Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).

BACKGROUND: Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. PATIENTS AND METHODS: Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. RESULTS: Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. CONCLUSION: Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. CLINICALTRIALS.GOV ID: NCT02746796.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

Long-term results of salvage photodynamic therapy for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Local failure after chemoradiotherapy (CRT) remains a major problem for patients with esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the long-term results of salvage photodynamic therapy (PDT) for local failure. PATIENTS AND METHODS: Patients were treated with CRT, consisting of more than 50 Gy irradiation and concurrent chemotherapy. The indications for salvage PDT were as follows: 1) absence of lymph-node or distant metastasis after CRT; 2) failure lesion limited to T2; 3) refusal by patient to undergo salvage esophagectomy; 4) written informed consent. PDT was performed using an excimer dye laser at 48 and 72 hours after administration of Photofrin. RESULTS: A total of 37 consecutive patients underwent salvage PDT. The baseline stage before CRT was as follows: T1/T2/T3/T4 in 3/4/24/6 and N0/1 in 13/24 patients, respectively. Prior to PDT, 20 patients had a uT1 lesion, and 17 had a uT2 lesion; 24 patients had histologically proven local failure. A complete response was achieved in 22 patients (59.5%) following PDT. Esophageal fistulae, stenosis, and phototoxicity occurred in 4 (10.8%), 20 (54.1%), and 2 (5.4%) patients, respectively. Over a median follow-up period of 55 months, the 5-year progression-free (PFS) and overall survival rates of 37 patients following PDT were 20.7% and 36.1%, respectively. The 5-year PFS and overall survival of 24 patients with proven local failure were 17.6% and 34.6%, respectively. CONCLUSION: Salvage PDT is a curative treatment option for patients with local failure after CRT for ESCC.

Submucosal tumor appearance is a useful endoscopic predictor of early primary-site recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) for esophageal cancer is disadvantageous because of a high locoregional failure rate. Detecting early small recurrent cancers at the primary site is necessary for potential salvage treatment. However, most endoscopists are inexperienced and therefore, a role for surveillance endoscopy after complete remission (CR) has not been established. We retrospectively evaluated serial surveillance endoscopic images from patients eventually proved to have primary-site recurrence in order to identify useful endoscopic features for early diagnosis. From January 2000 to December 2004, 303 patients with esophageal squamous cell carcinoma underwent definitive CRT, and 133 of them achieved CR. The surveillance endoscopic images stored at intervals of 1-3 months for the 16 patients with recurrence only at the primary tumor site and the 61 patients with no recurrence were collected for reexamination. Among 133 patients who achieved CR, 16 (12%) developed only local recurrence at the primary site. Thirteen of the 16 primary-site recurrent tumors (81%) appeared as submucosal tumors (SMT), with the remaining appearing as erosions or mild strictures. Of biopsy-proven recurrences, 81% were preceded by newly developed lesions such as SMT, erosions, or mild strictures detected by earlier surveillance endoscopies. For all 77 patients achieving CR with no metastasis, 86% of the evolving SMT with negative biopsies were eventually confirmed as cancer at later endoscopies. Thirteen of the 21 evolving lesions were subsequently confirmed as recurrent cancer. Early primary-site recurrence of esophageal cancer after a complete response to CRT is detectable with frequent endoscopic surveillance. SMT appearance is a useful endoscopic sign of early recurrence, as well as a predictor of subsequent diagnosis of recurrence.

Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer.

BACKGROUND: Chemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified. PATIENTS AND METHODS: Using a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East. RESULTS: Of 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2)). CONCLUSIONS: ILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.

Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Local failure after definitive chemoradiotherapy (CRT) in patients with esophageal cancer remains one of the major problems in finding a cure. Endoscopic mucosal resection (EMR) is one treatment option when failure lesions are superficial. However, there are no relevant long-term survival data. The aim of this study was to clarify the long-term survival of salvage EMR. PATIENTS AND METHODS: Between January 1998 and March 2004, 289 patients with esophageal squamous cell carcinoma were treated with definitive CRT at the National Cancer Center Hospital East, Japan. Of these 289 patients, 21 patients with local failure without lymph-node or distant metastases were treated with salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively analyzed the long-term survival data for the patients who underwent salvage EMR. RESULTS: At a median follow-up period of 54 months (range, 16-108 months), eight of 21 patients (38%) were alive with no recurrence and two patients had died from another disease but with no recurrence of esophageal cancer. Local recurrence after EMR was detected in four patients, with local and lymph-node recurrence in two patients, and lymph-node and/or distant metastases in five patients. The 5-year survival rate from the initiation of salvage EMR was 49.1%. There were no severe complications associated with EMR. CONCLUSION: EMR is one of the curative salvage treatment options for local failure after definitive CRT, if the failure lesion is superficial and there are no lymph-node or distant metastases.

[Motility disorders of the esophagus, excluding achalasia].

Esophageal motor disorders can be primarily focused in the esophagus or secondarily related to a systemic disease. Based on the manometric findings, primary esophageal motor disorders can also be classified into achalasia and spastic disorders, such as diffuse esophageal spasm, nutcracker esophagus, hypertensive lower esophageal sphincter, and nonspecific esophageal motility disorders.

[Esophageal peristalsis, lower esophageal function, and the methods of their evaluation].

Esophageal peristalsis and lower esophageal sphincter(LES) function have an influence on gastroesophageal reflux disease(GERD). Incomplete contraction during primary and secondary peristalsis leads to poor clearance of refluxed gastric acid. Failure of LES function can result in a low basal LES pressure, absent or incomplete LES relaxation after swallowing, or an inadequate increase of LES pressure accompanying gastric activity. In addition, transient LES relaxation(TLESR) has been suggested as an important factor in GERD. Recent studies have indicated that TLESR has a relationship to nitric oxide(NO) and cholecystokinin(CCK).