Patients (N=246) with resectable/borderline resectable pancreatic cancer were randomly assigned to receive preop chemoRT or immediate surgery in this phase 3 trial. Overall survival trended towards improvement with preop chemoRT (16.0 months, HR 0.78 (95% confidence interval [CI], 0.58 to 1.05), N=119) vs 14.3 months, (N=127), with P=0.096). R0 resection occurred in 71% vs 40% of patients with vs without preop chemoRT. Disease-free and locoregional failure-free survival were improved with vs without preop chemoRT. Overall survival was improved in a subset of patients who underwent resection and adjuvant chemotherapy with vs without preop chemoRT.

Reference (PubMed Link): Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: Results of the dutch randomized phase iii preopanc trial. J Clin Oncol 2020;38:1763-1773.

Key Institution: Multi-Institutional (Netherlands)
Keywords: Pancreas, Surgery, Chemoradiation 

Twenty-one participants had locally advanced, unresectable, stage III NSCLC, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function.

Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Progression-free survival was good, with relatively few serious immune-related adverse events.

Consolidative immunotherapy following chemoradiation for locally advanced NSCLC was shown to improve survival in the PACIFIC trial. The use of concurrent immunotherapy with radiation in intriguing but there is little data regarding safety and efficacy. This Phase 1 study demonstrates that concurrent chemoimmunoradiotherapy is tolerable in this population, with further studies required to evaluate efficacy.

(Open Access)

Reference (PubMed Link): Jabbour SK, Berman AT, Decker RH, et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol 2020;6:1-8.

Key Institution: Multi-Institutional (Royal Marsden Hospital, Institute of Cancer Research, London, UK)
Keywords: Immunotherapy, Chemoradiotherapy, Locally Advanced Non-small Cell Lung Cancer 

This is a large, multi-institutional, retrospective, nonrandomized comparative effectiveness study that included 1483 adult patients with nonmetastatic, locally advanced cancer that was treated with concurrent chemotherapy and radiotherapy with curative intent. The primary endpoint was 90-day CTCAE adverse events of grade3 or above. The results showed that proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse event of at least grade 3 (relative risk = 0.31, with 95% confidence interval 0.65- 0.93, p=0.006), as well as decline in performance status during treatment (relative risk = 0.561, 95% confidence interval0.37 - 0.71, p<0.001). There was no difference in disease-free or overall survival.

Reference (PubMed Link): Baumann BC, Mitra N, Harton JG, et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol 2019.

Key Institution: Multi-Institutional (US)
Keywords: Proton therapy, toxicity

Cancer outcomes are relatively good for patients with hereditary retinoblastoma. However, long term survivors are at risk for developing secondary cancers as a result of radiotherapy. This study analyzed 952 long-term survivors diagnosed between 1914 and 2006. The authors found that there were 105 bone and 124 soft tissue sarcomas, more than half in the head and neck (in/near the radiation field), one quarter in the body and extremities, and about 1/5th elsewhere. These were diagnosed as early as early childhood and well into adulthood. These data provide some guidance as to the risk of developing secondary sarcomas after radiation therapy in childhood and point to the need for effective and risk-based screening. 

(Open Access)

Reference (PubMed Link): Kleinerman RA, Schonfeld SJ, Sigel BS, et al. Bone and soft-tissue sarcoma risk in long-term survivors of hereditary retinoblastoma treated with radiation. J Clin Oncol 2019;37:3436-3445.

Key Institution: National Cancer Institute, Bethesda, MD
Keywords: Retinoblastoma, radiation, secondary malignancy 

471 patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), of whom 251 were early stage, 76 were intermediate stage, and 144 were advanced stage.  All received first line treatment in the randomized GHSG HD7 to HD15 studies, which consisted of radiation alone, chemotherapy alone, or chemo-RT. 

Median follow up was 9.2 years. PFS and OS estimates were 75.5% and 92.1% respectively.  Early stage PFS and OS were 79.7% and 93.3%, intermediate stage PFS and OS were 72.1% and 96.2%, and advanced stage PFS and OS were 69.8% and 87.4%.  Patients older than 45 years and with splenic involvement at diagnosis had worse survival outcomes, as did patients with liver or bone marrow involvement. 10% of patients developed a secondary malignancy, of which almost half were solid tumors.  Only 9% of patients died. Among these, the majority of causes of death were from secondary malignancies or from non-malignant conditions possibly associated with RT or chemotherapy (such as cardiovascular disease), rather than from NLPHL. 

Given the good cause-specific survival of patients with NLPHL treated on GHSG protocols, treatment optimization with consideration of long-term side effects from radiation and/or chemotherapy should be evaluated. 

Reference (PubMed Link): Eichenauer DA, Plutschow A, Fuchs M, et al. Long-term follow-up of patients with nodular lymphocyte-predominant hodgkin lymphoma treated in the hd7 to hd15 trials: A report from the german hodgkin study group. J Clin Oncol 2019:Jco1900986.

Key Institution: German Hodgkin Study Group
Keywords: Hodgkin Lymphoma, RT, chemotherapy, chemoradiotherapy, secondary malignancy 

The optimal treatment for locally advanced esophageal cancer is trimodality therapy (surgery, radiation, and chemotherapy) or chemoradiation. However, locoregional failure is at least 50%. A major past study (Intergroup 0123) attempted to escalate the radiation dose from 50.4 Gy to 64.8 Gy but this showed no difference in survival. However, many of these deaths occurred at or before even 50.4 Gy was delivered, so perhaps modern RT techniques (IMRT and/or protons) can allow for safer delivery of higher doses of RT. These techniques allow for dose escalation in the form of an SIB. 

The present study is a phase I/II trial evaluating the safety and efficacy of an SIB approach for unresectable locoregionally advanced esophageal patients, which entailed delivery of 50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions.  

46 patients received this therapy, either with protons or photons. 24% of patients were ultimately able to receive surgery. No patients experienced grade 4 or 5 toxicity. There were 10 acute grade 3 events which included esophagitis, dysphagia, and anorexia. There were 3 late esophageal strictures. The actuarial local recurrence risks were 22%, 30%, and 33% at 6 months, 1 year, and 2 years, respectively. 33% of patient experienced local failure and the medial overall survival was 21.5 months. An exploratory analysis suggested that this local control compares favorably with standard radiation approaches. These findings are encouraging and support the initiation of larger trials to further study the safety and efficacy of this approach. 

Reference (PubMed Link): Chen D, Menon H, Verma V, et al. Results of a phase 1/2 trial of chemoradiotherapy with simultaneous integrated boost of radiotherapy dose in unresectable locally advanced esophageal cancer. JAMA Oncol 2019.

Key Institution: MD Anderson Cancer Center, Houston, Texas
Keywords: Unresectable esophageal cancer, simultaneous integrated boost 

NBTXR3 is a spherical nanoparticle composed of crystalline hafnium oxide with a negatively charged phosphate coating. The particles can be administered into the tumor. Initial phase I trial evaluated dose escalation to obtain an optimal dose. Patients then received pre-operative radiotherapy followed by surgical resection. Initial studies showed a 40% tumor shrinkage with median residual tumor cells 26%. This trial concluded that the optimal nanoparticle volume was 10% of tumor size. The present trial then evaluated the use of NBTXR3 + RT versus RT alone followed by surgery for both groups. The pathologic complete response (CR) rate was 16% in NBTXR3 + RT versus 8% in RT alone. There was an absolute improvement in R0 resection of 12% (77% vs 64%, p=0.04). There were no significant differences in toxicity between the two groups. Overall, this is a new technology that requires ongoing study to further establish its value. This study did not show a survival benefit, but long-term follow-up will confirm whether this benefit exists.

Reference (PubMed Link): Bonvalot S, Rutkowski PL, Thariat J, et al. Nbtxr3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (act.In.Sarc): A multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol 2019;20:1148-1159.

Key Institution: Multi-Center International Trial (Nanobiotix)
Keywords: Nanoparticles, sarcoma, radiosensitizer

Immunotherapy continues to revolutionize the treatment of metastatic cancer with expanding applications across many tumor types. There is significant interest in combining radiation therapy with immunotherapy to potentially enhance immune responses and trigger abscopal effects. While there is some thought that SBRT may be particularly effective at triggering immune responses when compared with conventional fractionation, the safety of combining SBRT with immunotherapy and the number of lesions that should be treated remains unclear. In this prospective phase I trial of patients who had progressed on standard therapies, SBRT followed by pembrolizumab appeared to be safe. The overall response rate was encouraging in this population of patients not selected forPD-L1 expression, providing preliminary support for tumor debulking with SBRT and possible evidence of synergism. Furthermore, the correlation of interferon-gamma gene expression after SBRT with the development of abscopal responses suggests that this maybe a helpful biomarker for future studies. Ultimately, the progression-free and overall survival in this heterogenous group of patients with metastatic disease remains poor, and this approach will need to be tested in randomized trials.

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