By Robert K. Chin, MD, PhD, and Deborah J.L. Wong, MD, PhD
- Within the metastatic setting, immunotherapy in combination with radiotherapy may be synergistic and may be an effective strategy to enhance the effect of immunotherapy.
- The radiation oncology community has begun to appreciate the role of the immune response itself as an important component in the treatment effect of radiotherapy.
- Successful integration of immunotherapy into definitive radiotherapy regimens may require a drastic alteration of radiotherapy dosing and field design to maximize benefit.
The incorporation of immunotherapy into the armamentarium of cancer treatments has resulted in significant improvements in outcomes for many patients with advanced cancers. To date, antibodies that block the PD-1/PD-L1 pathway have been approved as monotherapy for melanoma, renal cell carcinoma, non–small cell lung cancer, head and neck cancers, and others.
For example, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) who have experienced progression during or after a platinum-based chemotherapy regimen, response rates to nivolumab were 13.3% versus 5.8% for patients treated with investigator’s choice of chemotherapy. An improvement in median overall survival to 7.5 months in the group that received nivolumab versus 5.1 months for patients who received standard therapy also was seen.1 In addition, responses may be durable for patients whose diseases respond, and toxicity from anti–PD-1/PD-L1 therapy generally is minimal or mild. However, although certainly an improvement compared with prior available therapies, anti–PD-1/PD-L1 monotherapy is not effective for many patients or may not result in durable responses.
Therefore, several novel approaches are being evaluated to improve upon patient outcomes with immunotherapy. These include incorporation of PD-1/PD-L1 immunotherapy earlier in the treatment course as neoadjuvant or adjuvant therapy, addition of anti–PD-1/PD-L1 therapy in combination with cytotoxic chemotherapy or targeted therapy, and ongoing investigations of novel immunotherapy combinations for patients with recurrent or metastatic disease, whether naive to or pretreated with anti–PD-1/PD-L1 therapy.
Creating Effective Combinations
Within the metastatic setting, immunotherapy in combination with radiotherapy may be synergistic and may be an effective strategy to enhance the effect of immunotherapy. There is ample evidence that suggests focused radiotherapy enhances both the strength of the immune response against the targeted antigen and the specificity of the response to the specified target. This connection between radiotherapy and immune modulation is popularly seen in clinical reports of the abscopal effect, the spontaneous regression or resolution of lesions outside of radiation targets.2 This effect is the foundation of a large number of clinical trials for oligometastatic disease in which stereotactic body radiotherapy directed to a subset of lesions is used to enhance systemic immune response against the patient’s remaining disease.
Although the value of immunotherapy is becoming established in the metastatic setting, its value in enhancing outcomes of definitive therapy remains unexplored. In this setting, the synergy between immunotherapy and radiotherapy is used to enhance conventional radiotherapy, much as concurrent chemotherapy does. Indeed, a large array of ongoing clinical trials is integrating immunotherapy into existing treatment paradigms of surgery and adjuvant radiotherapy with or without concurrent chemotherapy, or into definitive concurrent chemoradiotherapy. Particularly with radiotherapy, these approaches have merits beyond simple treatment intensification. Traditionally, radiotherapy’s mechanism of action was thought to involve creation of free radicals and introduction of DNA double-strand breaks.
Although these certainly play a significant role, as witnessed in decades of in vitro and in vivo assays, the radiation oncology community more recently has begun to appreciate the role of the immune response itself as an important component in the treatment effect of radiotherapy. More concretely, this can be seen in the lack of efficacy of radiotherapy in controlling tumors implanted in murine models of immune deficiency relative to wild-type models.3 Clinically, resistance of SCCHN to conventional therapy in immunocompromised patients is well known. Finally, reports of the abscopal effect in lesions outside the radiation field also are supportive of the potential for radiotherapy to function as an immune modulator. Therefore, the addition of immunotherapy promises to enhance an existing mechanism of radiotherapy efficacy.
This integration of immunotherapy and radiotherapy is far from frictionless, however, because radiotherapy fields were designed in an era that gave little consideration to generation and propagation of immune responses. For example, definitive radiotherapy fields for SCCHN almost inevitably involve not just coverage of the gross disease but also intervention at high-risk regions and elective nodal irradiation. Elective nodal irradiation is omitted only if the risk of regional recurrence is considered low, such as in early-stage glottic primary tumors. Although the radiotherapy dosing—which ranges from 70 Gy for gross disease to 54 Gy for low-risk neck regions—is risk adapted, the treatment fields cover the entirely of the neck. Thus, a T1N0 squamous cell carcinoma of the base of tongue has roughly the same field dimensions as a much more advanced T3N2c squamous cell carcinoma.
These large fields are designed to eradicate microscopic disease in high-risk neck regions but may have the unintended consequence of eliminating the organizing immune response in precisely these same draining lymph nodes. In addition, the daily fractionation schedule during 7 weeks of 1.5 to 2.2 Gy per day are designed to maximize daily normal tissue repair but are exactly high enough to eliminate the highly radiosensitive adaptive immune response that tracks daily to the drainage area from rest of the body. This also is the caveat in extrapolating murine models of synergy between radiotherapy and systemic immunotherapy: no graduate student has sufficient mental fortitude to sedate, treat, and recover mice with a schedule of conventionally fractionated 2 Gy per day for 35 daily fractions. Thus, it may be that any benefits seen in this first generation of studies to integrate anti–PD-1/PD-L1 immunotherapy into definitive radiotherapy or chemoradiotherapy may be only the beginning of what is possible and that additional benefits can be garnered from using existing immunotherapies—if they are not working at cross purposes with traditional radiotherapy field design.
Successful integration of immunotherapy into definitive radiotherapy regimens may require a drastic alteration of radiotherapy dosing and field design to maximize benefit. This is not a simple matter of wholesale adoption of stereotactic ablative radiotherapy fields and dosing schedules (i.e., highly conformal fields confined to gross disease, with high doses delivered in one to five sessions), though. Preliminary data from studies incorporating anti–PD-1/PD-L1 immunotherapy and stereotactic ablative radiotherapy for patients with oligometastatic disease have shown variable response rates of only 18%, similar to that seen with anti–PD-1/PD-L1 monotherapy.4 Although elective nodal irradiation may hamper the developing immune response promoted by immunotherapy, relying too heavily on stereotactic radiotherapy in the absence of sufficiently robust immunotherapies risks unjustified regional failures in regions previously protected by elective nodal irradiation.
Care must be taken in this period of transition. Additional safety designs can arise from the exploratory aims of this present generation of studies. For example, a design of treatment paradigms can incorporate two distinct radiotherapy courses: first, a stereotactic course to enhance the immune response; then, a second course that includes elective nodal irradiation after sufficient time has passed to allow the adaptive immune response to develop independent from the regional lymph nodes. Conversely and more elegantly, biomarkers may be discovered to help decide whether a patient has achieved sufficient immune activation and no longer requires elective nodal irradiation. Finally, ongoing progress to identify more potent and effective immunotherapeutics must be pursued and incorporated with the advances in our understanding of optimal radiotherapy techniques that maximize the potential response to immunotherapies.
This is a period of great promise for the oncology community, in which we have the opportunity to radically change our long-held treatment conventions. However, this must be done carefully and thoughtfully, not only to accelerate the pace of discovery but also to safeguard the well-being of the patients under our care.
About the Authors: Dr. Chin is an assistant professor in the Department of Radiation Oncology at University of California, Los Angeles, UCLA Health. Dr. Wong is an assistant clinical professor in the Department of Medicine, Division of Hematology/Oncology at University of California, Los Angeles, UCLA Health.