Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy. METHODS: In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0-2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241. FINDINGS: Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9-6·0), 3-year progression-free survival was 93·7% (90% CI 88·5-96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours). INTERPRETATION: Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed. FUNDING: Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.

Online Adaptive MR-Guided Ultrahypofractionated Radiotherapy of Prostate Cancer on a 1.5 T MR-Linac: Clinical Experience and Prospective Evaluation.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

Dose-escalated radiotherapy with simultaneous integrated boost for bone metastases in selected patients with assumed favourable prognosis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) concepts for dose escalation are increasingly used for bone metastases in patients with oligometastatic or oligoprogressive disease. For metastases that are not suitable for SBRT-regimens, a treatment with 30/40 Gy with simultaneous integrated boost (SIB) in 10 fractions represents a possible regimen. The aim of this study was to investigate the feasibility of this concept and the acute and subacute toxicities. PATIENTS AND METHODS: Clinical records for dose-escalated radiotherapy of all consecutive patients treated with this regimen were evaluated retrospectively (24 patients with 28 target volumes for oncologic outcomes and 25 patients with 29 target volumes for treatment feasibility and dose parameters analysis). Analysis of radiotherapy plans included size of target volumes and dosimetric parameter for target volumes and organs at risk (OAR). Acute and subacute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0. RESULTS: The most common localization was the spine (71.4%). The most common histology was prostate cancer (45.8%). Oligometastatic or oligoprogressive disease was the indication for dose-escalated radiotherapy in 19/24 patients (79.2%). Treatment was feasible with all patients completing radiotherapy. Acute toxicity grade 1 was documented in 36.0% of the patients. During follow up, one patient underwent surgery due to bone instability. The 1-year local control and patient-related progression-free survival (PFS) were 90.0 ± 6.7% and 33.3 ± 11.6%, respectively. CONCLUSIONS: Dose-escalated hypofractionated radiotherapy with simultaneous integrated boost for bone metastases resulted in good local control with limited acute toxicities. Only one patient required surgical intervention. The regimen represents an alternative to SBRT in selected patients.

Long-term Follow-up and Patterns of Recurrence of Patients With Oligometastatic NSCLC Treated With Pulmonary SBRT.

INTRODUCTION: This multicenter study aims to analyze outcome as well as early versus late patterns of recurrence following pulmonary stereotactic body radiotherapy (SBRT) for patients with oligometastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 301 patients with oligometastatic NSCLC treated with SBRT for 336 lung metastases. Although treatment of the primary tumor consisted of surgical resection, radiochemotherapy, and/or systemic therapy, pulmonary oligometastases were treated with SBRT. RESULTS: The median follow-up time was 16.1 months, resulting in 2-year overall survival (OS), local control (LC), and distant control (DC) of 62.2%, 82.0%, and 45.2%, respectively. Multivariate analysis identified age (P = .019) and histologic subtype (P = .028), as well as number of metastatic organs (P < .001) as independent prognostic factors for OS. LC was superior for patients with favorable histologic subtype (P = .046) and SBRT with a higher biological effective dose at isocenter (P = .037), whereas DC was inferior for patients with metastases in multiple organs (P < .001) and female gender (P = .027). Early (within 24 months) local or distant progression was observed in 15.3% and 36.5% of the patients. After 24 months, the risk of late local failure was low, with 3- and 4-year local failure rates of only 4.0%, and 7.6%. In contrast, patients remained at a high risk of distant progression with 3- and 4-year failure rates of 13.3% and 24.1%, respectively, with no plateau observed. CONCLUSION: SBRT for pulmonary oligometastatic NSCLC resulted in favorable LC and promising OS. The dominant failure pattern is distant with a continuously high risk of disease progression for many years.

Ex vivo γH2AX radiation sensitivity assay in prostate cancer: Inter-patient and intra-patient heterogeneity.

INTRODUCTION: The aim of the study is to assess inter-patient and intra-patient heterogeneity in tumour cell radiosensitivity using the ex vivo γH2AX assay in prostate cancer specimens. METHODS: Excised specimens from untreated prostate cancer patients were cultivated 24h in media, irradiated ex vivo and fixed after 24h. Residual γH2AX foci were counted and the slope of the dose response was calculated. Intra-patient heterogeneity was studied from three to seven different biopsies. RESULTS: In pathology-confirmed tumour samples from 21 patients the slope of residual γH2AX foci and radiation dose showed a substantial heterogeneity ranging from 0.82 to 3.17 foci/Gy. No correlation was observed between the slope values and the Gleason score (p=0.37), prostate specific antigen (p=0.48) and tumour stage (p=0.89). ANOVA indicated that only in 1 out of 9 patients, biopsies from different tumour locations yielded statistically significant differences. Variance component analysis indicated higher inter-patient than intra-patient variability. Bootstrap simulation study demonstrated that one biopsy is sufficient to estimate the mean value of residual γH2AX per dose level and account for intra-patient heterogeneity. CONCLUSIONS: In prostate cancer inter-patient heterogeneity in tumour cell radiation sensitivity is pronounced and higher than intra-patient heterogeneity supporting the further development of the γH2AX ex vivo assay as a biomarker for individualized treatment.

Impact of tumor control and presence of visible necrosis in head and neck cancer patients treated with radiotherapy or radiochemotherapy.

PURPOSE: Tumor volume after the lymph node involvement is one of the most important single prognostic factor in patients of head and neck cancers treated with radiotherapy. We have recently demonstrated that the hypoxic subvolume is more important than the total tumor volume. We therefore propose the hypothesis that the presence of visible necrosis might be an important factor for cure by radiotherapy in squamous cell cancers of the head and neck. METHODS: A total of 51 patients with locally advanced inoperable (T3-4 or N2-3) squamous cell cancers of the head and neck (mean age 57 years, range 41-75 years) were prospectively investigated with regard to a possible impact of tumor volume. All patients received CT examination of the head and neck according to a standardized protocol (spiral CT, contrast enhancement after automatic injection), and the total tumor volume was calculated as the sum of volumes of all visible macroscopic tumor sites. Poorly perfused and necrotic areas (no contrast enhancement) within macroscopic tumor sites were also calculated. Patients were then treated with accelerated-hyperfractionated radiotherapy in about 6 weeks. Seventeen patients were treated with only radiation. Patients without contraindications to cisplatin chemotherapy received cisplatin chemotherapy or a combination of cisplatin and paclitaxel (N=34). The allocation of patients to certain treatment regimens was based on individual decisions in each case and not randomized. RESULTS: In patients treated with radiation alone, 12/17 (71%) got recurrence whereas in patients treated with radiation plus cisplatin, only 14/34 (41%) recurred (P=0.05). The 2-year overall survival was for radiation alone versus radiation plus cisplatin 0% vs. 62% (P<0.0008). Tumors with smaller amount of necrosis (necrosis volume<4 cm3) had a good prognosis irrespective of type of treatment (radiation alone or radiation plus cisplatin). However, patients with tumors with a larger amount of necrosis (necrosis volume> or =4 cm3) had a significantly better outcome if they were treated with radiation plus cisplatin as compared to patients treated with radiation alone. In a multi-variate analysis using a Cox-regression model the type of treatment (radiotherapy plus versus without cisplatin) was the only independent prognostic factor for event-free survival (P<0.03) in the whole group. CONCLUSIONS: In this non-randomized retrospective investigation with limited sample size, radiation plus cisplatin was superior to radiation alone. This resulted mainly from a higher efficacy of the radiochemotherapy regimen in patients with large and especially necrotic tumors. The prognostic and predictive impact of visible necrosis should be further evaluated.

Definitive radiotherapy and single-agent radiosensitizing ifosfamide in patients with localized, irresectable soft tissue sarcoma: a retrospective analysis.

BACKGROUND AND PURPOSE: Standard therapy for soft-tissue sarcomas remains complete resection. For primary radiotherapy local control rates of 30-45% have been reported. We analyzed retrospectively 11 cases of radiochemotherapy with single-agent ifosfamide in patients with macroscopic soft-tissue sarcomas. PATIENTS AND METHODS: The patients were treated in irresectable high risk situations. Radiation therapy was performed with median 60 Gy. During the first and fifth week the concomitant chemotherapy with ifosfamide was added. Two patients received trimodal therapy with additional regional hyperthermia. RESULTS: The therapy was completed in 73% of the patients. Average local control time was 91 months, median disease-free-survival/overall-survival was 8/26 months. Five-year rates for local control/disease free survival/overall survival were 70%/34%/34%. The limited prognosis is mainly caused by systemic treatment failure. CONCLUSIONS: The data strongly suggest a better outcome of radiochemotherapy with ifosfamide compared to radiotherapy alone and radiotherapy in combination with other radiosensitizers.