Abstract
Introduction
Photodynamic therapy (PDT) is a salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Salvage PDT is the treatment available for vulnerable patients with various comorbidities at risk of salvage esophagectomy. This study assessed the impact of the Charlson comorbidity index (CCI) on the outcomes of salvage PDT using talaporfin sodium (TS) for esophageal cancer.
Metohds
Consecutive patients with esophageal cancer who underwent salvage TS-PDT from 2016 to 2022 were included in this retrospective study. We investigated the local complete response (L-CR), progression-free survival (PFS) and overall survival (OS) and evaluated the relationship between the CCI and therapeutic efficacy.
Results
In total, 25 patients were enrolled in this study. Overall, 12 patients (48%) achieved an L-CR, and the 2-year PFS and OS rates were 24.9% and 59.4%, respectively. In a multivariate analysis, a CCI ≥1 (p=0.041) and deeper invasion (p=0.048) were found to be significant independent risk factors for not achieving an L-CR. To evaluate the efficacy associated with comorbidities, we divided the patients into the CCI=0 group (n=11) and the CCI ≥1 group (n=14). The rate of an L-CR (p=0.035) and the 2-year PFS (p=0.029) and OS (p=0.018) rates in the CCI ≥1 group were significantly lower than those in the CCI=0 group.
Conclusion
This study found that the CCI was negatively associated with the efficacy of salvage TS-PDT for esophageal cancer.
Keywords: photodynamic therapy, esophageal cancer, charlson comorbidity index, talaporfin sodium
Introduction
Photodynamic therapy (PDT) is a treatment that combines a photosensitizer drug with activation light of a specific wavelength. It results in tumor shrinkage in various malignancies due to three main mechanisms, direct effects of reactive oxygen species (ROS), vascular shutdown leading to tumor infarction, and acute inflammation with immune response (1,2). Esophageal cancer was one of the first clinical indications for PDT approved in the United States. In Japan, PDT using porfimer sodium (PS, PhotofrinⓇ; Pfizer Japan, Tokyo, Japan) was approved as a curative treatment for superficial esophageal cancer in 1994 (3). However, PS-PDT has some disadvantages such as a long sunshade period of approximately 6 weeks to avoid risk of skin phototoxicity.
PDT using talaporfin sodium (TS; LaserphyrinⓇ; Meiji Seika Pharma, Tokyo, Japan), which is characterized by rapid clearance from the skin and low skin phototoxicity even within 2 weeks or less (4), was introduced for esophageal cancer as a salvage treatment option for local failure after chemoradiotherapy (CRT) or radiotherapy and has been covered by Japanese health insurance since 2015 (5). In the guidelines for the diagnosis and treatment of carcinoma of the esophagus, 5th edition, published by the Japan Esophageal Society, salvage PDT for esophageal cancer was first described as “weakly recommended” (6). In Japan, where the aging population is growing, the importance of this low-invasiveness treatment will increase in the future.
One of the eligibility criteria for salvage TS-PDT for esophageal cancer is focused on patients with a physical status intolerant to undergoing salvage esophagectomy, which is associated with an elevated risk of postoperative morbidity and mortality (7-9). Salvage PDT is therefore the final curative treatment procedure available for high-risk patients with multiple underlying comorbidities for whom salvage surgery is deemed to be too risky.
Comorbidities have been considered to affect the efficacy and adverse effects of treatment for several cancers. The Charlson comorbidity index (CCI) is one of the indicators that objectively quantifies comorbidities and is the most commonly used score to quantify multiple comorbidities (10). A previous study showed that a high CCI was associated with increased mortality in esophageal cancer patients who underwent surgery (11,12). Therefore, comorbidities should be taken into consideration when deciding the treatment strategy, especially for patients with esophageal cancer.
This retrospective study clarified the impact of comorbidities on the therapeutic outcomes of salvage TS-PDT in patients with esophageal cancer.
Materials and Methods
Patients and study design
We examined consecutive patients who underwent salvage TS-PDT between May 2016 and November 2022. All PDT procedures were performed at Miyazaki University Hospital. The eligibility criteria were as follows: (i) histologically proven local failure of esophageal cancer after CRT or radiotherapy (≥50 Gy); (ii) refusal of salvage esophagectomy or lack of tolerability for salvage esophagectomy; (iii) non T3/4 in invasion depth of lesion; (iv) no invasion to the cervical esophagus; (v) <3 cm in size, (vi) <1/2 of the esophageal circumference; and (vii) absence of lymph node metastasis or distant metastasis. The exclusion criteria were as follows: (i) baseline lesions before CRT that were judged to involve the aorta; (ii) a history of treatment with PDT using PS or TS; and (iii) a history of porphyria.
This study was a retrospective, observational study centered on the University of Miyazaki Faculty of Medicine and was approved by the institutional ethical committee of Miyazaki University (registration number: O-1368). Consent was obtained from all participants included in this study via an opt-out format.
Staging
Clinical staging of esophageal cancer was determined using the TNM classification of the International Union Against Cancer 8th edition (13). The clinical T stage was evaluated by endoscopy, endoscopic ultrasound, and computed tomography of the chest. Clinical N and M stages were evaluated by computed tomography of the neck, chest, and abdomen.
PDT procedures
All PDT procedures were performed in an inpatient setting, in which a 40-mg/m2 dose of TS was slowly injected intravenously. Four to six hours after administration of TS, the local failure lesion was irradiated with a diode laser at a 664-nm wavelength. The diode laser light was delivered via a frontal light distributor through an endoscope. The fluence of the diode laser was set to 100 J/cm2, and the fluence rate was 150 mW/cm2. Multiple treatment fields were overlapped to cover the lesion depending on its size. Endoscopic observation was performed on the following day. If a residual tumor was found, additional diode laser irradiation was performed. After the administration of TS, the patient stayed in a room maintained at <500 lux and avoided direct sun exposure for 2 weeks. A skin photosensitivity test was performed two weeks after the administration of TS, and patients were discharged if skin photosensitivity and other adverse events related to PDT had disappeared. An endoscopic examination was performed one week after PDT, and further endoscopy was performed at the discretion of each attending investigator.
Efficacy and safety
The efficacy of PDT was assessed based on the local complete response (L-CR), progression-free survival (PFS) and overall survival (OS). An L-CR was defined as (i) absence of an obvious residual tumor with two consecutive endoscopic observations after discharge; (ii) disappearance of post-PDT ulcers; and (iii) histological confirmation of the absence of cancer cells by a biopsy. A biopsy was not performed if no obvious residual lesions were observed. The PFS was defined as the period from the date of PDT to local progression, new metastasis or death from any cause. In addition, the OS was defined as the period from the date of PDT to death from any cause. We examined skin phototoxicity, esophageal stenosis, and esophageal fistula as adverse events related to TS-PDT for esophageal cancer according to the Common Terminology Criteria for Adverse Events (14) and assessed skin phototoxicity as mentioned above.
The CCI
The CCI was categorized according to the sum of pretreatment comorbidity values in this study, and comorbidities were scored as follows: (i) score of 1 for myocardial infarction, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, ulcer disease, mild liver disease, diabetes without complications, cerebrovascular disease, and collagen disease; (ii) score of 2 for diabetes with end-organ damage, hemiplegia, moderate to severe renal disease, second solid tumor (nonmetastatic), leukemia, and malignant lymphoma; (iii) score of 3 for moderate to severe liver disease; and (iv) score of 6 for second metastatic solid tumor and acquired immunodeficiency syndrome (10).
Assessment of patients' background characteristics
To evaluate patients' background characteristics in addition to their CCI, information on the body mass index (BMI), smoking habit (Brinkmann index), and daily alcohol consumption was collected. The prognostic nutritional index (PNI), which was used to predict nutritional status and immune status based on serum biological data, was calculated according to the following formula:
PNI=10×Serum albumin concentration (g/dL)+0.005×Total lymphocyte count (/mm3)
Statistical analyses
All continuous variables are expressed as mean±standard deviation. The Mann-Whitney U test was used to compare continuous variables. Categorical variables are summarized as numbers and percentages and were compared between groups using Fisher's exact test or the chi-squared test, as appropriate. The PFS and OS rates were calculated from the date of random assignment, validated using the Kaplan-Meier method, and compared using the log-rank test. p<0.05 was considered statistically significant.
Statistical analyses were performed using the StatFlex software program version 7 (Artech, Osaka, Japan).
Results
Patient and lesion characteristics
In total, 25 patients with esophageal cancer who had local failure after CRT were studied. With the exception of 1 individual, all of the patients were men, and their ages ranged from 53-91 years old.
The characteristics of the 25 lesions are summarized in Table 1. All lesions were pathologically diagnosed as squamous cell carcinoma. The tumor location was the upper esophagus in 6 (24%), middle esophagus in 15 (60%), and lower esophagus in 4 (16%). The baseline clinical stages before CRT were almost all cStage 0-II (84%), whereas there were 2 patients with cStage IVa in whom esophageal cancer was diagnosed having invaded into the trachea (cT4a). Six patients had residual lesions after CRT, and 19 experienced local recurrence. There were eight patients with ycT1a (mucosal cancer) at PDT. It was difficult to treat these lesions by endoscopic resection due to scarring after CRT despite the shallowness of the lesions.
Table 1.
Characteristics of 25 Lesions of Esophageal Cancer before Salvage PDT Procedure.
| Variables | Number or average | % or (range) | ||
|---|---|---|---|---|
| Pathological feature, SCC | 25 | 100% | ||
| Tumor location | ||||
| Upper thoracic | 6 | 24% | ||
| Middle thoracic | 15 | 60% | ||
| Lower thoracic | 4 | 16% | ||
| c Stage at prior CRT | ||||
| 0 | 2 | 8% | ||
| I | 10 | 40 % | ||
| II | 9 | 36% | ||
| III | 2 | 8% | ||
| IVa | 2 | 8% | ||
| Tumor status after CRT | ||||
| Recurrent tumor | 19 | 76% | ||
| Residual tumor | 6 | 24% | ||
| Invasion depth at 1st PDT | ||||
| ycT1a | 8 | 32% | ||
| ycT1b | 14 | 56% | ||
| ycT2 | 3 | 12% | ||
| Size of the lesions at 1st PDT, mm | 17.4±8.5 | 5-30 | ||
| Circumference of the lesions at 1st PDT | ||||
| From 1/3 to 1/2 | 12 | 48% | ||
| Less than 1/3 | 13 | 52% | ||
| Total irradiation, joule | 288±181 | 100-700 | ||
| Additional irradiation on following day | 3 | 12% |
SCC: squamous cell carcinoma, PDT: photodynamic therapy, CRT: chemoradiotherapy
Efficacy and safety
The median total irradiation dose was 200 J/cm2, ranging from 100 to 700 J/cm2. Three patients (12%) received additional irradiation the following day, as a single session each. The median hospital stay was 18 days. The median follow-up duration in this study was 18 (range: 4-76) months. Overall, 12 patients (48%) achieved an L-CR, and the 2-year PFS and OS rates were 24.9% and 59.4%, respectively (Fig. 1a, b). Three (25%) of the patients with an L-CR achieved a 2-year PFS, and they had no local recurrence within the observation period (35, 42, and 74 months). Local recurrence after an L-CR was observed in 4 patients (33.3%) at 11, 14, 17, and 22 months after the PDT procedure. The remaining 5 patients with an L-CR could not be followed up from 4, 4, 5, 16, and 22 months after PDT treatment. Additional salvage PDT was performed on all 13 non-L-CR patients, but no procedure was able to achieve a 2-year PFS in these patients.
Figure 1.
The local progression-free survival (a) and overall survival (b) in all patients.
With regard to the safety of TS-PDT, concerning adverse events, no patient showed ≥grade 3 skin phototoxicity, but the rate of a positive skin photosensitivity test at 2 weeks after TS administration was 36%. Esophageal stenosis due to PDT occurred in 7 patients (28%), all of whom required multiple endoscopic balloon dilatations to improve the obstructed passage. No esophageal fistulas were observed in any of the study patients.
Factors associated with response to TS-PDT
The results of a univariate analysis of the impact of the clinical variables on the efficacy of TS-PDT for esophageal cancer are shown in Table 2 between the non-L-CR group (n=13) and L-CR group (n=12). Patients with an L-CR had a significantly higher rate of CCI=0 than patients with a non-L-CR (66.7% vs. 23.1%; p=0.028). There was no significant difference between the 2 groups in the frequency of chronic respiratory disease, which was the most common factor of the CCI (46.2% vs. 33.3%; p=0.513). As a lesion factor, clinical invasion tended to be deeper in the non-L-CR group than in the CR group, although no significance was observed (p=0.072). In a multivariate analysis considering the CCI and depth of invasion as explanatory variables, a CCI ≥1 (p=0.041) and deeper invasion (p=0.048) were found to be significant independent risk factors for not achieving an L-CR.
Table 2.
Univariate and Multivariate Analysis of the Impact of Clinical Variables on Local Response of Salvage PDT for Esophageal Cancer.
| Variables | Non-L-CR (n=13) | L-CR (n=12) |
p value | |
|---|---|---|---|---|
| Univariate | Multivariate | |||
| Age | 71.0±10.2 | 69.2±9.1 | 0.641 | |
| Body mass index | 21.4±2.8 | 20.7±2.9 | 0.551 | |
| Charlson comorbidity index | 0.028 | 0.041 | ||
| CCI=0 | 3 (23.1%) | 8 (66.7%) | ||
| CCI ≥1 | 10 (76.9%) | 4 (33.3%) | ||
| Prognostic nutritional index | 45.3±3.9 | 45.4±3.7 | 0.964 | |
| Tumor location | 0.328 | |||
| Upper thoracic | 4 (30.8%) | 2 (16.7%) | ||
| Middle thoracic | 6 (46.2%) | 9 (75.0%) | ||
| Lower thoracic | 3 (23.1%) | 1 (8.3%) | ||
| cStage at prior CRT | 0.327 | |||
| 0-I | 4 (30.8%) | 6 (50.0%) | ||
| II-IV | 9 (69.2%) | 6 (50.0%) | ||
| Failure pattern of CRT | 0.409 | |||
| Residual lesion | 4 (30.8%) | 2 (16.7%) | ||
| Recurrence | 9 (69.2%) | 10 (83.3%) | ||
| Invasion depth at PDT | 0.072 | 0.048 | ||
| ycT1a | 2 (15.4%) | 6 (50.0%) | ||
| ycT1b | 8 (61.5%) | 6 (50.0%) | ||
| ycT2 | 3 (23.1%) | 0 (0%) | ||
| Tumor size at PDT, mm | 19.8±8.4 | 14.8±8.3 | 0.152 | |
| Circumference at PDT | 0.320 | |||
| From 1/3 to 1/2 | 8 (61.5%) | 5 (41.7%) | ||
| Less than 1/3 | 5 (38.5%) | 7 (58.3%) | ||
| Total irradiation, joule | 323±192 | 250±168 | 0.324 | |
| Additional irradiation on following day | 2 (15.4%) | 1 (8.3%) | 0.588 | |
PDT: photodynamic therapy, L-CR: local complete response, CRT: chemoradiotherapy
Efficacy and safety associated with comorbidities
The CCI scores before the PDT procedure were 0 (n=11, 44%), 1 (n=8, 32%), 2 (n=3, 12%), 3 (n=1, 4%), and 6 (n=2, 8%). The most common comorbidity was chronic pulmonary disease (n=10, 40%), which included chronic obstructive pulmonary disease, radiation pneumonia, and postlobectomy for primary lung cancer. Three patients (12%) had alcohol-associated liver disease, including 2 with a mild stage and 1 with a severe stage with portal hypertension.
To evaluate the efficacy and safety associated with comorbidities, we divided the patients into the CCI=0 group (n=11) and the CCI ≥1 group (n=14). The clinical characteristics and outcomes of the patients belonging to each group are shown in Table 3a and b. In the univariate analysis, a low BMI (p=0.043), high Brinkmann index (p=0.029), and low L-CR rate (p=0.028) were found to be significantly associated with CCI ≥1 (Table 4). There were no significant differences between the two groups in lesion factors, such as the invasion depth, size, or circumference, or in treatment factors such as the total irradiation dose. In the multivariate analysis, only the L-CR rate showed a significant difference between the two groups. The occurrence of the adverse events of a positive skin sensitivity test and esophageal stenosis after TS-PDT was not significantly different between the two groups. The 2-year PFS (p=0.029) and OS (p=0.018) rates were significantly lower in the CCI ≥1 group than in the CCI=0 group (Fig. 2).
Table 3a.
Clinical Characteristics and Outcomes of PDT for Patients Belonging to CCI=0 Group (n=11).
| No | Age | Sex | ycT | Local response | PFS (months) | Follow-up duration (months) | Alive/dead (cause) |
|---|---|---|---|---|---|---|---|
| 1 | 58 | M | 1a | CR | 14 | 39 | Dead (esophageal cancer) |
| 2 | 70 | M | 1b | CR | 74 | 76 | Alive |
| 3 | 76 | M | 1b | CR | 35 | 35 | Alive |
| 4 | 65 | M | 1a | CR | 42 | 42 | Alive |
| 5 | 68 | M | 1b | CR | 5 | 5 | Alive |
| 6 | 73 | M | 1b | CR | 22 | 22 | Alive |
| 7 | 59 | M | 1b | Non-CR | 22 | 34 | Alive |
| 8 | 87 | M | 1b | Non-CR | 1 | 4 | Alive |
| 9 | 84 | M | 1b | Non-CR | 1 | 17 | Alive |
| 10 | 60 | M | 1a | CR | 16 | 18 | Alive |
| 11 | 70 | F | 1b | Non-CR | 1 | 7 | Alive |
CCI: Charlson comorbidity index, PFS: progression-free survival, CR: complete response
Table 3b.
Clinical Characteristics and Outcomes of PDT for Patients Belonging to CCI ≥1 Group (n=14).
| No | Age | Sex | CCI | Comorbidities | ycT | Local response | PFS (months) | Follow-up duration (months) | Alive/dead (cause) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 62 | M | 1 | Lobectomy for primary lung cancer | 1a | Non-CR | 1 | 13 | Dead (pneumonia) |
| 2 | 67 | M | 6 | COPD, severe LC, ASO, DM | 1a | CR | 17 | 37 | Dead (pneumonia) |
| 3 | 67 | M | 2 | COPD, mild LC | 2 | Non-CR | 1 | 24 | Dead (heart failure) |
| 4 | 70 | M | 1 | Mild LC | 2 | Non-CR | 1 | 8 | Alive |
| 5 | 91 | M | 1 | COPD, radiation pneumonia | 1a | CR | 4 | 5 | Alive |
| 6 | 87 | M | 1 | COPD | 1a | Non-CR | 1 | 13 | Alive |
| 7 | 53 | M | 2 | COPD, DM | 1b | Non-CR | 2 | 22 | Dead (esophageal cancer) |
| 8 | 64 | M | 1 | DM | 2 | Non-CR | 1 | 5 | Alive |
| 9 | 78 | M | 2 | BA, ICA stenosis | 1b | Non-CR | 1 | 23 | Alive |
| 10 | 65 | M | 1 | Lobectomy for primary lung cancer | 1b | Non-CR | 2 | 10 | Alive |
| 11 | 75 | M | 3 | COPD, prostate cancer | 1b | CR | 11 | 18 | Alive |
| 12 | 68 | M | 1 | DM | 1b | Non-CR | 1 | 8 | Dead (pneumonia) |
| 13 | 68 | M | 6 | Rectal cancer liver metastasis | 1b | Non-CR | 1 | 6 | Alive |
| 14 | 68 | M | 1 | COPD | 1a | CR | 4 | 4 | Alive |
>CCI: Charlson comorbidity index, PFS: progression-free survival, CR: complete response, COPD: chronic obstructive pulmonary disease, LC: liver cirrhosis, ASO: arteriosclerosis obliterans, DM: diabetes mellitus, BA: bronchial asthma, ICA: internal carotid artery
Table 4.
Univariate and Multivariate Analysis of the Backgrounds and Clinical Outcomes of the Esophageal Cancer Patients in between CCI=0 Group and CCI ≥1 Group.
| Variables | CCI=0 (n=11) |
CCI ≥1 (n=14) |
p value | |||||
|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | |||||||
| Age | 70.0±9.6 | 70.2±9.9 | 0.957 | |||||
| Body mass index | 22.3±2.6 | 20.1±2.7 | 0.043 | 0.056 | ||||
| Brinkmann index | 471±412 | 906±500 | 0.029 | 0.379 | ||||
| Daily alcohol consumption, g | 57.7±30.2 | 55.2±45.5 | 0.876 | |||||
| Prognostic nutritional index | 45.8±3.4 | 44.9±4.0 | 0.565 | |||||
| Invasion depth at PDT | 0.176 | |||||||
| ycT1a | 3 (27.3%) | 5 (35.7%) | ||||||
| ycT1b | 8 (72.7%) | 6 (42.9%) | ||||||
| ycT2 | 0 (0%) | 3 (21.4%) | ||||||
| Tumor size at PDT, mm | 15.9±8.6 | 18.6±8.6 | 0.450 | |||||
| Circumference at PDT | 0.165 | |||||||
| From 1/3 to 1/2 | 4 (36.4%) | 9 (64.3%) | ||||||
| Less than 1/3 | 7 (63.6%) | 5 (35.7%) | ||||||
| Total irradiation, joule | 264±129 | 307±217 | 0.562 | |||||
| L-CR | 8 (72.7%) | 4 (28.6%) | 0.028 | 0.035 | ||||
| Skin sensitivity test, positive | 4 (36.4%) | 5 (35.7%) | 0.973 | |||||
| Esophageal stenosis | 3 (27.3%) | 4 (28.6%) | 0.943 | |||||
CCI: Charlson comorbidity index, PDT: photodynamic therapy, L-CR: local complete response, CRT: chemoradiotherapy
Figure 2.
The local progression-free survival (a) and overall survival (b) in patients stratified according to the CCI. CCI: Charlson comorbidity index, PDT: photodynamic therapy
Discussion
This preliminary retrospective study found that the CCI was negatively associated with the efficacy of salvage TS-PDT for esophageal cancer. We believe that this result has important implications for reconsidering the salvage strategy for recurrent esophageal cancer after CRT. Currently, highly invasive surgery is recommended over TS-PDT for patients with few comorbidities as a curative strategy in salvage treatment for local failure after CRT. However, the results of our study suggest that salvage TS-PDT may offer more benefit in providing a curative effect in tolerant patients for whom salvage surgery is recommended than in vulnerable patients with several comorbidities.
Thus far, five studies have reported independent clinical outcomes of salvage TS-PDT for esophageal cancer from 2012 to 2021 (7,15-18). According to these studies, the L-CR rate ranged from 55.6% to 88.5%, and the likelihood of an L-CR was significantly affected by the clinical invasion depth of the tumor before PDT. There are few comprehensive reports on the long-term prognosis of salvage TS-PDT. Amanuma et al. reported long-term follow-up (median period of 26.0 months) data in 34 salvage PDT cases including 16 with TS-PDT and 18 with PS-PDT (19)．They showed that the 2-year PFS rate was 32%, which is slightly better than the 24.9% rate in the present study using only TS-PDT.
To our knowledge, this is the first study to focus on comorbidities as a patient factor regarding the therapeutic efficiency of salvage TS-PDT for esophageal cancer. With the aging of society, the number of elderly patients with esophageal cancer has been increasing, and elderly patients tend to have multiple comorbidities. In particular, patients with ESCC, for which both smoking and alcohol consumption are well established risk factors, tend to have many comorbidities, and the proportion was previously reported to be 69.9% (20). Several studies have been conducted on the relationship between comorbidities and clinical outcome in esophageal cancer. In a Swedish study that included 1,822 patients with esophageal cancer, Backemar et al. showed that a CCI score of >2, myocardial infarction, and congestive heart failure before surgery were significant risk factors for an unfavorable OS and disease-specific survival after esophagectomy (11). Furthermore, Yamashita et al. found that a high CCI before a diagnosis of esophageal cancer was significantly associated with a poor prognosis in 318 patients with stage ≥II disease (12).
Regarding why a high CCI is associated with a poor prognosis in patients with esophageal cancer, a previous study suggested that this might be due to the decreased number of lymph nodes dissected, R0 resection rate, dose of neoadjuvant therapy as well as to the high rate of complications, such as pneumonia (12,21). In addition, Kubo et al. investigated the relationship between the CCI and PNI in patients with esophageal cancer (22). Their analysis found that a high CCI was a significant risk factor for a low prognostic nutrition index at one month after surgery and concluded that postoperative malnutrition might be associated with a poor prognosis in patients with a high CCI.
We speculated about the reasons as to why the CCI might have a negative impact on the efficacy of salvage PDT for esophageal cancer from the perspective of the therapeutic mechanism of PDT. The photochemical reactions initiated by light absorbance of PS are known to comprise two types of processes. The radicals that are produced at the time PS is transformed from its basic state to its excited state by light exposure interact with oxygen to produce oxygenated products (Type I). Alternatively, the activated PS transfers its energy to oxygen to form singlet oxygen (Type II). While both reactions occur simultaneously, ROS generation via the Type II process is known as the major pathway of the antitumor effect in PDT (23). In the present study, approximately 80% of the patients with a CCI ≥1 had chronic pulmonary disease or liver cirrhosis, which are comorbidities associated with smoking and excessive alcohol consumption and are risk factors for esophageal cancer. Respiratory dysfunction due to chronic pulmonary disease naturally causes hypoxia, and liver cirrhosis also decreases the saturation of arterial oxygen due to a ventilation-perfusion imbalance (24). We hypothesized that these chronic shortages in oxygenation might have interfered with the supply of ROS, a key factor in cell death initiated by PDT. To verify this hypothesis, it will be necessary to confirm negative efficacy in in vivo experiments with TS-PDT in a mouse model of lung injury.
Several limitations associated with the present study warrant mention. First, the number of patients studied was small, as only a limited number of patients are eligible for this therapy, and this was a retrospective study performed in a single institution. The limitation of a small patient population hindered the ability to conduct higher-quality studies beyond comparing CCI 0 and ≥1, such as comparing CCI 0, 1, and ≥2 or CCI 0-2 and ≥3, which could have provided more robust insights. Second, comorbidities were determined based on the diagnosis given in the information provided by each patient's previous hospital, and detailed investigations were not conducted to confirm the comorbidities. Third, we did not perform detailed examinations related to oxygenation such as blood gas analyses and respiratory function tests.
In conclusion, the CCI correlated significantly with the prognosis of patients with esophageal cancer who underwent salvage TS-PDT for cancer recurrence after curative CRT. We hope that this finding will help improve the therapeutic strategy for esophageal cancer patients through further research with a larger number of patients.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This work was supported by JSPS KAKENHI Grant Number JP 20K17694, and a grant for Clinical Research from Miyazaki University Hospital.
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