Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial.

BACKGROUND: Adjuvant chemotherapy with oral fluoropyrimidine alone after D3/D2 lymph node dissection improves disease-free survival and overall survival in patients with stage III colon cancer. Adjuvant S-1 has been shown to be non-inferior to uracil and tegafur plus leucovorin in terms of disease-free survival. This study aims to confirm the non-inferiority of S-1 compared with capecitabine as adjuvant treatment in patients with stage III colorectal cancer. METHODS: This study was an open-label, non-inferiority, randomised, phase 3, multicentre trial done in 56 Japanese centres to assess the non-inferiority of S-1 to capecitabine as adjuvant chemotherapy. Eligible patients were aged 20-80 years with stage III colorectal adenocarcinoma, as defined by the presence of an inferior margin of the primary tumour above the peritoneal reflection; R0 resection; and colectomy with D3 or D2 lymph node dissection. Patients were randomly assigned (1:1) to receive eight courses of capecitabine (1250 mg/m2 orally twice daily, days 1-14, every 21 days) or four courses of S-1 (40 mg/m2 orally twice daily, days 1-28, every 42 days). Randomisation was done via phone call, fax, or web-based systems to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component adjusted by institution, tumour location (colon vs rectosigmoid and upper rectum), number of positive lymph node metastases (≤3 vs ≥4), and surgical technique (conventional vs non-touch isolation). The primary endpoint was disease-free survival with a non-inferiority margin for the hazard ratio (HR) set at 1·24, analysed by intention to treat. This trial was registered with UMIN Clinical Trial Registry, number UMIN000003272. FINDINGS: Between March 1, 2010, and Aug 23, 2013, 1564 patients were randomly assigned to capecitabine (n=782) or S-1 (n=782), all of whom were included in the efficacy analysis; 777 patients in the capecitabine group and 768 in the S-1 group were included in the safety analysis. At the prespecified second interim analysis after final accrual, 258 (48%) of 535 required events were reported, and the Data and Safety Monitoring Committee recommended early publication because S-1 could not show non-inferiority compared with capecitabine for disease-free survival. With a median follow-up of 23·7 months (IQR 14·1-35·2), 3-year disease-free survival was 82·0% (95% CI 78·5-85·0) for the capecitabine group and 77·9% (74·1-81·1) for the S-1 group (HR 1·23, 99·05% CI 0·89-1·70; one-sided pnon-inferiority=0·46). The most frequent grade 3 or higher adverse events in the capecitabine group were hand-foot skin reactions (123 [16%] of 777 patients), and in the S-1 group were diarrhoea (64 [8%] of 768 patients) and neutropenia (61 [8%]). There was one (<1%) treatment-related death in each group. INTERPRETATION: Adjuvant capecitabine remains one of the standard treatments for stage III colorectal cancer in Japan; S-1 is not recommended. FUNDING: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205.

BACKGROUND: NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection. METHODS: Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193). FINDINGS: Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported. INTERPRETATION: Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Limitations of airway dimension measurement on images obtained using multi-detector row computed tomography.

OBJECTIVES: (a) To assess the effects of computed tomography (CT) scanners, scanning conditions, airway size, and phantom composition on airway dimension measurement and (b) to investigate the limitations of accurate quantitative assessment of small airways using CT images. METHODS: An airway phantom, which was constructed using various types of material and with various tube sizes, was scanned using four CT scanner types under different conditions to calculate airway dimensions, luminal area (Ai), and the wall area percentage (WA%). To investigate the limitations of accurate airway dimension measurement, we then developed a second airway phantom with a thinner tube wall, and compared the clinical CT images of healthy subjects with the phantom images scanned using the same CT scanner. The study using clinical CT images was approved by the local ethics committee, and written informed consent was obtained from all subjects. Data were statistically analyzed using one-way ANOVA. RESULTS: Errors noted in airway dimension measurement were greater in the tube of small inner radius made of material with a high CT density and on images reconstructed by body algorithm (p<0.001), and there was some variation in error among CT scanners under different fields of view. Airway wall thickness had the maximum effect on the accuracy of measurements with all CT scanners under all scanning conditions, and the magnitude of errors for WA% and Ai varied depending on wall thickness when airways of <1.0-mm wall thickness were measured. CONCLUSIONS: The parameters of airway dimensions measured were affected by airway size, reconstruction algorithm, composition of the airway phantom, and CT scanner types. In dimension measurement of small airways with wall thickness of <1.0 mm, the accuracy of measurement according to quantitative CT parameters can decrease as the walls become thinner.

[A case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant 5-FU+CDDP therapy for esophageal cancer].

We present a case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant chemotherapy with 5-FU+CDDP for esophageal cancer. A 52-year-old woman visited another hospital with the complaint of discomfort during swallowing. Upper gastrointestinal endoscopy revealed an ulcerated lesion in the lower thoracic esophagus, which was pathologically diagnosed as squamous cell carcinoma. She was admitted to our institution, and the diagnosis of esophageal cancer Mt-Lt, type 2, cT2N1M0, stage II was made. We obtained informed consent for her treatment with both CRT and surgery, and she selected surgery. Therefore, she was administered neoadjuvant chemotherapy with 5-FU+CDDP therapy. On day 4, abnormalities of the central nerve, such as unconsciousness, difficulty in speaking, and muscle cramps were, observed. After the examinations she was diagnosed with encephalopathy. It should be noted that hyponatremia induced by renal sodium wasting syndrome(RSWS)was considerd to be the cause, and we report our case with the literature cited.

[Genetic counseling and practice of hereditary cancers at Shikoku Cancer Center].

Although the progress in understanding human genetics regarding cancer has been applied to the medical practice of treating hereditary cancers in developed western countries, it is not widely implemented in Japan. We started treating hereditary cancers at NHO Shikoku Cancer Center in November 2000. Our institution has a multidisciplinary team that provides medical care and genetic counseling for patients with hereditary cancers, and their relatives. The team consists of doctors from several related departments, and paramedics including a genetic counselor who participated as of 2009. Medical care of patients with hereditary cancers should not be separated from general oncological practice, but incorporate all medical professionals, including doctors of related departments and paramedic. We have attempted to identify patients with hereditary cancer and their family members and relatives at high risk; we followed them up and provided risk-reducing therapies for them at our cancer center. Here we present the framework of our practice in treating hereditary cancers. We discuss appropriate goals and future perspectives in the field of hereditary cancer in Japan.

[A case of lung infection complicated by pneumothorax caused by Mycobacterium marinum].

Mycobacterium marinum is a waterborne mycobacterium that commonly infects fish and amphibians worldwide, but transmission to humans can occasionally occur, typically as a granulomatous skin infection following minor hand trauma. Infection involving the lungs is very rare. We herein describe a case of M. marinum-associated pneumonia and pneumothorax. In August 2008, an 81-year-old man was admitted to a hospital for detailed examination of weight loss and an abnormal shadow on chest imaging. Based on a sputum test, nontuberculous mycobacteriosis caused by M. marinum was diagnosed. At that time, the blood chemistry revealed no respiratory symptoms or inflammatory findings, and the patient was treated on an outpatient basis with erythromycin and an expectorant. In late November 2008, sputum and coughing were observed. Furthermore, the patient developed a fever and chest pain that increased while breathing and he visited the emergency outpatient unit of our hospital on December 1. Hypoxemia, bilateral pneumonia, and right pneumothorax were observed, and a chest tube was inserted into the right thoracic cavity. Results of an acid-fast bacteria smear from the sputum and pleural effusion were positive, and M. marinum was identified on culture. The patient was diagnosed as having a lung infection complicated by pneumothorax caused by M. marinum. The lung infection was ameliorated with clarithromycin, rifampicin and ethambutol. However, no decreased in the air leaking from the chest tube was noted and inflation of the lung was incomplete. The department of respiratory surgery therefore performed thoracoplasty and lung cerclage. Subsequently, the air leak subsided, allowing removal of the chest tube and the patient was discharged.

Diverting stoma in rectal cancer surgery. A retrospective study of 329 patients from Japanese cancer centers.

BACKGROUND: A diverting stoma (DS) has been constructed for many patients with low anterior resection (LAR), but it is still controversial whether DS can prevent anastomotic leakages. The aim of this study was to investigate the risk factors of anastomotic leakage including DS construction, and to evaluate the clinical course affected by DS according to the necessity of urgent abdominal reoperation for anastomotic leakage. PATIENTS AND METHODS: This was a retrospective analysis of 329 middle or lower rectal cancer patients who underwent LAR with mechanical reconstruction using circular staplers. Clinical data were collected from five cancer centers in Japan. RESULTS: The overall anastomotic leakage rate was 10.0% (33 of 329). We experienced one mortality in this series (0.3%; 1/329). Clinical factors associated with DS construction included tumor location, operation time, intraoperative bleeding, lateral lymph node dissection, simultaneous resection of other organs, and the level of anastomosis, respectively. On univariate analysis, high ligation of the inferior mesenteric artery had a significantly high leakage rate, but not on multivariate analysis. DS construction had no connection with the overall leakage rate. Concerning the clinical course affected by DS, the frequency of urgent reoperation was significantly increased in patients without DS compared with those with DS, 11.1% and 54.2%, respectively (p = 0.04). CONCLUSIONS: LAR was the safe and preferred option for rectal cancer patients with very low mortality and an acceptable leakage rate. DS did not have a relationship with overall anastomotic leakage, but did seem to mitigate its consequences and reduce the requirement for urgent abdominal reoperation.

[A case of interstitial pneumonia with autoimmune hemolytic anemia].

A 71-year-old man noticed that he was producing brown urine in November 2007, and he also experienced dyspnea on exertion, a nonproductive cough and a pruritic eruption on his extremities and trunk in December 2007. He was admitted with suspected interstitial pneumonia (IP). IP was diagnosed based on the findings of blood tests, chest X-rays, computed tomography, bronchoalveolar lavage, and a transbronchial lung biopsy. His hemoglobin (Hb) level was low (6.4 g/dL), and autoimmune hemolytic anemia (AIHA) was diagnosed based on the presence of reticulocytosis (187%), a low level of haptoglobin (< 10 mg/dL), and positive direct and indirect Coombs tests. His symptoms improved after receiving corticosteroid therapy. To the best of our knowledge there are only 15 reported cases of patients demonstrating the occurrence of these 2 diseases together. Most patients who develop AIHA first have a favorable prognosis, while those who develop IP first tend to have a poor prognosis. The current patient had increased levels of serum IgG, IgA and immunocomplexes. These findings suggest that IgG, IgA and immunocomplexes were associated with the comorbid IP and AIHA.

Risk factors for metachronous gastric cancer in the remnant stomach after early cancer surgery.

BACKGROUND: Early gastric cancer patients have a good prognosis after radical resection. However, if the patients have a gastric remnant after the surgery, the risk of metachronous gastric cancer remains. The aim of this study was to clarify the risk factors for metachronous gastric cancer after partial gastrectomy for early gastric cancer. METHODS: Data on a series of 1281 consecutive gastrectomy patients with pathologically confirmed early gastric cancer from 1991 to 2007 in Shikoku Cancer Center were analyzed retrospectively. RESULTS: The gastric remnants of 868 patients were periodically surveyed by endoscopic examination. Among those surveyed cases, 26 patients were diagnosed as having metachronous gastric cancer in the gastric remnant. They underwent curative resection by remnant gastrectomy (n = 13 patients) or endoscopic mucosal resection (n = 13 patients). Multivariate analysis showed that male sex, older age, submucosal invasion, and proximal gastrectomy were independent risk factors. CONCLUSIONS: Our data suggested that more intensive endoscopic follow-up is needed for the remnant stomach in patients with these risk factors to detect metachronous gastric cancer at its early stage.

Local control of metastatic lung tumors treated with SBRT of 48 Gy in four fractions: in comparison with primary lung cancer.

OBJECTIVE: The optimal dose of stereotactic body radiotherapy (SBRT) for metastatic lung tumors has not been clarified. Local control rates of metastatic lung tumors treated with SBRT of 48 Gy in four fractions, which is one of the common dose schedules for Stage I primary lung cancer in Japan, were examined. METHODS: Between 2006 and 2008, 12 metastatic lung tumors (colorectal cancer, 7; others, 5) in 10 patients and 56 lesions of Stage I primary lung cancer (T1, 43; T2, 13) in 52 patients were treated with SBRT of 48 Gy in four fractions at the isocenter. RESULTS: Two-year overall survival rates were 86% for patients with metastatic lung tumors and 96% for patients with Stage I primary lung cancer (P = 0.4773). One- and 2-year local control rates were 48% and 25% for metastatic lung tumors, and 91% and 88% for Stage I primary lung cancer, respectively (P < 0.0001). CONCLUSIONS: The local control rates after SBRT of 48 Gy in four fractions were significantly worse in metastatic lung tumors compared with Stage I primary lung cancer. In SBRT, metastatic lung tumors should be clearly differentiated from primary lung cancer and should be given higher doses.

Unusual abscesses associated with colon cancer: report of three cases.

Three cases of colon cancer accompanied by unusual abscess formation are reported. Case I : A 77-year-old man was diagnosed with a paracolic abscess formation behind the cecum and a swollen appendix by computed tomography (CT) scan. Case II : An 85-year-old woman was diagnosed with an abscess formation of the right iliopsoas muscle, a swollen appendix, and a thickened right colon wall by CT scan. After antibiotic therapy failed, both patients underwent ileocecal resection urgently under suspicion of appendicitis, but cecal cancer around the entrance to the appendix caused secondary appendicitis in both cases. Case III : A 50-year-old woman was diagnosed with sigmoid colon cancer with an abscess formation in the pelvic cavity concomitant with ovarian tumor. A Hartmann procedure was performed, and a pathological examination revealed that a subserosal abscess behind the sigmoid colon cancer perforated the rectum with abscess formation. All cases were definitively diagnosed intraoperatively. The cancer recurred in cases I and III. We emphasize that precise surgical evaluation has an important role in the diagnosis of these complicated diseases. In addition, surgery affords the patient the best chance of recovery, and in these advanced cases radical treatment is recommended as early as possible.

[The long-term results of hepatic resection for metastatic lesions from colorectal cancer].

We reviewed the clinical course of 51 patients who underwent hepatic resection for metastatic lesions from colorectal cancer between January 1984 and December 1997. The cumulative survival rate at 3 and 5 years were 57% and 43%, respectively. Sex, age, chronology of liver metastases (LM), number of LM, maximum diameter of LM, macroscopic surgical resection margin, type of hepatic resection, chemotherapy after hepatic resection, and site of primary tumor were not found to be statistically significant prognostic factors. The presence of lymph node metastases for the primary tumor was a predictor of shorter survival duration by univariate analysis (p=0.03). Recurrence was not observed in 15 patients. However, recurrence was observed in 36 patients, of which 4 were in remission by undergoing repeated resection for recurrence sites (2 were in lung, 2 were in liver). Although the long term survival of the 19 patients with no significant remarks to be noted, but no one survived with more than 4 hepatic metastases among the long term survivors.

[Clinical study of irinotecan therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer].

The clinical efficacy and safety of irinotecan (CPT-11) therapy were studied retrospectively in patients with fluoropyrimidine-resistant advanced colorectal cancer. The subjects were 44 patients who were treated with CPT-11 alone or with a combination of CPT-11 and mitomycin C (MMC) at our institute from April 1999 to March 2003. CPT-11 (120-150 mg/m2) alone or CPT-11 with MMC (5 mg/m2) was administered every 2 weeks. The objective overall response rate was 11% (95% confidence interval, 3.8-25%). In 38 patients who were treated until October 2002, the median survival time was 12 months. Two-year survival rate was 13%. Grade 3 anorexia or diarrhea occurred in 6 patients (14%) and 5 patients (11%), respectively. There was no treatment-related death or early death within 30 days from the last administration of CPT-11 (+MMC). This retrospective study demonstrated the reproducible activity and safety of CPT-11 for the treatment of fluoropyrimidine-resistant advanced colorectal cancer in clinical practice.

[Clinical study of TS-1 therapy for inoperable and recurrent gastric cancer].

The clinical efficacy and safety of TS-1 therapy were studied retrospectively in patients with inoperable and recurrent gastric cancer. The subjects were 45 patients who were treated with TS-1 for more than 4 weeks at our center between May 1999 and July 2002. The objective overall response rate was 32% (14/44; 95% confidence interval, CI, 19-48). The response rate in the chemo-naive patients was 44% (11/25; 95% CI, 24-65), and that in the patients with previous chemotherapy was 16% (3/19; 95% CI, 3.4-40). Although doses or durations of TS-1 administration were reduced in 22 patients (reduction group) due to adverse effects or poor performance status, they achieved a fairly high response rate of 38% (8/21). For primary lesions, the response rate was 30% (8/27). The prevalence of adverse reactions with a grade of 3 or 4 was 36%. However, the prevalence of each grade 3 or 4 adverse effect was relatively low, at 13% for neutropenia, and around 5% for anorexia, nausea, vomiting, and diarrhea. The median administration period was 10 weeks (4-47 weeks) in all patients and 11 weeks (6-47 weeks) in the reduction group. The relative dose intensity was 0.89 in all patients and 0.81 in the reduction group. In patients who were treated until August 2001, the median survival time (MST) was 13 months with 1-year and 2-year survival rates of 53% and 14%, respectively. These results were similar to those reported in the phase II study for the new drug approval. This study demonstrated the reproducible activity and safety of TS-1 in practice.