This study was a multi-institutional open label phase I laser dose escalation study with a fixed dose of talaporfin sodium for patients with local failure after CRT or RT for ESCC. The study protocol was approved by the institutional review board of all participating institutions. This study was conducted in accordance with the Ethical Guideline for Clinical Research by the Ministry of Health, Labour and Welfare and the Declaration of Helsinki. The study was also registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, and the identification number is UMIN000003970.
Patients
The eligibility criteria of this study were as follows: 1) local failure after CRT or RT(≥ 50 Gy) for esophageal cancer; 2) refusal of salvage esophagectomy or lack of tolerability for salvage esophagectomy; 3) local failed lesions limited within the muscularis propria (T2); 4) local failed lesions that were not involved in the cervical esophagus, 5) longitudinal lesion length of shorter than 3 cm and less than one half the circumference of the lumen; 6) no more than 2 failure lesions; 7) enrollments of patients with lymph node or distant metastasis were accepted, except for those with indication for systemic chemotherapy 8) local failure lesions which meet at least one of the following criteria; a) histologically proven carcinoma by biopsy specimen, b) emerged ulceration in the lesions, c) enlarged submucosal tumor like protrusion in the lesion, d) presence of heteroechoic solid component with endoscopic ultrasound (EUS) observation, 9) age ≥ 20, 10) Eastern Cooperative Oncology Group performance status ≤ 2; 11) adequate bone marrow function (white blood cell count ≥2000/mm3 and ≤ 12,000/mm3, hemoglobin >8.0 g/dL, platelet count ≥75,000/mm3), renal function (serum creatinine level ≤ 2.0 mg/dL), and liver function (serum total bilirubin level ≤ 2.0 mg/dL, both alanine aminotransferase and aspartate aminotransferase ≤ 100 IU/L); and 12) provision of written informed consent.
The exclusion criteria were 1) significant cardiovascular diseases (uncontrolled hypertension, myocardial infarction, unstable angina, congestive heart failure), uncontrolled diabetes mellitus, or severe liver cirrhosis; 2) systemic infection requiring antibiotics; 3) inability to obey the sun shade restrictions; 4) additional PDT just after salvage endoscopic mucosal resection or endoscopic submucosal dissection for local failures; 5) baseline lesions before CRT or RT judged to involve the aorta; 6) porphyria; 7) preexisting of sun photosensitivity; 8) previous treatment with PDT using talaporfin sodium, or treatment with PDT using porfimer sodium at least 3 months before enrollment; 9) pregnant or nursed women, or unwillingness to use of contraception; and 10) judged by investigator that enrollment was inappropriate for the patient.
Study design
In the present study, the dose of talaporfin sodium was the same as that used for lung cancer, because the safety profile of the 40 mg/m2 dose was already clarified in the PDT regimen for lung cancer. Therefore, we planned this laser fluence escalation study to find the optimum fluence level of diode laser treatment for local failure after CRT or RT for esophageal cancer. The primary endpoint of this study was to assess the dose limiting toxicity (DLT) related with PDT at each level. The secondary endpoints were to evaluate the adverse events and toxicity related to PDT. The starting fluence of the diode laser was 50 J/cm2 (level 1), with the escalation plan increasing the fluence to 75 J/cm2 (level 2) and 100 J/cm2 (level 3). The starting fluence of 50 J/cm2 was chosen based on results of a pre-clinical study using canine esophagus model [11]. A minimum of 3 patients were assessed for toxicity at each level. If a DLT was not observed within 28 days after laser irradiation, then the level was raised. If a DLT was observed in one of the 3 patients, an additional 3 patients were treated at the same fluence level. The maximam tolerated dose (MTD) was defined at each level when DLT was observed in 2 or more of the 3 patients, or 3 or more of the two 3 patient groups that were treated at the same fluence level. The recommended dose (RD) for further study in phase II was defined as just below the level of the MTD. If the DLT was not observed in the level, then level 3 (100 J/cm2) was defined as the RD for the phase II study.
Staging
In this study, clinical stage was determined according to the TNM classification of the International Union Against Cancer 6th edition [12] and the Japanese Classification of Esophageal Cancer, 10th edition, revised version [13]. Clinical T stage was evaluated by endoscopy, EUS, and computed tomography (CT) of the chest. Clinical N and M stages were evaluated by EUS and CT of the neck, chest, and abdomen.
Treatment and surveillance
All PDT procedures were performed in an inpatient setting. One hundred milligrams of talaporfin sodium were dissolved in 4 mL of saline, and a 40 mg/m2 dose was slowly injected intravenously. Four to 6 hours after administration of talaporfin sodium, the local failure lesion was irradiated with diode laser at a 664 nm wavelength. The diode laser light was delivered via a straight type fiber without any balloon or light diffuser through the operative channel of the scope. A plastic attachment was fitted to the tip of the scope to keep it facing the lesion and to maintain the distance between the tip of the straight type fiber and the surface of the lesion during the procedure. If the lesions were larger than 1 cm2, multiple treatment fields were overlapped to cover the entire lesion. In this phase I study, the starting fluence was 50 J/cm2 (level 1), with a fixed fluence rate of 150 mW/cm2. If the post laser treatment change (e.g. ischemic change of mucosa) by endoscopic observation was suspected to be insufficient, additional laser irradiation was performed on the next day as a second session.
Before enrollment, patients were evaluated with a physical examination, performance status, dysphagia score [14] assessment, complete blood count, blood chemistry, electrocardiogram, and a chest-X ray study. After patient enrollment, adverse events were observed and graded until 28 days after laser irradiation. Patients were assessed through physical examinations, measurements of hematological and biochemical variables in the blood, chest X-ray studies, and endoscopic examinations, at least once a week until 28 days after PDT. All patients were instructed to avoid direct exposure to sunlight for 2 weeks after the injection of talaporfin sodium to protect them from skin photosensitization. Patients were allowed to discharge 2 weeks after laser irradiation if there were no complications related to PDT. Adverse events and toxicity were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [15].
DLT was defined as follows; 1) pain that requires administration of opioid analgesics for relief and persists for 4 days or more; 2) grade 2 or higher fever that persists 4 days or more, in spite of antipyretic administration; 3) grade 3 or higher esophageal fistula without any evidence of disease progression; 4) grade 3 or higher esophageal stenosis without any evidence of disease progression; 5) grade 3 or higher esophageal hemorrhage without any evidence of disease progression, 6) grade 4 or higher non-hematological toxicity.
Efficacy
Treatment efficacy and toxicity at the primary site were evaluated by endoscopy every week for the first 4 weeks after PDT, and every 2 weeks thereafter until the efficacy was confirmed. The clinical criteria of CR at the primary site after PDT were as follows: 1) residual lesion not observed; 2) disappearance of post PDT ulceration and confirmation of the scar formation; and 3) histological confirmation of the absence of cancer cells by biopsy. In addition, when the ulceration or erosion was not cured within 6 months after PDT, but the biopsy specimen did not continuously reveal residual cancer cells, treatment efficacy was assessed as uncertain CR and they were evaluated as a CR case.
CT was used to evaluate distant organ or lymph node metastasis every 3 months after PDT. In this study, lymph node metastasis was diagnosed clinically if the lymph node was larger than 10 mm in diameter on CT, and distant metastasis was diagnosed if the emergent metastatic lesion was confirmed with CT.
