days and, at the end of 3 months’ follow-up, 18 patients (69%) showed complete response and two patients (8%) showed partial response. The 2- and 5-year actuarial disease-free survival were 90% and 65%, respectively, and 2- and 5-year actuarial overall survival were 60% and 38%, respectively. Conclusion Accelerated fractionation using weekend boost, along with concurrent weekly concurrent cisplatin, is an effective and promising approach with favorable impact on initial tumor response, comparable results, and acceptable toxicities.

Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART). Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400 mg/m2) and then with a weekly dosage of 250 mg/m2 during HART. HART was started with a prescribed dosage of 2.0 Gy per day for 3 weeks, followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumour volume. CIS (40 mg/m2) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2‑year progression-free survival (PFS). Between November 2007 and November 2010, a total of 74 patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2‑ and 5‑year overall survival rates were 64 and 41%, the 2‑ and 5‑year PFS rates were 45 and 32%, and the 2‑ and 5‑year locoregional control rates were 47 and 33%, respectively. The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation.Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%.110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients.The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.

Purpose Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. Methods and Materials A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m 2 day 1; cisplatin, 75 mg/m 2 day 1; 5-fluorouracil [5-FU], 750 mg/m 2 day 1-5) and cetuximab, 250 mg/m 2 weekly (loading dose of 400 mg/m 2 ). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. Results Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). Conclusions C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.

Objectives: To evaluate the feasibility and efficacy of simultaneous accelerated radiation therapy (SMART) and concurrent weekly paclitaxel in the treatment of locally advanced nasopharyngeal carcinoma. Methods: Fortyone patients with pathologically confirmed nasopharyngeal carcinoma were treated by SMART with concurrent weekly paclitaxel. Daily fraction doses of 2.5 Gy and 2.0 Gy were prescribed to the gross tumor volume (GTV) and clinical target volume (CTV) to a total dose of 70 Gy and 56 Gy, respectively. Paclitaxel of 45 mg/m 2 was administered concurrently with radiation therapy every week. Adjuvant chemotherapy was given four weeks after the completion of the radiotherapy (RT) if the tumor demonstrated only a partial response (PR). Results: All patients completed the radiotherapy (RT) course. Adjuvant chemotherapy was administered to 12 patients due to PR. The CR (complete remission) rate was 82.9% three months after RT. Thirty-nine (95.1%) patients completed the concurrent weekly chemotherapy with paclitaxel, and two patients skipped their sixth course. Seven patients had a 15% dosage reduction at the fifth and sixth course due to grade 3 mucositis. The median follow-up was 30 (range, 14-42) months. The three-year overall survival (OS), metastases-free survival (MFS), and local control rates were 77.0%, 64.4%, and 97.6%, respectively. No correlation between survival rate and T or N stage was observed. Grade 3 acute mucositis and xerostomia were present in 17.1% and 7.1%, respectively. Conclusion: SMART with concurrent weekly paclitaxel is a potentially effective and toxicity tolerable approach in the treatment of locally advanced NPC.

Purpose We performed a phase 2 trial of neoadjuvant temozolomide (TMZ), followed by hypofractionated accelerated radiation therapy (HART) with concurrent TMZ, and adjuvant TMZ in patients with newly diagnosed glioblastoma to determine whether neoadjuvant TMZ would safely improve outcomes in this group of patients prior to subsequent cytotoxic therapy. Methods and Materials Adult patients with newly diagnosed glioblastoma and a Karnofsky Performance Status >60 were eligible. Neoadjuvant TMZ administration started 2 to 3 weeks from surgery at a daily dose of 75 mg/m 2 for 2 weeks prior to delivery of HART (60 Gy in 20 daily fractions) with concurrent and adjuvant TMZ. The primary endpoints were feasibility and toxicity. The secondary endpoints included overall survival (OS) and progression-free survival. Results Fifty patients were accrued. The median follow-up period was 44.0 months for patients at risk and 22.3 months for all 50 patients. Except for 1 patient in whom infection developed and another patient with progression during HART, all patients completed protocol therapy as planned. The median OS and progression-free survival were 22.3 months (95% confidence interval, 14.6-42.7 months) and 13.7 months (95% confidence interval, 8.0-33.3 months), respectively. The 4-year OS rates were 30.4% for the entire cohort and 53.3% and 14.0% for patients with methylated (n=21) and unmethylated (n=27) MGMT gene promoter tumors, respectively. One patient had grade 5 pancytopenia during HART, and another patient had transient grade 4 hepatotoxicity. A second surgical procedure was performed in 13 patients: 2 had intracranial infection, 3 had recurrences, 4 had recurrences and radiation-induced damage, and 4 had only radiation-induced damage. Conclusions This novel approach of neoadjuvant TMZ is associated with an encouraging favorable long-term survival with acceptable toxicity. A future comparative trial of the efficacy of this regimen is warranted.

Accelerated radiation therapy protocols address the specific biology of aggressive oropharyngeal squamous cell carcinoma and this approach was applied in 5 feline and 3 canine oropharyngeal squamous cell carcinoma patients where surgery was not possible (4/5 feline and 2/3 canine cases) or was declined (1/5 feline and 1/3 canine cases). A protocol using 14 fractions of 3.5 Gy over 9-days, combined with carboplatin chemotherapy as a radiosensitiser (total dose 180 mg/m2 in feline and 300 mg/m2 in canine cases) resulted in a complete tumor response in most cases (4/5 feline and 3/3 canine cases) with acceptable acute and long-term side effects. Results achieved in feline cases correspond with published data where these specific radiotherapy protocols were employed. A complete response and long-term survival (> 2-years) was achieved in all canine patients. Although no standardized chemoradiotherapy protocols currently exist, this therapeutic approach can be a useful addition for the management of oropharyngeal squamous cell carcinoma of cats and dogs when the goals of treatment include maximizing tumor control while maintaining function and quality of life.

There is increased interest in establishing the therapeutic efficacy of shorter RT schedules in the treatment of early-stage breast cancer. In this study, we compared the acute toxicity of 3-week accelerated whole-breast irradiation with a concomitant boost to conventional fractionation delivered over 6 to 7 weeks. The results suggested no increased radiation toxicity with the shorter schedule. Background: We aimed to evaluate the incidence of acute toxicity in a 3-week accelerated radiation therapy (RT) schedule with a concomitant boost compared with the 6.5-week conventional schedule with a sequential boost for early-stage, node-negative breast cancer. Materials and Methods: This study included the first 50 patients treated on protocol using the accelerated schedule as well as 74 patients with comparable stages of disease treated over the same period using the conventional schedule. An accelerated schedule of 40.5 Gy 2.7 Gy/fraction to the whole breast with 4.5 Gy 0.3 Gy/fraction concomitant boost, for a delivered total dose of 45.0 Gy 3.0 Gy/fraction in 15 fractions to the lumpectomy site. The conventional schedule used 46.8 Gy 1.8 Gy to the whole breast with a sequential boost of 14.0 Gy 2.0 Gy/fraction, delivering a total dose of 60.8 Gy 33 fractions to the lumpectomy site. The side effects observed during RT and through the initial 8 weeks after treatment were scored for acute toxicity. Results: A lower incidence of grade 2 skin toxicity was observed among patients treated on the accelerated schedule compared with those treated on the conventional schedule (p .0015). There was a higher incidence of breast pain among patients receiving the conventional schedule (p .045). No significant difference in the incidence of breast edema, fatigue, or hematologic side effects was observed between the 2 groups. Conclusion: Our observations suggest that there is acceptable toxicity with the accelerated schedule as used in this study. Further, it is not associated with a higher risk of acute toxicity when compared with the conventional schedule. Patients in the study are being followed, and clinical outcomes will be reported as the data mature.

Background: Feline oral squamous cell carcinoma (SCC) carries a very poor prognosis with traditional treatments. Hypothesis/Objectives: To examine the effectiveness of adding carboplatin to a previously published accelerated radiation protocol in the treatments of oral SCC in cats. Animals: Thirty-one cases of oral SCC in cats. Tumor sites included lingual (n = 9), mandible (n = 10), maxilla (n = 7), tonsil (n = 4), and cheek (n = 1). Methods: Prospective trial using a planned radiation protocol consisting of 14 fractions of 3.5 Gy given within a 9-day period with the addition of carboplatin given at 90–100 mg/m2 on day 1 and day 4.5. Treatments were twice daily with a 6-hour delay between treatments. All cats presenting with oral SCC without evidence of distant metastasis were eligible. Results: Median survival for all cats was 163 days (range 53–770 days) with a mean of 319 ± 53 days with significant predictors of survival being site (P= .004) and whether there was a complete response at 30 days (P= .001). Cats with tumors of tonsil origin or cheek responded best to therapy and were long-term survivors with a mean survival of 724 days and the median had not been reached because of continued survival of 4 cats. Conclusions and Clinical Importance: This protocol offers an aggressive yet tolerable treatment of oral SCC in cats that might offer improved survival as compared with previously reported treatments. The long-term survival of cats with tonsillar SCC has not been reported previously.

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions. OBJECTIVES: To assess the effects of postoperative external beam radiation dose escalation in adults with HGG. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials. SELECTION CRITERIA: We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy. DATA COLLECTION AND ANALYSIS: The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate‐certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low‐certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high‐certainty evidence). There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks. All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these RCTs. The number of participants lost to follow‐up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. AUTHORS' CONCLUSIONS: Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma. There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis. Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.

Objectives: To assess the effectiveness of a SHort-course Accelerated RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Materials and Methods: A phase II clinical trial was designed. Eligibility criteria included patients with at least 3 brain metastases or metastatic disease in >3 organ systems, and Eastern Cooperative Oncology Group performance status of ≤3. Fifty patients were treated with whole brain radiotherapy at 18 Gy (4.5 Gy per fraction) in 2 days with a twice daily fractionation. The primary endpoint was the assessment of efficacy in terms of overall survival. Results: Characteristics of the 50 enrolled patients were: male/female: 24/26; median age: 65 years (range, 45 to 80 y). Eastern Cooperative Oncology Group performance status was

Background To determine the outcome, acute and late toxicity in locally advanced head and neck cancer stage IVA with mitomycin-C (MMC), cisplatin (DDP) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART). Patients and methods Thirty-five patients, with squamous cell cancer of the oral cavity (20%), oropharynx (37%), hypopharynx (26%) and larynx (17%), received 30Gy (2Gy every day) followed by 1.4Gy bid to a total of 70.6Gy concurrently with MMC 10mg/m 2 (day 1 plus 36) and DDP 6mg/m 2 given Mondays through Fridays during weeks 1–3. Median follow up was 19 months. Results C-HART was given as planned in 12 of 35 patients, with radiotherapy completed per protocol in 91%. Overall, patients received 70% of the intended dose of MMC and 91% of DDP. Mucositis CTC III/IV occurred in 27%, leucopenia CTC III/IV in 47%, and three early deaths were observed. Osteoradionecrosis occurred in 14% with cT4-tumours. At 3 years the locoregional control and survival rates were 60% and 46%, respectively. Conclusion C-HART resulted in promising overall response with acceptable toxicity. Mucositis is a frequent, severe toxicity in patients treated with C-HART for head and neck cancer. While it appears that mucositis and hematological toxicity may lead to hospitalization and omitting of the second dose of mitomycin C, its impact on radiotherapy interruptions is marginal.

Purpose To compare once-daily radiation therapy (qdRT) with hyperfractionated accelerated radiation therapy (HART) after two cycles of induction chemotherapy. Patients and Methods Eligible patients were treatment naive, and had stage IIIA and B unresectable non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and normal organ function. Induction chemotherapy consisted of two cycles of carboplatin area under time-concentration curve 6 mg/mL · min plus paclitaxel 225 mg/m2 on day 1. RT consisted of arm 1 (qdRT), 64 Gy (2 Gy/d), versus arm 2 (HART), 57.6 Gy (1.5 Gy tid for 2.5 weeks). A total of 388 patients were needed to detect a 50% increase in median survival from 14 months of qdRT to 21 months of HART; accrual was not achieved and the study closed prematurely. Results Of 141 patients enrolled, 83% were randomly assigned after chemotherapy to qdRT (n = 59) or HART (n = 60). Median survival was 20.3 and 14.9 months for HART and qdRT, respectively (P = .28). Overall response was 25% and 22% for HART and qdRT, respectively (P = .69). Two- and 3-year survival was 44% and 34% for HART, and 24% and 14% for qdRT, respectively. Grade ≥ 3 toxicities included esophagitis in 14 v nine patients, and pneumonitis in 0 v 6 patients for HART and qdRT, respectively. Any subsequent trials of the HART regimen must address the issues that led to early closure, including slow accrual, logistics of HART, mucosal toxicity, and the fact that concurrent chemoradiotherapy now seems more effective than sequential treatment. Conclusion After two cycles of induction chemotherapy with carboplatin-paclitaxel, HART is feasible with an acceptable toxicity profile. Although statistical significance was not achieved and the study closed early, there was a positive statistical trend suggesting a survival advantage with the HART regimen.

BACKGROUND This Phase I clinical trial was developed to assess the feasibility of combining high-dose intraarterial cisplatin chemotherapy with concurrent, concomitant boost accelerated radiation therapy for patients with previously untreated T4 and select patients with T3N0–N3M0 squamous cell carcinoma of the upper aerodigestive tract. METHODS Between July 1999, and February 2002, 19 patients were treated with 3 or 4 weekly cycles of intraarterial Cisplatin chemotherapy (150 mg/m2) with concurrent, concomitant boost accelerated radiation therapy (72 grays in 42 fractions over 6 weeks). RESULTS Two patient deaths occurred among the first 15 patients enrolled. Both patients presented with febrile neutropenia, and both died of complications related to infection. The number of cycles of intraarterial cisplatin was reduced from four cycles to three cycles, and an additional four patients were treated. The fourth patient treated on the modified protocol developed febrile neutropenia, sepsis, and a thromboembolic event, which resulted in lower extremity amputations. The maximum acute toxicity experienced was Grade 2 in 6 patients, Grade 3 in 5 patients, Grade 4 in 6 patients, and Grade 5 in 2 patients. With a median follow-up of 21 months (range, 6.2–34.6 months), the overall survival at 1 year was 89.5% (95% confidence interval [95%CI], 76.7–100%). At 1 year, 92.9% of the patients were free from disease progression (95%CI, 80.3–100%). CONCLUSIONS The results of this study suggest that concurrent intraarterial cisplatin chemotherapy at a dose of 150 mg/m2 with concomitant boost accelerated radiation therapy is not feasible. Cancer 2005. © 2004 American Cancer Society.

Background and purpose To evaluate the feasibility, toxicity and the efficacy for locally advanced non-small cell lung cancer (NSCLC) treated with escalated hyperfractionated accelerated radiation therapy (EHART) combined with chemotherapy. Patients and methods The EHART consisted of irradiation delivered twice per day with >6-h interval and five treatment days per week. In the first and second weeks, 1.2 Gy/fraction b.i.d, was given, and then 1.3 Gy/fraction b.i.d in the third week; 1.4 Gy/fraction b.i.d in the fourth week; and 1.5 Gy/fraction b.i.d in the fifth week, respectively. The total tumor dose delivered was 66 Gy/50 fractions/5 weeks. All patients received neoadjuvant and adjuvant chemotherapy. The chemotherapeutic regimen used was either MVP (mitomycin C, vindesine, cis-platinum), or EP (etoposide and cis-platinum). Results From February 1997 to February 1999, 73 eligible patients were registered. All were in stage IIIb with median age of 60 years (33–70). Of the 73 patients, 12 cases were withdrawn from the study due to Grade (Gr) III acute complications, distant metastases, or intercurrent diseases. Sixty-one patients completed the combined treatment as planned. A median of 4 cycles of chemotherapy (1–7) was administered and 66 Gy/50 fractions/36 days was delivered finally. The most common acute complication was radiation esophagitis, which occurred in 56 cases (77%), with Gr III in 11 cases (15%). Twenty-nine patients (40%) had acute pulmonary toxicity; with Gr III in 6 cases (8%). The median survival time was 13 months for the entire group. The 1-year and 2-year survival rates were 51 and 10%, respectively. Of the 61 patients who finished EHART, 34 were found to have locoregional progression. Thirty-two patients failed inside radiation fields, and 2 patients, outside radiation fields. The 1-year and 2-year locoregional progression-free rates were 71 and 34%, respectively. The 1-year and 2-year distant metastasis rates were 57 and 84%, respectively. Conclusions EHART combined with chemotherapy could be tolerated by most of the stage IIIb NSCLC patients with acceptable complications. Locoregional control was improved, but the long survival was not prolonged significantly predominantly due to distant metastases.

Among patients with lung cancer, approximately 15% have small cell lung cancer (SCLC), SCLC is usually staged as either limited and extensive. Extensive-stage SCLC is treated primarily with chemotherapy. A recent Japanese randomized trial compared cisplatin and irinotecan (IP) with cisplatin and etoposide (EP). Patients in the IP arm did significantly better than patients in the EP arm. In the IP arm, the response rate was 84%, and the median overall survival period was 12.8 months. Limited- stage SCLC is usually treated with concurrent chemotherapy and accelerated radiation therapy, and approximately 20% of patients are cured. Future research should focus on optimizing chemotherapy regimens and radiation therapy schedules. The role of molecular targeted drugs in the treatment of SCLC must also be evaluated.

Radiation therapy plays a central role in patients with locally advanced NSCLC who are not eligible for surgery. In fit patients, radiation is administered with concurrent chemotherapy leading to improved survival compared to either modality alone or the sequence of both. Different strategies to improve local control have been explored. Multiple dose escalation protocols produced higher local control rates and promising 2-year survival rates at radiation doses above 70 or even 80 Gy. However, higher doses are currently not recommended following the results of the recent phase III RTOG 0617 trial comparing standard dose radiotherapy with highdose (74 Gy) conformal radiotherapy which demonstrated a significant increase in the risk of death in the high dose arm. Altered fractionation regimens using concomitant boost or hyperfractionated and/or accelerated radiation therapy have reported to be successful, but logistics limited its use in routine practice. Technical advances in radiation therapy include PET CT planning, visualization of tumour hypoxia by dynamic PET-CT, stereotactic boost on hypoxic areas, proton beam therapy, IMRT and image-guided radiation therapy. The best systemic regimen to be used concurrently with radiation has yet to be defined; as has the role of induction and consolidation therapy in addition to concurrent chemoradiotherapy. Monoclonal antibodies such as bevacizumab and cetuximab have not been able to improve outcomes and the results of the phase III study of the novel anti-folate pemetrexed in combination with cisplatin compared to standard etoposide/cisplatin are awaited. The role of targeted agents in molecularly selected subgroups and the optimal treatment approach in unfit and elderly patients has yet to be defined and are the subject of ongoing clinical trials.

TO THEEDITOR: Angetal 1 recentlypresentedRadiationTherapy Oncology Group 0522 (RTOG 0522; Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With Stage III or Stage IV Head and Neck Cancer), a large randomized phase III trial of 940 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) that tested whether the addition of cetuximab to cisplatin and accelerated radiation therapy (RT) improved progression-free survival (PFS) compared with cisplatin and radiation (CRT) alone. 1 It did not. Survival, locoregional failure, and distant metastases end points were not significantly different between the two groups. However, cetuximab plus CRT versus CRT resulted in more interruptions in RT, more treatment-relatedgrade5adverseevents(death),andmoregrade3 to 4 radiation mucositis, rash, fatigue, anorexia, and hypokalemia. These results are extremely disappointing. Should we be surprised? Let us look at prior data that led to the development of RTOG 0522. The rationale for performing RTOG 0522includedphaseIIItrialsshowingimprovedoverallsurvival(OS) with the addition of cetuximab to RT in patients with curable HNSCC 2 andimprovedOSwiththeadditionofcetuximabtochemotherapy in patients with incurable HNSCC. 3 Importantly, one small

The authors review the main contributions of the international literature concerning the role of hyperfractionation (HF), accelerated fractionation (AF), and accelerated hyperfractionation (AHF) of the dose in radiation therapy (RT) of central nervous system tumors. Basic rationales, clinical results, acute/late toxicity, and current prospectives are summarized in three sections focusing on malignant gliomas, pediatric brainstem tumors, and brain metastases. In supratentorial malignant gliomas the superiority of AHF (0.89 Gy × 3 fractions/day; total dose 61.4 Gy) over conventional fractionation ((CF) total dose 58 Gy) was demonstrated by a randomized trial. However, the gain in median survival time was less than 6 months. No other randomized trials support the preferential choice of non-CF schedules outside clinical trials. Ongoing trials are exploring the role of AHF in combination with chemotherapy, hypoxic cell and radiosensitizing agents. As for pediatric brainstem tumors, there are no data to support the routine use of HF that should be preferably used in an investigative setting. As late sequelae have been reported in the few long-term survivors, patients should be carefully selected. Regarding brain metastases AF RT and AHF RT, with their faster treatment course, may represent a convenient alternative to CF RT for the palliation of brain metastases. In carefully selected patients with solitary brain metastases non-CF RT may be part of aggressive treatment approaches.

Inflammatory breast carcinoma (IBC) is the most lethal and fulminant of all breast cancers. IBC can be either clinically or pathologically defined, but the prognosis is equally poor, whether it is diagnosed using clinical or pathological criteria or a combination of both. Rapid growth and short doubling times are characteristic of IBC, resulting in local growth analogous to a "brush fire," extending rapidly in all directions across all surfaces and tissue planes. In addition, rapid systemic dissemination results in the death of the majority of these patients. Traditional treatment of IBC consisted of surgery or radiation therapy alone, with cure rates rarely achieving 15%. The advent of successful combination chemotherapy regimens, along with local irradiation of the breast and regional lymphatics, has increased the 5-year disease-free survival rate to 35% to 50%. In spite of recent innovative European programs combining radiation therapy and chemotherapy without mastectomy, optimal treatment is still considered to be induction chemotherapy, mastectomy, and comprehensive chest wall/nodal irradiation following by maintenance chemotherapy. Some centers are also investigating accelerated radiation therapy fractionation schemes that may further improve local control through maximizing the radiobiological response of tumor cells. Attention to radiotherapy technique can minimize local-regional tumor control and minimize long-term complications. There is considerable room for improvement. Numerous studies are in progress attemping to improve survival rates, including use of autologous bone marrow transplantation. Better systemic agents and more effective drug combinations are needed. Once systemic micrometastases are reliably eradicated, improvement in local-regional control will become even more important for IBC patients.

Purpose/Objective(s): Currently, no biological molecular targets exist for women diagnosed with triple negative breast cancer (TNBC). In an in vitro murine breast cancer model, we have shown that radiation therapy (RT) combined with carboplatin potentiates immunogenic tumor cell death, thereby contributing to a pro-immunogenic milieu (Golden et al., Oncoimmunology 2014). Thus, we hypothesized that this regimen may not only radio-sensitize, but also trigger an adaptive anti-tumor immune response. We are conducting a phase I-II IRB-approved trial [clinicaltrials. gov NCT01289353] to test the feasibility and clinical efficacy of this combination in terms of rates of local control, distant recurrence, and overall survival. Materials/Methods: Women with Stage I e II (pT1-T2, pN0) TNBC are eligible after segmental mastectomy and axillary lymph node assessment. Weekly carboplatin (AUCZ2.0) is delivered x6 weeks with RT to the whole breast being delivered during weeks 2-4, via a 3D-CRT or IMRT technique in the prone position. The whole breast receives 40.5 Gy in 15 fractions (Monday-Friday). The tumor bed receives an additional 3 Gy boost, delivered on 2 consecutive Sundays (beginning of the 2 and 3weeks of RT). Consequently, a total of 46.5 Gy is delivered to the tumor bed in 17 fractions over 19 days. Adverse effects of treatment are assessed weekly during treatment, and once at 45-60 days, thereafter, using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 33 patients have accrued so far. Acute toxicities are displayed below and never exceeded grade 3. Twenty patients received adjuvant chemotherapy. With a median follow-up of 25.9 months, 97% (32/33) of all women remain alive and without recurrent disease. One patient died with possible distant recurrence occurring at 5.6 months from beginning treatment. Conclusion: Adjuvant concurrent carboplatin and prone accelerated radiation therapy appears to be a safe and effective treatment for women diagnosed with early stage TNBC. Since approximately 50% of TNBC carriers recur within 2 years from treatment, it is encouraging that 97% of the patients in the trial have not experienced a recurrence.

Randomized data support use of chemotherapy concurrently with radiation in treatment of advanced squamous cell carcinoma (SCC) of the oropharynx. Intensity modulated radiation therapy (IMRT) is increasingly being used to deliver such radiotherapy; no published reports specifically describe results of chemotherapy with IMRT for SCC of the base of tongue (BOT). We present outcomes data using simultaneous modulated accelerated radiation therapy (SMART) combined with platinum-based chemotherapy in treatment of locally advanced SCC of the BOT METHODS: The records of the Otolaryngology/Head and Neck Surgery Department of Emory University were screened for patients undergoing definitive chemoradiotherapy for SCC of the BOT. Radiation Oncology records were reviewed for dosimetry and prescription data. Hospital and clinic records were reviewed for control and toxicity data. All patients were treated definitively with platinum-based chemotherapy and once-daily RT. Median dose and dose per fraction to sites of gross primary or nodal disease, clinically involved neck, and clinically uninvolved neck were 70.29 Gy (2.13 Gy/fx), 63.03 Gy (1.91 Gy/fx), and 57.75 Gy (1.75 Gy/fx), respectively.Between January 2003 and August 2005, 34 patients underwent definitive therapy for SCC of the BOT using SMART and chemotherapy. Follow-up was documented in all cases (median, 20.1 months). There have been 3 distant failures and 3 locoregional failures.With moderate follow-up, chemotherapy and SMART contributes to excellent results, with 24-month actuarial overall survival and local control of 90% and 92%, respectively. Toxicity may be increased, however, with 15% of patients developing esophageal stricture or stenosis. .

Summary Purpose Current treatment for unresectable stage III lung cancer includes standard radiotherapy with chemotherapy. Continuous hyperfractionated radiotherapy has been shown to be more effective than standard radiotherapy but may be associated with increased toxicity. In this study, we evaluated the feasibility and outcomes of patients treated with a hyperfractionated accelerated regimen in combination with neoadjuvant chemotherapy. Methods and materials We prospectively studied 61 consecutive patients with unresectable stage III non-small-cell lung cancer. All patients received three dimensional conformal radiotherapy using three daily fractions of 1.5 Gy to a total dose of 54–60 Gy omitting elective mediastinal irradiation. Approximately two-thirds of the patients also received platinum-based neoadjuvant chemotherapy. The primary outcome was locoregional disease-free survival. Secondary analyses were performed to assess tolerability, response rates, and overall and disease-free survival among study participants. Results Overall, 56% of patients had a complete response. Locoregional recurrence was observed in 55% of patients with only a 3% rate of dissemination to non-irradiated mediastinal lymph nodes. Median locoregional disease-free survival, disease-free survival, and overall survival were 16 months (95% CI: 12–20), 15 months (95% CI: 12–18), and 19 months (95% CI: 15–30), respectively. Additionally, no episodes of severe toxicity were reported among study participants. Poor performance status and radiation response were independent predictors of survival. Conclusions This study suggests that conformal three-dimensional hyperfractionated accelerated radiotherapy omitting elective node irradiation can be used in combination with neoadjuvant chemotherapy to treat patients with stage III lung cancer. Future studies should compare this approach with the standard treatments for patients with stage III lung cancer.

Purpose Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors' initial experience with image-guided SBRT in treating primary and metastatic RCC. Materials and methods The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins. Results Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects. Conclusion Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC.

Purpose In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). Patients and Methods After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). Results Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). Conclusion Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.

Background Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria. Methods Randomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in Results Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX). Conclusion RT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.

Purpose Accelerated repopulation is a main reason for locoregional failure after fractionated radiotherapy for head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) is a key controller of cellular proliferation in HNSCC, which stimulated the current study to look for a direct link between EGFR status and a possible clinical advantage of accelerated radiotherapy. Patients and Methods Immunohistochemical staining for EGFR was performed in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to receive continuous hyperfractionated accelerated radiotherapy versus conventionally fractionated radiotherapy. The EGFR index was estimated as the proportion of tumor cells with EGFR membrane staining. Results Significant benefit in locoregional tumor control from continuous hyperfractionated accelerated radiotherapy was seen in patients with HNSCC with high EGFR expression (2P = .010) but not in those with low EGFR expression (2P = .85). EGFR status had no significant effect on survival or rate of distant metastases. The EGFR index was significantly associated with histologic grade and microvessel density. There was moderate support for an association between EGFR status and subsite within the head and neck region but no significant association with Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index. Conclusion This study indicates a key role for the EGFR receptor in determining the proliferative cellular response to fractionated radiotherapy in HNSCC. It also shows that we can select the dose-fractionation regime that has the greatest chance of benefiting the patient. These results also encourage further development of EGFR targeting combined with fractionated radiotherapy in HNSCC.

Purpose To fit the situation of developing countries, where supportive care is not sufficient, a modified combined therapy of cisplatin/etoposide (EP) and hyperfractionated accelerated radiation therapy (HART) was conducted as a Phase II trial for limited-stage small-cell lung cancer (LSCLC) to evaluate the feasibility, toxicity, and tolerance of the combined therapy and to observe its efficacy and patterns of failure. Methods and materials Chemotherapy and radiation were sequentially administered in 1 to 3 cycles before and 3 to 5 cycles after HART. Chemotherapy contained cisplatin in doses of 25 to 30 mg/m 2 from Day 1 to Day 3 and etoposide in doses of 50 to 70 mg/m 2 from Day 1 to Day 3. The HART schedule consisted of radiation delivered in 1.4-Gy fractions, twice a day, at intervals longer than 6 h for 5 treatment days a week, to a total dose of 56 Gy in 40 fractions over 4 weeks. Results From June 1997 to December 2000, 57 eligible patients were registered for this trial. All were limited stage, and the median age was 60 years (range, 25 to 70 years). Of the 57 patients, 3 were withdrawn because of distant metastases (1 case), Grade (Gr) III thrombocytopenia (1 case), and financial problems (1 case). Fifty-four patients completed the planned combined treatment. A median of 6 cycles of chemotherapy (range, 5–8 cycles) was administered during a median interval of 4.9 weeks (range, 3.0–8.9 weeks), and a radiation dose of 56 Gy in 40 fractions was delivered over 29 days. The most common acute complication was radiation esophagitis, which occurred in 41 cases (72%), 4 with Gr III. Thirty-six patients (64%) had acute pulmonary toxicity, 2 with Gr III. The median survival time was 24 months (95% CI, 21–28 months). The 1-year, 2-year, and 3-year survival rates were 81% (95% CI, 70%–91%), 49% (95% CI, 36%–62%), and 21% (95% CI, 10%–32%), respectively. Of 57 patients, 13 had locoregional progression. Nine patients failed inside radiation fields and 4 patients failed outside. The 1-year, 2-year, and 3-year locoregional progression-free survival rates were 85% (95% CI, 75%–95%), 74% (95% CI, 61%–87%), and 68% (95% CI, 52%–84%), respectively. Forty-four patients suffered distant metastases, 66% of which were in brain. The 1-year, 2-year, and 3-year distant metastasis rates were 31% (95% CI, 19%–43%), 59% (95% CI, 46%–72%), and 79% (95% CI, 68%–91%), respectively. Conclusions The study led to the following conclusions: ( 1 ) LSCLC patients tolerate HART at 56 Gy in 40 fractions over 4 weeks combined with 6 cycles of EP chemotherapy. ( 2 ) Both control of the tumor in the thorax and survival appear superior to conventional fractionated radiation but not as good as that in a study by Turrisi and colleagues. ( 3 ) This modified chemoradiation schedule could be recommended to LSCLC patients in developing countries. ( 4 ) The lessons learned from our study are ( a ) higher radiation doses may be needed for better locoregional control, and ( b ) prophylactic cranial irradiation is necessary for LSCLC patients who show complete response.

Aim: The feasibility and improved efficacy of six conventional fractions per week has previously been proven in a Danish randomized trial. We tested the tolerance and efficacy of seven conventional fractions per week using a concomitant boost technique. Methods: From September 1996 to May 1998, 20 patients with squamous cancer of the head and neck were treated with radiation alone. The site of disease was oropharynx in 35%, larynx in 30%, oral cavity 20%, and hypopharynx in 15%. All patients had stage III (10%)/IV (90%) disease. The planned total dose to gross disease was 66Gy delivered in 33 fractions of 2Gy each in 31 days. Large volumes were treated to 46Gy, 2Gy per fraction, once each morning, Monday–Friday. Boosts to gross disease consisted of 20Gy in 10 fractions ≥6h after the morning dose on Tuesday and Thursday. Results: Acute toxicity ≥grade 3 was mucous membrane 75%, pharynx 60%, skin 65%, and larynx 35%. One acute toxicity was fatal. Chronic toxicity ≥grade 3 (three patients) was mucous membrane 5%, pharynx 10%, skin 5%, salivary 15%, and larynx 5%. All patients with grade III or greater late toxicity had grade III acute toxicity in each toxicity category. At 30 months Kaplan–Meier survival is 55%, and local control is 39%. Conclusions: Without increasing resource utilization this scheme accelerates treatment by 30%. As expected acute toxicity is high but manageable. Chronic toxicity appears comparable to other altered fractionation strategies however the median follow up is only 30 months more toxicity may emerge as the data matures. We plan further trials using 1.8Gy fractions to reduce toxicity.

combination in terms of rates of local control, distant recurrence, and overall survival. Materials/Methods: Women with stage I II (pT1-T2, pN0) TNBC are eligible after segmental mastectomy and axillary lymph node assessment. Weekly carboplatin (AUC Z 2.0) is delivered x 6 weeks with RT to the whole breast, delivered during weeks 2-4 via a 3D-CRT or an IMRT technique in the prone position. The whole breast receives 40.5 Gy in 15 fractions (Monday-Friday). The tumor bed receives an additional 3 Gy boost, delivered on 2 consecutive Sundays (beginning on the 2nd and 3rd weeks of RT). Consequently, a total of 46.5 Gy is delivered to the tumor bed in 17 fractions over 19 days. Adverse effects of treatment are assessed weekly during treatment, and once at 45-60 days, thereafter, using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 27 patients have accrued so far. The median age was 56 years (range: 27-82). Reported acute skin toxicities are displayed (see Table). With a median follow-up of 26 months all of the women remain alive and without recurrent disease. Conclusions: Adjuvant concurrent carboplatin and prone accelerated radiation therapy appears to be a safe and effective treatment for women diagnosed with early stage TNBC. Since approximately 50% of TNBC carriers recur within 2 years from treatment, it is encouraging that none of the patients in the trial have experience a recurrence. The trial remains open for patient accrual. Author Disclosure: E.B. Golden: None. R.E. Vatner: None. M. FentonKerimian: None. Y. Novik: None. R. Oratz: None. J. Speyer: None. S.C. Formenti: None.