Anti-PD-1 immunotherapy with dose-adjusted ultra-hypofractionated re-irradiation in patients with locoregionally recurrent head and neck cancer

Introduction Patients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in 25% of patients. Immunogenic death produced by large radiotherapy (RT) fractions may enhance immune response. Materials and methods We evaluated the efficacy and tolerance of ultra-hypofractionated immuno-radiotherapy (uhypo-IRT) in 17 patients with recurrent HNSCC and 1 with melanoma. Four of HNSCC patients also had oligometastatic disease. Using a dose/time/toxicity-based algorithm, 7, 7 and 4 patients received 1, 2 and 3 fractions of 8 Gy to the tumor, respectively. Nivolumab anti-PD-1 immunotherapy was administered concurrently with RT and continued for 24 cycles, or until disease progression or manifestation of immune-related adverse events (irAEs). Results Early and late RT toxicities were minimal. Three patients developed irAEs (16%). After the 12th cycle, 7/17 (41.2%) and 5/17 (29.4%) patients with HNSCC showed complete (CR) and partial response (PR), respectively. CR was also achieved in the melanoma patient. The objective response rates in HNSCC patients were 57%, 86% and 66%, after 1, 2 and 3 fractions, respectively (overall response rate 70.6%). Most responders experienced an increase in peripheral lymphocyte counts. The median time to progression was 10 months. The 3-year projected locoregional progression-free survival was 35%, while the 3-year disease-specific overall survival was 50%. Conclusions Anti-PD1 uhypo-IRT is safe and effective in patients with recurrent HNSCC. The high objective response rates and the long survival without evidence of disease support further trials on uhypo-IRT (AU)

Anti-PD-1 immunotherapy with dose-adjusted ultra-hypofractionated re-irradiation in patients with locoregionally recurrent head and neck cancer.

INTRODUCTION: Patients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in 25% of patients. Immunogenic death produced by large radiotherapy (RT) fractions may enhance immune response. MATERIALS AND METHODS: We evaluated the efficacy and tolerance of ultra-hypofractionated immuno-radiotherapy (uhypo-IRT) in 17 patients with recurrent HNSCC and 1 with melanoma. Four of HNSCC patients also had oligometastatic disease. Using a dose/time/toxicity-based algorithm, 7, 7 and 4 patients received 1, 2 and 3 fractions of 8 Gy to the tumor, respectively. Nivolumab anti-PD-1 immunotherapy was administered concurrently with RT and continued for 24 cycles, or until disease progression or manifestation of immune-related adverse events (irAEs). RESULTS: Early and late RT toxicities were minimal. Three patients developed irAEs (16%). After the 12th cycle, 7/17 (41.2%) and 5/17 (29.4%) patients with HNSCC showed complete (CR) and partial response (PR), respectively. CR was also achieved in the melanoma patient. The objective response rates in HNSCC patients were 57%, 86% and 66%, after 1, 2 and 3 fractions, respectively (overall response rate 70.6%). Most responders experienced an increase in peripheral lymphocyte counts. The median time to progression was 10 months. The 3-year projected locoregional progression-free survival was 35%, while the 3-year disease-specific overall survival was 50%. CONCLUSIONS: Anti-PD1 uhypo-IRT is safe and effective in patients with recurrent HNSCC. The high objective response rates and the long survival without evidence of disease support further trials on uhypo-IRT.

Long-Term Results of Postoperative Hypofractionated Accelerated Breast and Lymph Node Radiotherapy (HypoAR) with Hypofractionated Boost.

We report long-term results (median follow-up 12 years) of hypofractionated accelerated radiotherapy (HypoAR) in patients treated with breast-conserving surgery. In total, 367 women were treated with HypoAR. Axillary and supraclavicular area (ASA) were treated in patients with involved nodes. In total, 290 patients (scheme A) received 3.5 Gy/day ×10 fractions (breast/ASA) followed by two 4 Gy fractions with electrons to the affected breast quadrant within 16 days. In total, 77 patients (Scheme B) received 2.7 Gy/day for 16 consecutive fractions (breast/ASA) within 22 days, while concurrently, the affected breast quadrant received an electron booster dose of 0.8 Gy for the first 13 fractions. Amifostine was offered to 252/367 patients. Early radiation toxicity was minimal. Regarding late toxicities, symptomatic breast edema was noted in 2.2%, asymptomatic breast fibrosis in 1.9%, and arm lymphedema in 3.7% of patients. Amifostine reduced early radiation dermatitis (p = 0.001). In total, 2.2% of patients developed contralateral breast and 1.6% other carcinomas. Locoregional recurrence (LR) occurred in 3.1% of patients (0% for in situ carcinomas). Positive margins after surgery, extracapsular node invasion, and HER2-enriched/triple-negative tumors were linked with significantly worse LR-free survival. The involvement of more than three nodes and luminal type other than A were independent prognostic variables of metastasis and death events. HypoAR delivering a biological dose of 50-52 Gy to the breast/ASA is a safe and effective therapy for patients treated with conservative surgery. The risk of carcinogenesis is low. Positive surgical margins, extracapsular node invasion, and HER2-enriched/triple-negative phenotypes appear as a cluster of features linked with a higher risk for locoregional relapse.

Cutaneous squamous-cell carcinoma of the head-neck area refractory to chemo-radiotherapy: benefit from anti-PD-1 immunotherapy.

OBJECTIVE: Radiotherapy provides excellent results in locally advanced cutaneous squamous-cell carcinoma of the head and neck area (cSCC-HN), with a 2-year local progression-free interval obtained for about 80% of patients. Overexpression of immune checkpoint co-inhibitory molecules, like PD-L1 (programmed death ligand 1), by cancer cells may define local immunosuppression, tumour escape from immune surveillance and reduced radiotherapy efficacy. METHODS: A 65-year-old female, with a large exophytic cSCC-HN invading adjacent soft tissues, was treated with hypofractionated accelerated chemo-radiotherapy. The patient received four bi-weekly cycles of chemotherapy concurrently with eight fractions of 5.5 Gy (two fractions per week). Two months after the end of chemo-radiotherapy, the tumour was stable in dimensions, without any signs of symptomatic relief. The patient was, after that, treated with anti-PD-1 immunotherapy (nivolumab). The tumour gradually regressed, reaching partial response after four cycles and complete response after 16 cycles of nivolumab. No side-effects related to immunotherapy were recorded. The patient is alive and without evidence of disease 28 months after radiotherapy. CONCLUSIONS: Treatment of patients with chemo- and radio-resistant cSCC-HN with immunotherapy may optimize the efficacy of radiotherapy by stimulating immunological tumour rejection mechanisms. cSCC-HN patients who fail to respond to chemo-radiotherapy completely are expected to benefit the most from immunotherapy because of the radio-vaccination effect expected from the preceded radiotherapy.

Hypofractionated Accelerated Chemo-radiotherapy (Chemo-HypoAR) With Cisplatin and Liposomal Doxorubicin for the Treatment of Patients With Uterine Sarcomas.

BACKGROUND/AIM: Uterine sarcoma is an aggressive tumor associated with poor survival, compared to endometrioid carcinoma. Postoperative local radiotherapy and chemotherapy are controversial. PATIENTS AND METHODS: We report a retrospective analysis of 14 patients with uterine homologous type carcinosarcoma (9 patients) or leiomyosarcoma (5 patients), treated with postoperative 3D-conformal accelerated hypofractionated radiotherapy (2.7 Gy/fraction for 14 fractions followed by one fraction of 6-8 Gy dose to the vagina). Chemotherapy with cisplatin (50 mg/m2) and liposomal doxorubicin (20 mg/m2), was also administered bi-weekly for two cycles before and for three cycles during radiotherapy. RESULTS: Chemotherapy induced only grade 1 neutropenia or anemia in 4/14 (28.5%) and 5/14 (35.7%) of patients, respectively. Two patients (2/14, 14.2%) interrupted their radiotherapy for one and two weeks, respectively, due to grade II persistent diarrhea. Within a median of 58 months (range=8-137 months) of follow-up, none of the patients presented with loco-regional relapse. Two patients developed distant metastasis. CONCLUSION: Concurrent hypofractionated and accelerated chemo-radiotherapy (chemo-HypoAR) is feasible and provides excellent survival figures.