Dr. Solanki then described what he calls the “radiation oncologist’s holy grail”: the abscopal effect – response to distant sites due to an immune response created by radiotherapy to a tumor. However, there are several issues with the abscopal effect according to Dr. Solanki, including (i) it remains elusive, (ii) it rarely leads to long-term immune memory, and (iii) radiotherapy may increase PD-1/PD-L1 expression and Treg infiltration, which interferes with cell-mediated toxicity. As such the hypothesis for combining radiotherapy with immunotherapy is that this will improve control of the primary tumor secondary to radio-sensitization, allow for systemic response, and result in immune memory.
There are two important clinical questions according to Dr. Solanki: (1) Can immunotherapy help curative bladder cancer radiotherapy? (2) Can radiotherapy help palliative immunotherapy for metastatic bladder cancer? As Dr. Solanki notes, studies from non-small cell lung cancer (NSCLC) inspire us to seek out the answers to these two questions for patients with bladder cancer. The recently published PACIFIC Trial assessed patients with stage III NSCLC treated with cisplatin-based chemotherapy and 54-66 Gy of radiotherapy and randomized them to durvalumab vs placebo . This lead to a 20% improvement in PFS favoring durvalumab compared to placebo, while OS data were not mature for evaluation. Secondly, the KEYNOTE-001 phase I trial assessing pembrolizumab in advanced NSCLC found that patients treated with radiotherapy had a significantly improved median PFS (4.4 months vs 2.0, p=0.019) and OS (10.7 months vs 5.5 months, p=0.026) compared to those not receiving radiotherapy . Bladder cancer has a relatively high somatic mutation burden akin to NSCLC and a good track record of immunotherapy. As such, according to Dr. Solanki it is a good malignancy for investigating combining radiotherapy and immunotherapy.
There are several practical questions moving forward with radiotherapy and immunotherapy for bladder cancer:
- What is the optimal sequencing of immunotherapy and radiotherapy?
2. What is the optimal radiotherapy dose and fractionation?
In vivo studies of breast cancer mice suggest that high dose per fraction appears to be more immune stimulating, whereas patients in the PACIFIC trial received 54-66 Gy in conventional fraction sizes .
3. What is the optimal radiotherapy field size to treat?
The bladder radiotherapy field frequently includes an initial lower dose to the proximal pelvic lymph nodes followed by a boost to the bladder tumor. However, antigen presenting and T-cell activation occur at the lymph nodes, so Dr. Solanki wonders if we are working against ourselves?
4. What sites should we irradiate?
For definitive radiotherapy, it likely makes sense to treat the primary tumor, but the question remains whether we have to treat the whole tumor? For palliative radiotherapy, can we choose lesions that are more likely to elicit an immune response?
5. What about concurrent chemotherapy? What is the best immunotherapy combination?
There are several ongoing bladder cancer trials combining radiotherapy and immunotherapy to assess the concurrent and best immunotherapy combination:
Dr. Solanki notes that we need to be vigilant for increased toxicity when combining radiotherapy with immunotherapy. There certainly is preclinical and clinical rationale for combining immunotherapy with radiotherapy in many malignancies, including bladder cancer. However, there are lots of unknowns that remain and the ongoing clinical trials should elucidate the “hows” of combining immunotherapy and radiotherapy in bladder cancer.
Presented by: Abhishek A. Solanki, MD, MS, Loyola University, Chicago, IL
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377(20):1919-1929.
2. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18(7):895-903.