Hypofractionation with simultaneous integrated boost after breast-conserving surgery: Long term results of two phase-II trials.

PURPOSE: To analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS). METHODS: Eligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities. RESULTS: Between 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36-72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast). CONCLUSION: Our analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.

Randomized phase-III-trial of concurrent chemoradiation for locally advanced head and neck cancer comparing dose reduced radiotherapy with paclitaxel/cisplatin to standard radiotherapy with fluorouracil/cisplatin: The PacCis-trial.

BACKGROUND AND PURPOSE: This multicenter, phase 3 trial investigates whether the incorporation of concurrent paclitaxel and cisplatin together with a reduced total dose of radiotherapy is superior to standard fluorouracil-cisplatin based CRT. MATERIALS AND METHODS: Patients with SCCHN, stage III-IVB, were randomized to receive paclitaxel/cisplatin (PacCis)-CRT (arm A; paclitaxel 20 mg/m2 on days 2, 5, 8, 11 and 25, 30, 33, 36; cisplatin 20 mg/m2, days 1-4 and 29-32; RT to a total dose of 63.6 Gy) or fluorouracil/cisplatin (CisFU)-CRT (arm B; fluorouracil 600 mg/m2; cisplatin 20 mg/m2, days 1-5 and 29-33; RT: 70.6 Gy). Endpoint was 3-year-disease free survival (3y-DFS). RESULTS: A total of 221 patients were enrolled between 2010 and 2015. With a median follow-up of 3.7 years, 3y-DFS in the CisFU arm and PacCis arm was 58.2% and 48.4%, respectively (HR 0.82, 95% CI 0.56-1.21, p = 0.52). The 3y-OS amounted to 64.6% in the CisFU arm, and to 59.2% in the PacCis arm (HR 0.82, 95% CI 0.54-1.24, p = 0.43). In the subgroup of p16-positive oropharyngeal carcinomas, 3y-DFS and 3y-OS was 84.6% vs 83.9% (p = 0.653), and 92.3% vs. 83.5% (p = 0.76) in arm A and B, respectively. Grade 3-4 hematological toxicities were significantly reduced in arm A (anemia, p = 0.01; leukocytopenia, p = 0.003), whereas grade 3 infections were reduced in arm B (p = 0.01). CONCLUSION: Paclitaxel/cisplatin-CRT with a reduced RT-dose is not superior to standard fluorouracil/cisplatin-CRT. Subgroup analyses indicate that a reduced radiation dose seems to be sufficient for p16+ oropharyngeal cancer or non-smokers. CLINICAL TRIAL INFORMATION: NCT01126216; EudraCT Number 2005-003484-23.

Hyperfractionated accelerated radiotherapy alone and with concomitant chemotherapy to the head and neck: treated within and outside of randomized clinical trials.

PURPOSE: A German multicenter randomized trial (ARO 95-6) compared hyperfractionated accelerated radiotherapy (RT) alone (to a total radiation dose of 77.6 Gy) with hyperfractionated accelerated radiochemotherapy (to 70.6 Gy) using concurrent mitomycin C and 5-fluorouracil. We analyzed the baseline patient characteristics and the influence of physician selection bias on treatment outcome for patients who were and were not enrolled in the randomized Phase III trial, with the therapies administered according to the trial protocols. METHODS AND MATERIALS: Between February 1996 and May 2000 at Tübingen University, 42 on-study patients and 41 off-study patients with Stage III-IV nonmetastatic squamous cell carcinoma of the head and neck were treated. The median follow-up for patients at risk (living at last evaluation) was 44 months, with a minimal follow-up of 2 years. RESULTS: The 4-year rate of overall survival, disease-specific survival, and locoregional tumor control was 25%, 40%, and 54%, respectively, for all 83 patients. Among patients enrolled in the study, the 4-year rate of overall survival for those receiving accelerated hyperfractionated radiochemotherapy was 33%, and that for patients receiving accelerated hyperfractionated RT alone was 18% (p = 0.25); among off-study patients, the comparable rates were 48% and 0% (p = 0.004). The 4-year rate of disease-specific survival among on-study patients receiving radiochemotherapy and RT alone was 41% and 36%, respectively (p = 0.5); among off-study patients the respective rates were 58% and 0% (p = 0.2). The rate of 4-year locoregional tumor control associated with radiochemotherapy and RT, respectively, was 51% and 54% among on-study patients and 72% and 23% among off-study patients (p = 0.08). CONCLUSION: Patients with advanced head-and-neck cancer who were entered into the randomized trial did not have statistically significantly different survival than patients treated according to the same protocol but outside the trial. Also, outside the trial, the physicians' selection bias in determining which patient received which treatment showed a much greater benefit from combined modality treatment than that found in the randomized trial.

Selective lymph node dissection following hyperfractionated accelerated radio-(chemo-)therapy for advanced head and neck cancer.

BACKGROUND: 2-year results of a German multicenter randomized trial showed that accelerated chemoradiation with MMC/5-FU to 70.6 Gy is more effective than accelerated radiation to 77.6 Gy alone at equivalent levels of acute and late radiation morbidity. Frequency, histopathology and impact on local tumor control of selective lymph node dissection were analyzed. PATIENTS AND METHODS: Between February 1996 and October 2000 at Tübingen University 42 randomized patients plus 45 non-randomized patients with stage III/IV MO head and neck cancer were treated according to this protocol. After completion of hyperfractionated accelerated (chemo-)radiation a selective lymph node dissection was performed, if the primary tumor was in complete remission and clinical plus computed tomography proved residual lymph node disease. 17 of 38 patients with residual node metastasis underwent uni- or bilateral selective node dissection, the remaining patients had residual primary tumors, clinical deterioration or refused neck dissection. RESULTS: After a median follow-up of 26 months, the Kaplan-Meier analysis showed a 2-year overall survival of 49%, disease-specific survival of 64% and loco-regional tumor control of 60%, respectively. 3-year loco-regional tumor control in randomized patients was 52% compared to 58% in non-randomized patients (log rank p = 0.23). 2-year loco-regional tumor control in stage cT4cN0 was 76% compared to 57% in cT2-4 cN1-3 tumors. Subgroup analysis of patients with involved nodes revealed a 2-year loco-regional tumor control of 74% after complete remission of primary tumor and neck disease, 53% after complete remission of primary tumor and partial remission of neck disease. In patients with selective lymph node dissection loco-regional tumor control was 62%. Histopathological examination showed viable tumor in eight of 17 patients. CONCLUSIONS: Selective lymph node dissection of residual neck masses after completion of hyperfractionated accelerated radio-(chemo-)therapy is likely to contribute to loco-regional tumor control in advanced head and neck cancer.

Intraindividual comparison of two different skin care conceptions in patients undergoing radiotherapy of the head-and-neck region. Creme or powder?

OBJECTIVES: This study evaluated for the first time in intraindividual comparison the conception of care with creme or powder. Acute skin reactions on the left and right side of the neck during symmetrically performed radiotherapy and subjective impairment were assessed. PATIENTS AND METHODS: Twelve patients receiving radiotherapy of the head-and-neck region up to 50, 60, 66 and 72 Gy, respectively, were asked to treat one side of the neck with creme, the contralateral side with powder after random assignment. Objective and subjective assessment and photodocumentation were performed at therapy onset and weekly during therapy. The photodocumentation provides an impressive course of acute skin reactions under these care concepts. RESULTS: Altogether we saw no relevant difference in favor of care with creme or powder according to objective as well as subjective assessment criteria (Figure 2 and 3). In this intraindividual comparison the results are independent from interindividual different sensitivity to radiotherapy, total dose or fractionation. Therefore the small patient number is a minor limitation for evidence. Our results are in accordance to trials comparing other care concepts. CONCLUSIONS: A relevant effect concerning onset and degree of acute skin reactions or differences in symptom relief could not be demonstrated. Both conceptions are to be regarded equal in terms of subjective symptom relief and in extent of acute skin reactions. The lack of differences may be explained by the fact that the underlying pathophysiological processes cannot be influenced by topical agents.