Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis

Abstract Background Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high‐dose reirradiation. Materials and methods Between 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high‐dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work‐up included a mandatory fluorodeoxyglucose‐positron emission tomography‐computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. Results In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5–21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8–25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log‐rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. Conclusion Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.


INTRODUCTION
Immunotherapy has led to revolutionary advancements in cancer treatment [1][2][3][4][5][6][7][8] and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first-and second-line therapy for patients with advanced lung cancer. [1][2][3][4]6,8 With the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, [10][11][12] the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1,2,13,14 As a result, clinical studies have shown remarkable benefits in terms of both progression-free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1,2,13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1,2,5,7,12,[15][16][17] In light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12,18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5,19,20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1,2 With respect to the combination of reirradiation for loco-regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials. gov identifier NCT03087760), which-as opposed to our study-uses proton reirradiation rather than photons.
The aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review.

Patients
Between 2013 and 2019, 47 consecutive patients who underwent high-dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high-dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose-positron emission tomographycomputed tomography ( 18 F-FDG-PET-CT) was required in the diagnostic work-up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out-of-field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020).

Radiation and systemic therapy
Patients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four-dimensional computed tomography (4D-CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18 F-FDG-PET-CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV-clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio-caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called "slow CT" with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respirationdependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dosedifferentiated accelerated RT in twice daily fractions of 1,8 Gy (dose-differentiated accelerated radiotherapy [DART]-bid) as described in two previous publications, 21,22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ.
Prior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin T A B L E 1 Patient-and treatmentrelated parameters in the cohort (N = 47)

Toxicity
The Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT.

Follow up
Patients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast-enhanced CTs, and pulmonary function tests were performed at every follow-up. If local recurrences or new lung lesions were suspected on the chest CT, 18 F-FDG-PET-CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively.

Statistics
The primary endpoint was OS, which was calculated using the Kaplan-Meier method. We defined OS as the time between the end of reirradiation and death or latest follow-up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients-20 of whom were only reirradiated-were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first-order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23,24 For intergroup comparisons the log-rank test was used.

Patients
Of the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52-83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1.

Overall survival
The median follow-up across the cohort was 11.7 months (range 0.3-64.4 months). Of the 47 patients, 21 are still alive (45%).
The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5-21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log-rank p value = 0.132; Figure 1(b)).
In the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8-25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4-60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer-related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression-free survival was 7.9 months (95% CI 6.7-9 months). The difference in OS was in favor of the immunotherapy subgroup (log-rank p value = 0.063; Figure 2(b)).

Toxicity
Of the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3). In contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4).

DISCUSSION
In this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log-rank p value = 0.063; Figure 2(b)).
Our finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5,19,26,27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study.
In the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first-time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. [1][2][3][4][5][6][7][8]15,16,20,[28][29][30] In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1,2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic antitumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5,7,12,17,18,29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor-derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect.
The details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5,7,16,17,29,30 Briefly summarized, tumor cells evade the immune response by upregulating specific proteins such as programmed cell death 1 ligand 1 (PDL-1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD-1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD-1/PDL-1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1,2,5,7,20 Relatedly, radiation-induced antitumor activity is immune-mediated F I G U R E 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8-25.8 months). (b) Patients who received immunotherapy or chemo-immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3-27.1 months, log-rank p value = 0.063) by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15,18,31 The sequence in which RT and immunotherapy would be applied is still under investigation, 13,32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12,14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported.
An obvious weakness of our analysis is the rather permissive threshold for first-order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23,34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking.

CONCLUSION
The combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated.