Photodynamic therapy for stage I and II non-small cell lung cancer

Abstract

We analyzed mortality (all-cause and lung cancer-specific) and time to follow-up treatment in stage I and II non-small cell lung cancer (NSCLC) patients treated with photodynamic therapy (PDT) compared with ablation therapy and radiation therapy.

From Surveillance, Epidemiology, and End Results-Medicare linked data, patients diagnosed with stage I and II NSCLC between 2000 and 2015 were identified. Outcomes were mortality (overall and lung cancer-specific) and time to follow-up treatment. We analyzed mortality using Cox proportional hazard models. We used generalized linear model to assess time to follow-up treatment (PDT and ablation groups). Models were adjusted for inverse probability weighted propensity score.

Of 495,441 NSCLC patients, 56 with stage I and II disease received PDT (mono or multi-modal), 477 received ablation (mono or multi-modal), and 14,178 received radiation therapy alone. None from PDT group had metastatic disease (M0) and 70% had no nodal involvement (N0). Compared with radiation therapy alone, PDT therapy was associated with lower hazard of overall (hazard ratio = 0.56, 95% CI = 0.39-0.80), and lung cancer-specific mortality (hazard ratio = 0.64, 95% CI = 0.43-0.97). Unadjusted mean time to follow-up treatment was 70days (standard deviation = 146) for PDT group and 67 days (standard deviation = 174) for ablation group. Compared with ablation, PDT was associated with an average increase of 125days to follow-up treatment (P = .11).

Among stage I and II NSCLC patients, PDT was associated with improved survival, compared with radiation alone; and longer time to follow-up treatment compared with ablation. Currently, PDT is offered in various combinations with surgery and radiation. Larger studies can investigate the efficacy and effectiveness of these combinations.

1. Introduction

Non-small cell lung cancer (NSCLC) is the second most common cancer among men and women in the United States. In year 2020, there were 228,820 new cases of lung cancer (116,300 in men and 112,520 in women) and 135,720 deaths from lung cancer (72,500 in men and 63,220 in women).^[1] The incidence of stage I and II NSCLC is likely to increase with the ageing population and introduction of screening for high-risk individuals.^[1-3] Patients with NSCLC tend to be older and thus present with multiple comorbid conditions. The substantial severity of NSCLC has led to the emergence of various therapeutic and palliative treatment options. For stage I and II of the cancer, surgical resection provides a strong opportunity of cure,^[4] however, comorbid conditions often make patients medically inoperable. Therapies such as photodynamic therapy (PDT), while used alone or as part of multi-modal therapy, can lower the probability of disease progression and/or mortality among NSCLC patients presenting with stage I and II, superficial, and centrally located endobronchial NSCLC tumors.^[2,5-9]

Among elderly patients who otherwise would not be suitable candidates for curative surgery, other treatments such as radiation therapy, chemotherapy, immunotherapy, ablation therapies, and radiofrequency ablation have shown to improve outcomes of care.^[2,5-11] Although surgical resection remains the standard treatment in stage I and II NSCLC, in non-surgical candidates, PDT has been used with curative intent in patients with centrally located stage I and II NSCLC.^[12-15] A total of 370 patients participated in prospective clinical studies that evaluated and validated the benefits of PDT, with different photosensitizers, in the treatment of stage I and II NSCLC with a complete response for stage I and II disease ranging from 72% to 100%.^[2,14,15] Also, PDT has shown to be effective for eradication of short (<1 cm) noninvasive endobronchial lesions that are accessible to conventional bronchoscopes.^[2,14,15] The key indications for the use of PDT for definitive treatment of NSCLC include: stage I and II, inoperable, superficial, and centrally located endobronchial tumors.^[2,14,15]

The first step in PDT involves systemic administration of a light-sensitive drug (i.e., photosensitizer). This is followed by illumination of the target tissue with visible light, which in turn leads to the generation of reactive oxygen species, notably singlet oxygen,^[6] and destruction of the tumor. The tumor destruction process is a combination of direct cellular and secondary vascular effects.^[7] Additionally, along with local tumor ablation, PDT also improves antitumor immunity in pre-clinical as well as in clinical settings and can be used as mono therapy or as part of combination therapy (surgery, chemotherapy, or standard radiation therapy).^{[2,3,5,12,14-18]}

For patients with stage I and II NSCLC who are high-risk candidates for surgery, or are at very high risk due to comorbidity, curative radiotherapy, especially stereotactic body radiation therapy (SBRT) or hypofactionated high-dose radiation therapy is a valid alternative.^[6,8,19-21] Among elderly patients, the introduction of SBRT or hypofactionated radiotherapy led to an improvement in population-based survival of patients with peripherally located stage I, as well as a reduction of the number of untreated patients.^[20,22-25] However, we know more research is needed in terms of use of radiation therapy among stage I and II stage NSCLC as a mono therapy or multimodal therapy in terms of toxicity and long-term survival outcomes.

In patients with stage I and II NSCLC, PDT has been approved for symptom management, or curative and palliative intent, especially among patients with tumors who are ineligible for standard surgery and radiation therapy. In general, PDT is well tolerated and severe toxicities are not common.^[3,5,12,16] Despite being an available treatment option, in the absence of randomized trials comparing PDT and conventional therapies, PDT remains underutilized for lung cancer, potentially due to its perceived complexity as a localized, light-activated chemotherapy, and bronchoscopic intervention. In this study of NSCLC patients with stage I or II disease, we analyzed the association between mortality (all-cause and lung cancer-specific), and PDT (mono or multimodal), and ablation (mono or multimodal), compared with radiation therapy alone; we also assessed the time to follow-up treatment across PDT and ablation groups. We hypothesized that after controlling for clinical and demographic covariates, PDT (mono or multimodal) will demonstrate improved survival (overall and lung cancer-specific) as well as longer time to follow-up treatment in NSCLC patients with stage I or stage II disease.

2. Materials and methods

2.1. Data sources and cohort definition

The Surveillance, Epidemiology, and End Results (SEER)-Medicare data from National Cancer Institute link the Medicare administrative claims data and clinical tumor registry data for Medicare enrollees residing in the SEER regions.^[26] The SEER program encompasses 26% of the population of the United States and gathers information regarding cancer incidence, treatment, and mortality from 20 SEER sites. Among cancer patients who are 65 years or older and are part of the SEER registries, 93% have been matched with Medicare enrollment records. In this retrospective cohort study, we used SEER-Medicare data to extract a cohort of patients aged 18 years or older, diagnosed with stage I or II NSCLC between 2000 and 2015, and the associated Medicare claims for the period between 2000 and 2016. Local institutional review board approved the study.

2.2. Measurement strategy

2.2.1. Key dependent variables. Key dependent variables were mortality (all-cause and lung cancer-specific), and time to followup treatments (for PDT and ablation groups only). Data on allcause and lung cancer-specific mortality were obtained using SEER’s Patient Entitlement and Diagnosis Summary File. Time to death was defined as number of days between date of treatment and date of death. Those who survived up to the end of the study (December 31, 2016) were censored. Time to subsequent treatment for the PDT group and ablation group was the time between first claim for PDT or ablation therapy and subsequent claim for surgery or radiation therapy.

2.3. Treatment type

We reviewed inpatient, outpatient, and provider claims to identify NSCLC treatments using International Classification of Diseases-9 and Healthcare Common Procedure Coding System codes shown in Supplemental Digital Content (Table S1, Supplemental Digital Content, http://links.lww.com/MD/G663). We identified PDT (alone or multimodal), ablation (argon plasma coagulation/cryotherapy/laser; alone or multimodal), and radiation therapy alone, as the 3 exclusive treatment groups.

2.4. Covariates

Sociodemographic characteristics including age, race and ethnicity, gender, marital status, and geographic location were obtained from SEER’s Patient Entitlement and Diagnosis Summary File database. To measure medical comorbidities, we calculated Charlson comorbidity index score using the hospitalization, outpatient, and provider claims from the year prior to the diagnosis of NSCLC.^[27,28]

2.5. Analytic strategy

First, we compared the demographic and clinical characteristics of our cohort of NSCLC patients from the 3 different treatment groups: PDT (alone or multimodal), ablation (alone or multimodal), and radiation therapy alone, using standard t tests and Chi-square tests. Next, we used Cox regression model to determine the association between treatment group and mortality (overall and lung cancer-specific), after adjusting for covariates. We used generalized linear model (GLM) regression to analyze the association between group membership (PDT vs ablation) and time to subsequent treatment, after adjusting for covariates. While assessing the relationship between treatment and outcomes among NSCLC patients, it is important to note that treatment assignment is non-random. Therefore, in order to minimize the observed bias due to treatment, we used propensity score approach. For each patient, we developed the probability or propensity of receiving PDT (alone or multimodal), ablation (alone or multimodal), or radiation therapy alone, as a function of age, gender, race and ethnicity, marital status, geographic location, cancer stage, and Charlson comorbidity score using multinomial logistic regression.^[29,30] All analytical models were adjusted for the covariates, and were weighted by the inverse probability of the propensity score. To examine the degree of matching, we compared the distribution for the covariates pre and post adjustment for propensity score.

2.6. Sensitivity analysis

We performed 2 types of sensitivity analyses. First one was a matched cohort analysis, and the other one was separate analysis by stage.

For the matched cohort analysis, the PDT group was the focal group. For our PDT group, we extracted a 1:2 match from the ablation group and from the radiation alone group. Matching was done by age (±3 years), race, gender, comorbidity score, and stage. We then performed survival analysis and time-to follow-up treatment analysis using these 3 matched groups. For the separate analysis by stage, we modeled the association between treatment group and all-cause mortality and lung cancer-specific mortality. We also assessed the time to follow-up treatment for PDT, compared with ablation treatment. All analytical models were adjusted for the covariates, and were weighted by the inverse probability of the propensity score. All analyses were performed using Statistical Analysis System (SAS), Version 9.4 (SAS Institute, Cary, NC).

3. Results

3.1. Sample characteristics

Between 2000 and 2015, 495,441 patients with NSCLC were identified. Of these, 56 patients with stage I and II disease received PDT (alone or multimodal), 477 patients with stage I and II disease received ablation (alone or multimodal), and 14,178 patients with stage I and II disease stage received radiation therapy alone. As shown in Table 1, those who received radiation therapy alone were older than those receiving PDT or ablation (mean 75.5 years vs 70.7, and 70.4years; P value <.0001). More than half of PDT group patients had at least one-comorbidity (51.8%), compared with 56.4% of ablation, and 46.4 of radiation alone groups (P value < .0001). Higher proportion of ablation group had stage II disease, compared with PDT group and radiation therapy group (60.8% vs 48.2%, and 46.1%, P value < .0001). Race and all cause mortality were comparable across the 3 groups.

Table 1 .

Comparison of baseline characteristics before and after propensity score weighting.

		Unadjusted				Weighted
		PDT* (n = 56) No (%)	Ablation† (n = 477) No (%)	Radiation (n = 14,178) No (%)	P value	PDT* (n = 37.8) No (%)	Ablation† (n = 353.9) No (%)	Radiation (n = 105,77.9) No (%)	P value
Age at diagnosis, mean (SD)		70.7 (6.4)	70.4 (9.8)	75.5 (8.9)	<.0001	72.6 (5.7)	74.8 (7.3)	75.3 (7.8)	.0514
Race/Ethnicity
	White	>45 (> 80.4)	400 (83.9)	11,625 (81.9)	.202	>26.8 (>70.9)	295.2 (83.4)	8677.5 (82.0)	.7227
	All other	<11 (<19.6)	77 (16.1)	2553 (18.1)		<11 (<29.1)	58.7 (16.6)	1900.4 (17.9)
Marital status
	Married	33 (58.9)	264 (58.4)	6681 (49.2)	.0002	18.2 (48.2)	162.4 (48.3)	5014.7 (49.6)	.8922
Gender
	Male	34 (64.7)	285 (59.8)	7,661 (54.0)	.0290	22.0 (58.3)	185.3 (52.4)	5735.3 (54.2)	.6904
Geographic area
	Metro	>45 (> 80.4)	376 (78.8)	12,094 (85.3)	.0002	>26.8 (>70.9)	295.3 (83.4)	8999.0 (85.1)	.6885
	Non-metro	<11 (<19.6)	101 (21.2)	2084 (14.7)		<11 (<29.1)	58.6 (16.6)	1578.9 (14.9)
No. of comorbidities
	0	27 (48.2)	208 (43.6)	7,608 (53.6)		22.6 (59.9)	203.1 (57.4)	5638 (53.3)	.2295
	≥1	29 (51.8)	269 (56.4)	6,570 (46.4)	<.00016	15.2 (40.1)	150.7 (42.6)	4939.7 (46.7)
Stage of cancer
	I	29 (51.8)	187 (39.2)	7,649 (53.9)	<.0001	19.3 (51.0)	174.4 (49.3)	5652.4 (53.4)	.2925
	II	27 (48.2)	290 (60.8)	6,529 (46.1)		18.5 (49.0)	179.5 (50.7)	4925.6 (46.6)
Mortality
	Deceased	>45 (>80.4)	421 (88.3)	12,376 (87.3)	.4168	>26.8 (>70.9)	318.9 (90.4)	9228.0 (87.2)	.1697
	Alive	<11 (<19.6)	56 (11.7)	1802 (12.7)		<11 (<29.1)	35 (9.9)	1349.9 (12.8)

^* PDT group includes photodynamic therapy alone or multimodal.

^† Ablation group includes ablation therapy alone or multimodal.

3.2. Overall mortality

As reported in Table 1, overall mortality was comparable across the 3 treatment groups (P value .4168). The mean number of survival was 47.2 months for the PDT group, 31.8 months for ablation group, and 22.4months for radiation group (P value < .0001). The mean number of survival months was significantly different between PDT and ablation group (P < .05). The PDT group mean was also different than that of radiation alone group (P value < .05; data not shown).

3.3. Survival analysis—overall mortality

Survival analyses evaluated the hazard of overall mortality and PDT exposure (Table 2) for NSCLC patients with stage I or stage II disease. Compared with radiation alone group, the PDT group had lower hazard of overall death (hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.39, 0.80). Similarly, ablation group also had lower hazard of death, compared with radiation alone (HR = 0.82, 95% CI = 0.74, 0.92), however, the advantage was lower than that observed for PDT group. The Kaplan-Meier curve for overall survival is presented in Fig. 1.

Table 2 .

Association between treatment type and mortality.

	All-cause mortality		Lung cancer-specific mortality
	OR	95% CI	OR	95% CI
PDT*	0.56	0.39, 0.80	0.64	0.43, 0.97
Ablation†	0.82	0.74, 0.92	0.94	0.83, 1.07
Radiation (reference)	-		-	-
Age at diagnosis	1.02	1.01, 1.04	1.02	1.01, 1.03
White	1.03	0.98, 1.09	1.03	0.97, 1.09
Other (reference)	-	-	-	-
Married	0.94	0.90, 0.98	0.96	0.91, 1.01
Other (reference)	-	-	-	-
Male	1.29	1.24, 1.35	1.25	1.19, 1.32
Female (reference)	-	-	-	-
Metro	0.95	0.89, 1.00	0.92	0.86, 0.99
Non-metro (reference)	-	-	-	-
Comorbidity ≥1	1.24	1.18, 1.29	1.05	0.99, 1.09
Zero comorbidity (reference)	-	-	-	-
Stage I	0.60	0.58, 0.63	0.49	0.46, 0.51
Stage II (Reference)	-	-	-	-

^* PDT group includes photodynamic therapy alone or multimodal.

^† Ablation group includes ablation therapy alone or multimodal.

Figure 1. Kaplan-Meier survival curves for comparing overall survival between photodynamic therapy, ablation, and radiation therapy. SEER-Medicare linked data between 2000 and 2016 for patients diagnosed with stage I and II NSCLC. ABLATION = ablation therapy, PDT = photodynamic therapy, RAD = radiation therapy, SEER = Surveillance, Epidemiology, and End Results.

3.4. Lung cancer specific mortality

In Table 2 we also present the results of survival analysis for lung cancerspecific mortality for NSCLC patients with stage I or stage II disease. It is observed that the hazard of lung-cancer specific mortality was lower for the PDT group, compared with the radiation alone group (HR = 0.64, 95% CI = 0.43, 0.97). On the other hand, hazard of lung cancerspecific mortality for ablation group was not different than that for radiation alone group (HR = 0.94, 95% CI = 0.83, 1.07). The Kaplan-Meier curve for lung cancer-specific survival is presented in Fig. 2.

Figure 2. Kaplan-Meier survival curves for comparing lung cancer-specific survival between photodynamic therapy, ablation, and radiation therapy. SEER-Medicare linked data between 2000 and 2016 for patients diagnosed with stage I and II NSCLC. ABLATION = ablation therapy, PDT = photodynamic therapy, RAD = radiation therapy, SEER = Surveillance, Epidemiology, and End Results.

3.5. Time to follow-up treatment

Unadjusted mean time to follow-up treatment was 70 days (standard deviation [SD] 146) for PDT group and 67days (SD 174) for ablation group. In Table 3, we report the results of the GLM regression to study the association between time to followup treatment and PDT, compared with ablation group. It was observed that compared with ablation, PDT was associated with an average increase of 125 days to follow-up treatment (P = .11).

Table 3 .

Association between treatment type and time to follow-up treatment.

		Parameter estimate	P value
Intercept		391	.0492
PDT*		125	.1101
	Ablation† (Reference)
Age at diagnosis		-2.2	.3979
White		66.0	.3286
	Other (Reference)
Married		49.3	.3248
	Other (Reference)
Male		-57.5	.2591
	Female (Reference)
Metro		-47.9	.4408
	Non-metro (Reference)
Comorbidity ≥ 1		-2.9	.9519
	Zero Comorbidity (Reference)
Stage I		-40.5	.4091
	Stage II (Reference)

^* PDT group includes photodynamic therapy alone or multimodal.

^† Ablation group includes ablation therapy alone or multimodal.

3.6. Sensitivity analysis

Results of the sensitivity analysis using matched cohorts are presented in Supplemental Digital Content (Table S2, Supplemental Digital Content, http://links.lww.com/MD/G664 and Table S3, Supplemental Digital Content, http://links.lww.com/MD/G665). As shown in Supplemental Digital Content (Table S2, Supplemental Digital Content, http://links.lww.com/MD/G664), for overall survival, the association between mortality (overall and lung cancer-specific) and PDT group, compared with radiation alone group, was similar to that observed in the main analysis (HR = 0.44, 95% CI = 0.30, 0.64; and HR = 0.44, 95% CI = 0.28, 0.70, respectively). The results of GLM model for time to follow-up treatment for PDT and ablation groups using matched cohorts are presented in Supplemental Digital Content (Table S3, Supplemental Digital Content, http://links.lww.com/MD/G665). It was observed that compared with ablation, PDT was associated with an average increase of 300days to follow-up treatment (P = .0004).

We carried out separate analysis for stage 1 (PDT n = 29, ablation n = 187, and radiation n = 7649), and stage 2 (PDT n = 27, ablation n = 290, and radiation n = 6529). For stage 1, unadjusted mean survival time in days were: PDT 1647 (std 1342); ablation 1126 (std 1046), and radiation 772 (std 702). The means of 3 groups were significantly different (P < .0001). Also, comparison of PDT and ablation means showed statistically significant difference (P < .05). Similarly, for stage 2, unadjusted mean survival time in days were: PDT 1219 (std 845); ablation 872 (std 960), and radiation 578 (std 772). The means of 3 groups were significantly different (P < .0001. Also, comparison of PDT and ablation means showed statistically significant difference (P < .05). For all-cause mortality, PDT and ablation showed lower hazard of death, for stage 2; and for stage 1, PDT showed lower hazard of death, compared with radiation only group as shown in Supplemental Digital Content (Table S4, Supplemental Digital Content, http://links.lww.com/MD/G666). For lung cancer-specific mortality, PDT and ablation showed lower hazard of death, for stage 2, compared with radiation only group (Table S4, Supplemental Digital Content, http://links.lww.com/MD/G666). Finally, time to follow-up was longer for PDT for stage 1, compared with ablation group (Table S5, Supplemental Digital Content, http://links.lww.com/MD/G667).

4. Discussion

Using SEER-Medicare data, we demonstrated that PDT was associated with enhanced survival (overall and lung cancer-specific) compared with treatment of radiation alone; and improved time to follow-up treatment compared to ablation treatment, among NSCLC patients with stage I or stage II disease. The survival advantage was also significantly larger for PDT than that observed for ablation therapy when comparing both modalities in stage I cancer and in stage II cancer, separately. To our knowledge, this is the largest study that examines the association between PDT and mortality in a United States cohort of patients with stage I or stage II NSCLC. The standard curative treatment for stage I and II NSCLC is surgery.^[4,21] However, due to aging of the population and improved screening, more elderly patients are being diagnosed with stage I and II NSCLC. Elderly patients are more likely to present with multiple comorbidities and may not be ideal candidates for surgery. Among selected group of stage I and II NSCLC patients, PDT as a mono or multimodal therapy offers viable treatment option with improved survival benefits.

An earlier randomized controlled study among 41 patients with inoperable non-small cell bronchogenic carcinoma obstructing a central airway, compared the safety and efficacy of PDT plus radiation versus radiation alone. It was observed that the addition of PDT prior to radiation yielded significantly better and longer lasting local control of the disease, compared with radiation alone.^[11] Another study assessed the safety and effectiveness of combined brachytherapy and PDT in 32 patients with bulky endobronchial lung cancer, of which 15 were technically inoperable and 17 had recurrent bronchogenic carcinomas. The complete histological response rate of PDT + brachytherapy was 97%. It was thus concluded that the combination of PDT and brachytherapy was safe with strong therapeutic efficacy in this group of lung cancer patients.^[10] Several clinical studies have shown the effectiveness of PDT as a palliative therapy to relieve airway obstruction due to NSCLC. Short, noninvasive endobronchial lesions accessible to conventional bronchoscopes can be effectively eradicated with PDT. Especially, interstitial PDT (I-PDT) is promising as this technique allows intratumoral delivery of light, and therefore can be used for treatment of large tumors. Currently, PDT is used in combination with other treatment modalities, such as chemotherapy, radiotherapy, and surgery, in the treatment of lung cancer.^[2,12,31] A meta-analysis of stage I NSCLC patients who received external beam radiation therapy showed that the rates of 3 years overall survival and cause-specific survival were 34% and 39%, respectively.^[8] Given the unfavorable survival outcomes associated with conventional external beam radiation, research has focused on alternative treatment modalities.^[21]

PDT can be administered as definitive monotherapy for patients with stage I and II NSCLC who have central or roentgenographically occult carcinomas or synchronous primary endobronchial carcinomas.^[12] Close surveillance following definitive PDT to assess for local recurrence is warranted, however, particularly in the first 2 years following therapy. One could also argue that the benefits of PDT compared with radiation alone were because the radiation group was older. While this is possible, we highlight that the PDT group had a significantly higher number of comorbidities. A recent study using National Cancer Database showed that in a selected patients with aggressive tumors including papillary and large cell histology, SBRT was associated with similar survival compared with sublobar resection.^[32] Thus, histologic diagnosis in patients with even small tumors may enable better treatment selection in those who cannot tolerate lobectomy. Also, stereotactic body radiation therapy (SBRT) was associated with higher overall survival compared with thermal ablative procedures or percutaneous local tumor ablation for treatment of nonoperative patients diagnosed with stage I and II NSCLC.^[33,34] However, an earlier study using National Cancer Database report worse outcomes in terms of overall survival among radiation therapy alone group for stage I and II NSCLC.^[35]

We note several limitations to our study. First, due to the observational nature of our data, we were not able to establish a causal relationship between PDT and outcomes. Some of the detailed clinical data such as margins of resection, is not available in the SEER-Medicare database. Our cohort consisted of fee-forservice Medicare beneficiaries aged 18 years and older, not enrolled in an HMO and living in a SEER region. The age and sex distribution for persons 66 years and older is comparable with that of older adults in the United States, however, SEER regions have a higher proportion of non-white persons. Additionally, the mortality rates obtained from SEER data may not represent national cancer mortality rates.^[26] We also note that the number of patients receiving PDT is small. As new data for additional years becomes available, in our future studies we will be able to identify larger numbers of patients with PDT. Despite these limitations, our study for the first time analyzes the long-term survival outcomes comparing PDT, ablation, and radiation therapy alone for stage I and II NSCLC using SEER-Medicare data.

Next, even after using propensity score to minimize bias, some residual bias may exist. While the SEER-Medicare database allows for propensity matching to adjust for differences in treatment types for each stage of disease, the presence or absence of intraluminal disease is not clear in the radiation group. The study could also be impacted by the missing data regarding concurrent central airway obstruction (CAO) in patients who received radiation alone. However, given the fact that patients with symptomatic CAO routinely receive some form of bronchoscopic intervention as recommended by guidelines, it is reasonable to assume that the radiation group did not have CAO. In addition, based on the standard of care for patients with CAO for several decades, it is unlikely that the radiation group patients in the present study had any significant symptomatic airway obstruction. Even if some of them did, the lower hazards of mortality in the PDT group compared with the radiation alone group, suggests the benefit of PDT versus radiation alone.

In summary, this SEER-Medicare based study spanning over a 15-year follow-up among NSCLC patients with stage I or stage II disease shows that PDT, alone or in combination with other conventional treatments, was associated with significantly improved survival (overall and lung cancer-specific), compared to radiation therapy alone; PDT also showed advantage in terms of significantly higher mean number of survival days, as well as a trend towards a more durable effect, compared with ablation therapy. The addition of PDT to local therapy may be considered a treatment option in select patients. PDT is often grouped into the category of NSCLC ablation therapeutic tools and an important question that has not been adequately addressed todate is if PDT results in differentiated and beneficial patient outcomes in stage I-II CAO NSCLC patients.

We believe future research in NSCLC patients with stage I and II disease can address and identify the pathways via which PDT enhances survival. Research can also assess if this association has an impact on the health related quality of life in NSCLC patients. Also, future studies are warranted to assess the combination therapies and sequencing of local and systemic therapies in stage I and II NSCLC. Healthcare providers must consider the incremental benefit associated with use of PDT in NSCLC patients with stage I or stage II disease.

Acknowledgments

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute (NCI); the Office of Research, Development and Information, Centers for Medicare and Medicaid Services (CMS); Information Management Services; and the SEER program tumor registries in the creation of the SEER-Medicare database.

Author contributions

Conceptualization: Sumedha Chhatre, Ravishankar Jayadevappa.

Data curation: Sumedha Chhatre, Ravishankar Jayadevappa.

Formal analysis: Sumedha Chhatre, Ravishankar Jayadevappa.

Methodology: Sumedha Chhatre, Ravishankar Jayadevappa.

Supervision: Ravishankar Jayadevappa.

Writing - original draft: Sumedha Chhatre, Septimiu Murgu, Anil Vachani, Ravishankar Jayadevappa.

Writing - review & editing: Sumedha Chhatre, Septimiu Murgu, Anil Vachani, Ravishankar Jayadevappa.