This special issue of Journal of Thoracic Disease (JTD) is a focused review of advances in radiation oncology for thoracic malignancies. The issue covers advances in technology relevant to the practice of radiation oncology in the modern era, as well as the most current treatment approaches for early-stage, advanced, recurrent and oligometastatic non-small cell lung cancer (NSCLC), while recognizing the importance of tumor biology, radiation fractionation, immunotherapy, and functional imaging in the modern treatment of NSCLC. The issue ends with reviews of current data and treatment approaches for small cell lung cancer (SCLC), thymic malignancies, and malignant pleural mesothelioma.
More specifically, the first article of the focused issue pertains to image guidance and motion management and mitigation. Molitoris and colleagues detail how the advent of and improvements in image-guided radiation therapy (IGRT) have enabled the increased utilization of advanced radiation modalities like intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy for the treatment of lung cancer. IGRT is the use of imaging during or just prior to radiotherapy delivery that verifies the agreement of anatomy between the treatment plan and the patient’s actual setup on the treatment table (1). While improving accuracy of treatment delivery by allowing visualization of the tumor on the treatment table, IGRT can also help inform for the need of adaptive replanning if notable anatomical changes (tumor or normal tissue) from the time of planning simulation are identified on daily imaging. Furthermore, thoracic tumors are unique in their susceptibility to motion with respiration, leading to uncertainties in target and normal tissue positioning. Motion management strategies, including motion encompassment, respiratory gating, and breath-hold methods, as well as motion mitigation strategies, including respiratory coaching, abdominal compression, and tumor tracking, are explained. Collectively, the authors detail how target volume expansions for both motion and set-up uncertainties can be minimized with motion management/mitigation strategies and with IGRT, allowing for better sparing of irradiation dose to adjacent critical structures.
Sebastian and colleagues next discuss contemporary insights and the latest advances in SBRT for early stage NSCLC. SBRT has emerged as the standard of care for patients with medically inoperable early stage NSCLC (2). Given its favorable toxicity profile and high rates of local control (3), which have allowed for population-based improvements in overall survival for NSCLC (4), interest in SBRT for operable patients has increased, with early results of under-accrued clinical trials suggesting at least equipoise for SBRT compared with surgery (5,6). The authors discuss practical questions and active areas of investigation for the still relatively young thoracic modality, including delivery technique, total radiation dose, dose-fractionation regimen, and timing of treatments, and they describe how these can be impacted based on tumor size, location, histology, and molecular phenotype.
Next, Roach and colleagues from Washington University School of Medicine review the optimal radiation dose and fractionation for treating locally advanced NSCLC. While the standard of care for medically inoperable or surgically unresectable patients is concurrent chemoradiation (7), local failure rates are significant after chemoradiation and are a major driver of death from lung cancer (8). One approach to counter these high local failure rates has been to escalate the total radiation dose. While this strategy showed promise in smaller, earlier phase studies (9,10), the recently reported RTOG 0617 phase III randomized demonstrated a survival decrement to unselective dose escalation to 74 Gy, largely due to increased toxicities with this higher dose (11). The authors describe other dosing strategies that have been investigated to overcome the high local failure rates of NSCLC and to minimize tumor repopulation during treatment, including accelerated hyperfractionation, hypofractionation, and the use of metabolic imaging during treatment to boost areas of residual disease.
Yegya-Raman et al. discuss advanced radiation techniques for locally advanced NSCLC, including IMRT and proton therapy. By potentially reducing normal tissue toxicities, these modalities may allow for safer concurrent chemoradiation dose escalation for unresectable patients. This may also be important in operable patients, where dose escalation of neoadjuvant irradiation may be associated with improved outcomes for trimodality NSCLC patients (12). With IMRT, the fluence of radiation across each beam is modified, thus allowing more conformal treatment delivery and better sparing of organs at risk near the target volume. Compared with 3CRT, retrospective studies have shown that IMRT can reduce the rate of radiation pneumonitis and even improve overall survival (13,14). Although a survival benefit was not seen with IMRT on secondary analysis of RTOG 0617, IMRT compared with 3DCRT as a preplanned stratification factor did allow for better preservation of quality of life, reduced rates of radiation pneumonitis, reduced cardiac irradiation doses, and better compliance with chemotherapy (15,16). With proton therapy, radiation can be deposited at a specific depth, after which the protons decelerate rapidly, allowing for dose deposition to the tumor and little to no dose beyond the tumor (17). Compared with photon therapy, including IMRT, proton therapy allows for better sparing of organs at risk (18,19). While single-arm prospective studies have reported lower rates of pneumonitis and esophagitis with proton therapy than would be expected with photon therapy (20,21), and national registry data have demonstrated a survival benefit with proton therapy (22), a recently reported randomized trial failed to show a significant benefit of proton therapy over IMRT in terms of pneumonitis or local control (23). The authors discuss indications for both IMRT and proton therapy, which patients might benefit most, implementation challenges, and key trials currently enrolling accessing these advanced modalities.
Badiyan and colleagues next report on a hot topic in thoracic oncology—combining radiation therapy with immunotherapy. While immunotherapy has clearly established itself as a standard treatment modality for advanced NSCLC (24,25), its role in early stage and locally advanced NSCLC is still being defined, with a highly promising early report from the PACIFIC trial demonstrating that maintenance durvalumab given after chemoradiation for locally advanced NSCLC tripled the progression free survival and improve the time to death or distant metastasis (26). As radiation therapy can mount a robust anti-tumor immune response, it has been hypothesized to have the potential to work synergistically with immunotherapy (27,28). In fact, preclinical data support synergy between radiation therapy and immunotherapy (29). This manuscript reviews the preclinical rationale for combining radiotherapy with immunotherapy, the clinical data to date on the combination of radiotherapy and immunotherapy across thoracic malignancies, and the ongoing clinical trials investigating the combination of radiation therapy and immunotherapy for thoracic cancers.
Positron emission tomography/computed tomography (PET/CT) has established itself as an essential part of diagnosis and staging for NSCLC, as a useful modality for monitoring treatment response following radiotherapy (30). Konert et al. detail how PET has an increasingly important role in prognostication and in radiation target volume delineation (31). The authors detail how PET metrics like standardized uptake value, total lesion glycolysis, and other functional measures have been shown to be prognostic for NSCLC (32). They also discuss how PET radiomics textural features can improve prognostication. Additional PET tracers and other future areas of research are also detailed. Furthermore, as advanced radiation modalities have allowed for more precise treatment delivery, accurate tumor delineation for thoracic malignancies is more critical than ever. The authors next discuss how PET can aid in target volume delineation, and they describe automatic target delineation using automated segmentation and other techniques.
Vyfhuis and colleagues report on reirradiation for locoregionally recurrent NSCLC. As previously discussed, locoregional recurrences in patients with locally advanced NSCLC are quite common. Standard treatment approaches for such recurrences have generally focused on non-curative systemic options like cytotoxic chemotherapy or immunotherapy due to the concerns of potentially life-threatening complications than can be seen with thoracic reirradiation. All of the advances detailed above, including IGRT, SBRT, IMRT and proton therapy, have allowed for potentially safer reirradiation options for recurrent NSCLC. The authors discuss conventional photon and SBRT reirradiation, as well as proton reirradiation, a particularly attractive use of the modality due to its ability to minimize or eliminate dose to previously irradiated adjacent critical structures (33). In fact, two relatively large studies, one retrospective (34) and one prospective (35), have recently been reported showing the ability of proton therapy to be generally safely administered in the reirradiation setting, with encouraging survival outcomes.
Oligometastatic disease, often defined as limited metastatic disease to five or fewer sites, is increasingly being recognized as a distinct entity from more widespread metastatic disease with a unique prognosis that warrants a different treatment paradigm (36). This recognition has led to oligometastases being incorporated into the new AJCC 8th edition staging manual. Investigators are now recognizing heterogeneity within oligometastatic patients, with patients having varied prognoses according to the number of sites with metastases, the specific sites of metastases, if metastases occur synchronously or metachronously, and if there are nodal metastases (37). Tumati and Iyengar describe how advances in imaging have allowed for a more apparent identification of a subset of patients with isolated metastatic deposits. They then discuss the implications of metastatic disease extent, detail the role of surgery for oligometastatic disease, and review the data for using radiotherapy and SBRT for oligometastases, including two recently reported randomized trials showing a benefit in progression free survival for local therapy compared with systemic therapy alone (38,39). The also detail oligoprogressive disease and its management, and they discuss how the role of local therapy is evolving with the rise in immunotherapy for NSCLC.
An international group of collaborators next discuss the evolving role of radiotherapy for SCLC. These authors discuss the long-standing question of once daily versus twice daily irradiation, the optimal dosing for once daily irradiation, the evidence for hypofractionation, the role of prophylactic cranial irradiation (PCI), and the impact PET/CT has had on staging for limited-stage SCLC. For extensive-stage SCLC they detail the data for (40) and against (41) PCI, and they summarize and put into context the recently reported CREST (42) and RTOG 0937 (43) trials of thoracic consolidative radiotherapy. They next discuss options for attempting to reduce neurocognitive dysfunction following PCI, including stereotactic radiosurgery and hippocampal avoidance whole brain radiation therapy. Finally, they discuss encouraging new data of advanced radiotherapy modalities like SBRT for stage I SCLC (44,45) and proton therapy for locally advanced SCLC (46).
Willmann and Rimner next review the role of radiation therapy for thymic malignancies. The most established role of radiotherapy for this group of rare malignancies is in the adjuvant setting, especially for advanced or incompletely resected disease. However, as recent reports have demonstrated a survival benefit to adjuvant radiotherapy (47,48), even for completely resection and early stage disease, a paradigm shift in the treatment approach for thymic malignancies is occurring and is described in this review. The roles of neoadjuvant radiotherapy for marginally resectable patients and definitive radiotherapy for unresectable patients are also detailed. Methods to reduce treatment toxicities for thymic malignancies, which generally have better prognoses than other thoracic malignancies, are critical, and data for IMRT (49) and proton therapy (50) are discussed.
The last article in this focused issue of JTD is on malignant pleural mesothelioma, another rare thoracic malignancy. Cramer and colleagues detail the unique challenges of delivering radiation therapy to large thoracic volumes that are often required for mesothelioma. Strategies of and data for employing radiation therapy before (51) or after (52) extrapleural pneumonectomy and after lung-sparing extended pleurectomy/decortication (53,54) are discussed. The concept of definitive irradiation is also described (55). The authors then discuss the controversial role of adjuvant prophylactic radiotherapy to intervention sites used in an attempt to reduce the risk of surgical tract dissemination, as well as the more common role of palliative radiotherapy for patients with mesothelioma who often present with dyspnea and/or pain. Lastly, the authors discuss future potential advances in treatment for mesothelioma, including the use of proton therapy (56) and of combining radiation therapy with immunotherapy (57).
In reading the manuscripts in this focused issue, it is clear there have been tremendous advances in thoracic radiation oncology in the past decade. We fully anticipate the next decade will bring further practice-changing progress, and we look forward to the evolving data from active areas of investigation integrating the use of advanced radiation therapy technologies with biological response modifiers and immunotherapy, and with treatment guided by modern anatomical and functional imaging. These modern approaches will well position the next generation radiation oncologists to continue to improve outcomes for patients with thoracic malignancies.
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