Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

Four-dimensional stereotactic radiotherapy for early stage non-small cell lung cancer: a comparative planning study.

In this study we sought to assess the potential of the respiratory tumor tracking system of the CyberKnife to administer 3 fractions of 15 Gy in the treatment of early stage non-small cell lung cancer (NSCLC). The CyberKnife plans were compared to those developed for 3-D conformal radiotherapy (3-D CRT) administering 20 fractions of 3 Gy based on a slow CT. Ten patients with stage I NSCLC, who were previously treated with 3-D CRT, were re-planned with the CyberKnife treatment planning system. In the 3-D CRT plan, the planning target volume (PTV) included the gross tumor volume (GTV)(slow) and a 15-mm margin, whereas in the CyberKnife plan the margin was 8 mm. The physical doses from both treatment plans were converted to normalized total doses (NTD) using the linear quadratic model with an alpha/beta(tumor) of 10 Gy and alpha/beta(organs at risk (OAR)) of 3 Gy. The average minimal and mean doses administered to the PTV with the CyberKnife and 3-D CRT were 93 and 115.8 Gy and 61 and 66 Gy, respectively (p<0.0001). The mean V(20) of the CyberKnife and 3-D CRT plans were 8.2% and 6.8%, respectively (p=0.124). Both plans complied with the OAR constraints. In conclusion, 4-dimensional stereotactic radiotherapy can increase the minimal and mean biological dose with 51% and 75%, in comparison with 3-D CRT without significantly increasing the V(20), respectively.

Curative stereotactic robotic radiotherapy treatment for extracranial, extrapulmonary, extrahepatic, and extraspinal tumors: technique, early results, and toxicity.

We investigated the technique, early results and toxicity of curative stereotactic radiotherapy with the CyberKnife (Accuray Incorporated, Sunnyvale, California, USA) in 15 extracranial, extrapulmonary, extrahepatic, and extraspinal tumors. Fourteen tumors were located close to the bowel or esophagus. The PTV = GTV + 2-5 mm. The dose to the tumors varied from 10 fractions of 4 Gy up to 3 fractions of 20 Gy (median dose/fraction: 7 Gy; median number of fractions: 6), and depended on the proximity of the bowel. A small volume of the bowel was allowed to receive a dose of 6 Gy/fraction. The dose to the PTV was prescribed to the 75-85% isodose line. With a median follow up of 18 months, the 2-year local control and overall survival was 100%. Due to our flexible fractionation schedules, we were able to prescribe the dose to at least 90% of the PTV (median 95%) without increasing the dose to the bowel > 6 Gy/fraction. Five acute side effects were seen in four patients: two patients had transient grade 1 lymph edema in the leg, one patient complained of grade 1 pain in the abdomen and diarrhea, and one patient complained of grade 1 radiation dermatitis. Late toxicity such as grade 1 rectal bleeding, grade 1 diarrhea, grade 2 painful subcutaneous fibrosis, grade 2 pain in a surgical scar on the abdominal wall and an asymptomatic occlusion of the ureter was observed. Curative stereotactic radiotherapy treatment with the CyberKnife for extracranial, extrapulmonary, extrahepatic, and extraspinal, locally recurrent or solitary metastatic tumors is feasible and results in excellent local control and survival with low acute and late toxicity. A small volume of the bowel is able to tolerate a dose of 6 Gy per fraction for a maximum of 6 fractions.

Robotic radiosurgery vs. brachytherapy as a boost to intensity modulated radiotherapy for tonsillar fossa and soft palate tumors: the clinical and economic impact of an emerging technology.

As a basis for making decisions regarding optimal treatment for patients with tonsillar fossa and soft palate tumors, we conducted a preliminary investigation of costs and quality of life (QoL) for two modalities [brachytherapy (BT) and robotic radiosurgery] used to boost radiation to the primary tumors following external beam radiotherapy. BT was well established in our center; a boost by robotic radiosurgery was begun more recently in patients for whom BT was not technically feasible. Robotic radiosurgery boost treatment has the advantage of being non-invasive and is able to reach tumors in cases where there is deep parapharyngeal tumor extension. A neck dissection was performed for patients with nodal-positive disease. Quality of life (pain and difficulty swallowing) was established in long-term follow-up for patients undergoing BT and over a one-year follow-up in robotic radiosurgery patients. Total hospital costs for both groups were computed. Our results show that efficacy and quality of life at one year are comparable for BT and robotic radiosurgery. Total cost for robotic radiosurgery was found to be less than BT primarily due to the elimination of hospital admission and operating room expenses. Confirmation of robotic radiosurgery treatment efficacy and reduced morbidity in the long term requires further study. Quality of life and cost analyses are critical to Health Technology Assessments (HTA). The present study shows how a preliminary HTA of a new medical technology such as robotic radiosurgery with its typical hypofractionation characteristics might be based on short-term clinical outcomes and assumptions of equivalence.

Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results.

Lung tumor tracking during stereotactic radiotherapy with the CyberKnife requires the insertion of markers in or close to the tumor. To reduce the risk of pneumothorax, three methods of marker placement were used: 1) intravascular coil placement, 2) percutaneous intrathoracal, and 3) percutaneous extrathoracal placement. We investigated the toxicity of marker placement and the tumor response of the lung tumor tracking treatment. Markers were placed in 20 patients with 22 tumors: 13 patients received a curative treatment, seven a palliative. The median Charlson Comorbidity Score was 4 (range: 1-8). Platinum fiducials and intravascular embolisation coils were used as markers. In total, 78 markers were placed: 34 intrathoracal, 23 intravascular and 21 extrathoracal. The PTV equaled the GTV + 5 mm. A median dose of 45 Gy (range: 30-60 Gy, in 3 fractions) was prescribed to the 70-85% isodose. The response was evaluated with a CTscan performed 6-8 weeks after the last treatment and routinely thereafter. The median follow-up was 4 months (range: 2-11). No severe toxicity due to the marker placement was seen. Pneumothorax was not seen. The local control was 100%. Four tumors in four patients showed a complete response, 15 tumors in 14 patients a partial response, and three tumors in two patients with metastatic disease had stable disease. No severe toxicity of marker placement was seen due to the appropriate choice of one of the three methods. CyberKnife tumor tracking with markers is feasible and resulted in excellent tumor response. Longer follow-up is needed to validate the local control.