[Show abstract][Hide abstract] ABSTRACT: The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy.
Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR).
A total of 31 patients were enrolled. DCR was 65 % [95 % confidence interval (CI), 48-100 %] and the response rate was 7 % (95 % CI, 0.7-22 %). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95 % CI, 2.1-9.3] and 9.9 [95 % CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26 %) and diarrhea (11 %), which were manageable by dose reduction/interruption.
SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC.
This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.
BMC Cancer 08/2015; 15(1):601. DOI:10.1186/s12885-015-1606-1 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bleeding negatively impacts quality of life in patients with unresectable advanced gastric cancer and has the potential to be lethal. When blood transfusion and endoscopic hemostasis are unsuccessful to stop bleeding, radiation to stomach is selected in patients with unsuitable condition for surgery. We performed a retrospective cohort study to clarify the utility of radiotherapy in treating gastric bleeding, particularly for patients with limited life expectancy.
We evaluated the efficacy and safety of palliative radiotherapy in patients with advanced gastric cancer between January 2007 and December 2012 in Aichi Cancer Center Hospital. All patients had gastric bleeding requiring blood transfusion. We defined hemostasis as an increase in hemoglobin level to more than 7.0 g/dL together with the cessation of melena or hematemesis for at least 1 week.
During the study period, 313 advanced gastric cancer patients treated in our institution. Of these 17 patients received gastric radiotherapy to stop bleeding. Two patients were excluded from analysis due to combined treatment of intravascular embolization. Eleven out of 15 patients (73 %) had undergone two or more previous chemotherapy regimens. Ten patients (67 %) had an Eastern Cooperative Oncology Group performance status of 3 and 14 patients (93 %) were in palliative prognostic index group B or C. The median total planned radiation dose was 30 Gy in 10 fractions. At a median interval of 2 days after initiation of radiotherapy, 11 patients (73 %) achieved hemostasis; rebleeding was observed in four patients (36 %). The median hemoglobin level before radiotherapy was significantly increased from 6.0 to 9.0 g/dL (p < 0.0001). The median volume of red blood cell transfusion was significantly decreased from 1120 to 280 mL (p = 0.007). The median rebleeding-free survival interval was 27 days, with a median overall survival of 63 days. The cause of death was bleeding in 1 patient (7 %) and cancer progression without bleeding in 12 patients (80 %). There were no severe adverse events attributable to radiotherapy.
Palliative radiotherapy for gastric bleeding achieves hemostasis within a short time frame. This appears to be a useful treatment option, especially for patients with end-stage, unresectable advanced gastric cancer.
BMC Palliative Care 08/2015; 14(1):37. DOI:10.1186/s12904-015-0034-y · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the influence of addition of docetaxel to neoadjuvant chemotherapy (NAC) with cisplatin plus 5-fluorouracil (CF) in patients with clinical stage III or T3 esophageal squamous cell carcinoma.
Information about 209 esophageal cancer patients with stage III or T3 disease, who underwent NAC consisting of CF with or without docetaxel, was reviewed. The survival outcomes were analyzed using the Kaplan-Meier method and propensity score-adjusted Cox proportional hazards models. The relevant variables were included in the propensity score model.
NAC was administered to 149 patients in the CF group and 60 patients in the docetaxel plus CF (DCF) group. Overall, 129 patients treated with CF and 58 patients treated with DCF underwent surgery after NAC. The overall response rate was significantly higher in the DCF group compared with the CF group (61.0 vs. 43.2 %, p = 0.021). After matching, recurrence-free survival did not differ statistically between the CF and DCF groups [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.50-1.37, p = 0.46]. After matching, the improvement in overall survival in the DCF group reached statistical significance (HR 0.49, 95 % CI 0.24-0.999, p = 0.050). No significant differences in rate of locoregional or distant recurrences were observed between the CF and DCF groups (53.0 vs. 48.3 %, p = 0.54).
NAC with DCF is superior to CF in patients with clinical stage III or T3 esophageal squamous cell carcinoma.
Cancer Chemotherapy and Pharmacology 06/2015; 76(2). DOI:10.1007/s00280-015-2806-8 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relative risk of cancer recurrence with postoperative adjuvant FOLFOX/CapeOX therapy(Ox)for stage III colorectal cancer is reduced by approximately 20%when compared to that with fluorouracil plus Leucovorin. We performed a questionnaire survey to evaluate the quality of life(QOL)and extent of side effects in patients who received adjuvant chemotherapy. In order to evaluate the risks and benefits of oxaliplatin administration, we also examined the differences in awareness of oxaliplatin side effects between patients and medical staff. Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Analysis of the patient responses showed higher current QOL scores regardless of the chemotherapy regimen, although patients in the Ox group had a high rate of residual sensory peripheral neuropathy. In the Ox group, 81% of patients responded that the side effects were moderate. In contrast, 40% of medical staff identified the side effects of oxaliplatin as severe, which differed from that reported by the patients. Considering that Ox adjuvant chemotherapy may reduce the risk of recurrence by approximately 20%, the risk/benefit balance is acceptable.
Gan to kagaku ryoho. Cancer & chemotherapy 04/2015; 42(4):457-61.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To identify predictive factors for the development of pericardial effusion (PCE) in oesophageal cancer patients treated with chemotherapy and radiotherapy (RT). Methods: From March 2006 to November 2012, oesophageal cancer patients treated with CRT using the following criteria were evaluated: radiation dose more than 50 Gy; heart included in the radiation field; dose volume histogram (DVH) data available for analysis; no previous thoracic surgery; and no PCE before treatment. The diagnosis of PCE was independently determined by two radiologists. Clinical factors, the percentage of heart volume receiving more than 5-60 Gy in increments of 5 Gy (V5-60, respectively), maximum heart dose, and mean heart dose were analysed. Results: A total of 143 oesophageal cancer patients was reviewed retrospectively. The median follow-up by CT was 15 months (range 2.1 - 72.6 months) after RT. PCE developed in 55 patients (38.5%) after RT, and the median time to develop PCE was 3.5 months (range 0.2 - 9.9 months). On univariate analysis, DVH parameters except for V60 were significantly associated with the development of PCE (p < 0.001). No clinical factor was significantly related to the development of PCE. Recursive partitioning analysis including all DVH parameters as variables showed a V10 cut-off value of 72.8% to be the most influential factor Conclusions: The present results showed that DVH parameters are strong independent predictive factors for the development of PCE in patients with oesophageal cancer treated with CRT. Advances in knowledge: Pericardial effusion, Oesophageal cancer, Radiotherapy, Dose volume histogram.
British Journal of Radiology 11/2014; 88(1046):20140168. DOI:10.1259/bjr.20140168 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adding oxaliplatin to fluorouracil-based chemotherapy can improve the survival of patients with stage III colorectal cancer by approximately 20 %. Reportedly, cancer patients are much more likely to prefer chemotherapy than medical professionals, although there is only a very small chance of achieving benefits from treatment. However, chronic neurotoxicity may be long lasting after the administration of oxaliplatin-based chemotherapy. This study aimed to evaluate potential side effects and differences in attitude between colorectal cancer patients and medical staff regarding the risk-benefit trade-offs of chemotherapy.
Relapse-free colorectal cancer patients who received adjuvant chemotherapy, doctors, and nurses were surveyed using a questionnaire regarding the side effects of chemotherapy and hypothetical clinical scenarios to quantify gains in the risk of relapse that were deemed necessary to make chemotherapy worthwhile.
Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Of these, 39 % of patients and 85 % of doctors replied that moderate side effects of adjuvant chemotherapy were worthwhile to achieve an absolute gain in the risk of relapse of 10 % from a baseline of 40 %. More severe side effects, as reported by colorectal cancer patients, were not associated with the larger gains necessary to make treatment worthwhile. Seven percent of patients treated with oxaliplatin, 40 % of doctors, and 43 % of nurses replied that side effects associated with oxaliplatin-based chemotherapy were severe.
Doctors should consider potential heterogeneity in side effects and attitudes regarding the risk-benefit balance of adjuvant chemotherapy, and that patient perspectives should enhance shared decision-making.
International Journal of Clinical Oncology 11/2014; 20(4). DOI:10.1007/s10147-014-0772-5 · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognostic and predictive values of carbohydrate antigen 19-9 (CA19-9) levels in metastatic colorectal cancer (mCRC) remain unclear. We reviewed all mCRC patients at a single institution to evaluate the relationship between CA19-9 levels and survival.
Two hundred and fifty-two patients underwent first-line chemotherapy using oxaliplatin-based regimens between April 2005 and December 2009. The relationship between baseline CA19-9 levels and survival was analyzed. Moreover, we evaluated the relationship between baseline CA19-9 levels and clinicopathological factors.
One hundred and fifty patients had elevated baseline CA19-9 levels (elevated group), and 79 patients had normal baseline CA19-9 (normal group) levels. Both KRAS and BRAF mutation rates were higher in the elevated group than in the normal group. Elevated CA19-9 level was a poor prognostic factor compared with normal CA19-9 levels (P = 0.0021). In the elevated group, the median survival time with bevacizumab was significantly longer with bevacizumab than without it (median OS, 27.8 vs. 15.3 months, P = 0.0019). However, the median survival time was not different with or without bevacizumab in the normal group (median OS, 36.5 vs. 38.0 months, P = 0.9515).
Our results suggest that baseline CA19-9 level is an independent prognostic factor in mCRC patients, and it correlated with the KRAS/BRAF mutation status. Bevacizumab exhibits clinical activity only for high CA19-9 levels in mCRC.
Cancer Chemotherapy and Pharmacology 12/2013; 73(2). DOI:10.1007/s00280-013-2367-7 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To the best of our knowledge, there have been no reports on the pharmacokinetics and pharmacodynamics during the conversion from continuous intravenous infusion (CII) to transdermal fentanyl administration. The primary objective of the present study was to clarify the pharmacokinetic characteristics during this conversion. A secondary objective was to identify an association between serum albumin and the absorption of fentanyl from the transdermal patch.
A prospective study was conducted from February 2010 to August 2011 that enrolled 19 patients with chronic cancer pain. Patients were classified into 2 study groups according to body mass index and albumin level. All patients received the conversion from CII to transdermal fentanyl using a 2-step taper of CII over 6 hours. Comparisons of efficacy, toxicity, and serum fentanyl concentrations between study groups were analyzed at baseline, 3, 6, 9, 12, 15, 18, and 24 hours after initiation of the conversion.
The dose-adjusted serum fentanyl concentrations for all patients were significantly decreased at 15 to 24 hours after conversion compared with baseline, although pain intensity and the number of rescue events remained stable during the conversion. The dose-adjusted serum fentanyl concentrations at 9 to 24 hours were significantly reduced in the low albumin group compared with the normal albumin group (P<0.05).
Our study demonstrated that the dose-adjusted serum fentanyl concentrations remained relatively stable, and pain intensity and the number of rescue events remained stable during conversion. Hypoalbuminemia was strongly associated with poor absorption of transdermally administered fentanyl.
The Clinical journal of pain 01/2013; 29(6). DOI:10.1097/AJP.0b013e318266f6a5 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Oral mucositis is one of the most common side-effects of 5-fluorouracil (5-FU)-based chemotherapy. The objective of this study was to evaluate the effects of irsogladine maleate (IM) on fluorouracil-induced oral mucositis through a double-blind, placebo controlled trial.Patients and methodsPatients (N = 66) were randomly assigned to receive either placebo or IM (4 mg/day for 14 consecutive days). The incidence and maximum severity of fluorouracil-induced oral mucositis and safety of the irsogladine dosing regimen were evaluated.ResultsA cohort of 33 patients received placebo and 33 patients received IM. The incidence of oral mucositis was significantly lower for IM than for placebo (27% versus 73%; P < 0.001 by chi-square test). Specific adverse events considered related to IM were not found.ConclusionIM significantly reduced the incidence and maximum severity of oral mucositis in patients treated with 5-FU-chemotherapy.
Annals of Oncology 11/2012; 24(4). DOI:10.1093/annonc/mds584 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although there appears to be incomplete cross-resistance between docetaxel and paclitaxel in several types of malignancies, to our best knowledge there have been no available data on this for advanced gastric cancer.
We retrospectively evaluated the efficacy and safety of docetaxel in patients with paclitaxel-resistant advanced gastric cancer. Docetaxel was administered at 50-60 mg/m2 every 3 weeks.
Twenty-one patients were evaluated. All patients had received 2 or more previous chemotherapy regimens. Among the 12 patients with measurable lesions, apparent tumor shrinkage was seen in 1 patient for an overall response rate of 8. 3% and a disease control rate of 33. 3%. Median progression free survival and overall survival of all patients were 2. 6 months and 6. 7 months, respectively. There were no correlations between the progression free survival of docetaxel and the progression free survival of previous paclitaxel and between the progression free survival of docetaxel and taxane-free interval(Spearman's correlation coefficients of ρ=-0. 14 and ρ=-0. 02, respectively). Grade 3/4 neutropenia developed in 8 patients(38%)and Grade 3 febrile neutropenia in 1 patient(4. 8%).
Docetaxel showed modest activity in paclitaxel-resistant advanced gastric cancer patients, and no correlations between previous efficacy of paclitaxel or taxane-free interval were seen.
Gan to kagaku ryoho. Cancer & chemotherapy 10/2012; 39(10):1511-5.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to assess the efficacy of alternating chemoradiation in patients with nasopharyngeal cancer. From 1990-2006, 100 patients with nasopharyngeal cancer were treated with alternating chemoradiation at the Aichi Cancer Center. Of these, 4, 2, 23, 34, 13 and 23 patients were staged as I, IIA, IIB, III, IVA and IVB, respectively. The median radiation doses for primary tumors and metastatic lymph nodes were 66.6 Gy (range, 50.4-80.2 Gy) and 66 Gy (range, 40.4-82.2 Gy), respectively. A total of 82 patients received chemotherapy with both cisplatin and 5-fluorouracil (5-FU), while 14 patients received nedaplatin (CDGP) and 5-FU. With a median follow-up of 65.9 months, the 5-year rates of overall survival (OAS) and progression-free survival (PFS) were 78.1% and 68.3%, respectively. On multivariate analysis (MVA), elderly age, N3, and WHO type I histology proved to be significantly unfavorable prognostic factors of OAS. As for PFS, there were T4, N3, and WHO type I histology in MVA. Acute toxicities of hematologic and mucositis/dermatitis ≥ Grade 3 were relatively high (32%); however, they were well-managed. Late toxicities of ≥ Grade 3 were three (3%) mandibular osteomyelitis and one (1%) lethal mucosal bleeding. Results for alternating chemoradiation for nasopharyngeal carcinoma are promising. In order to improve outcomes, usage of intensity-modulated radiation therapy and application of active anticancer agents are hopeful treatments, especially for groups with poor prognosis factors with WHO type I histopathology, T4 and/or N3 disease.
Journal of Radiation Research 08/2012; 54(1). DOI:10.1093/jrr/rrs071 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hyponatremia associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or renal salt-wasting syndrome (RSWS) after platinum-based chemotherapy is not uncommon. However, no reports of RSWS following taxane monotherapy have been previously published. We report a case of a 63-year-old man with esophageal cancer who developed RSWS after docetaxel administration. He was diagnosed as having esophageal cancer and underwent esophagectomy. This was followed by adjuvant chemoradiotherapy consisting of a total dose of 50 Gy plus cisplatin combined with 5-fluorouracil. Two years after primary treatment, he was admitted to our hospital because of severe pain due to bone metastasis and mediastinal lymph node metastases. Ten days following chemotherapy consisting of nedaplatin and 5-fluorouracil, he experienced severe hyponatremia (113 mEq/L) due to SIADH. Subsequently, 7 days following third-line chemotherapy with docetaxel, he again experienced severe hyponatremia (104 mEq/L), this time due to RSWS. He was treated with a sodium supplement, to which he responded well. He recovered from the hyponatremia episode within a few days without any complications. In summary, treatment with docetaxel may lead to RSWS, even in patients with normal renal function. To the best of our knowledge, this is the first reported case of RSWS related to taxane chemotherapy in esophageal cancer. Oncologists should be aware of the possibility that docetaxel could cause RSWS.
[Show abstract][Hide abstract] ABSTRACT: The 7th edition of the American Joint Committee on Cancer staging system does not include lymph node size in the guidelines for staging patients with esophageal cancer. The objectives of this study were to determine the prognostic impact of the maximum metastatic lymph node diameter (ND) on survival and to develop and validate a new staging system for patients with esophageal squamous cell cancer who were treated with definitive chemoradiotherapy (CRT).
Information on 402 patients with esophageal cancer undergoing CRT at two institutions was reviewed. Univariate and multivariate analyses of data from one institution were used to assess the impact of clinical factors on survival, and recursive partitioning analysis was performed to develop the new staging classification. To assess its clinical utility, the new classification was validated using data from the second institution.
By multivariate analysis, gender, T, N, and ND stages were independently and significantly associated with survival (p < 0.05). The resulting new staging classification was based on the T and ND. The four new stages led to good separation of survival curves in both the developmental and validation datasets (p < 0.05).
Our results showed that lymph node size is a strong independent prognostic factor and that the new staging system, which incorporated lymph node size, provided good prognostic power, and discriminated effectively for patients with esophageal cancer undergoing CRT.
International journal of radiation oncology, biology, physics 03/2012; 84(3):786-92. DOI:10.1016/j.ijrobp.2011.12.069 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to identify clinical and dosimetric factors for the development of radiation pneumonitis (RP) among patients with oesophageal cancer treated with three-dimensional radiotherapy without prophylactic nodal irradiation.
125 patients with oesophageal cancer had undergone dose-volume histogram (DVH) metrics and received chemoradiotherapy (CRT). Several clinical and dosimetric factors with regard to the lung were evaluated as predictive factors for the development of symptomatic RP.
26 patients (20.8%) developed symptomatic RP classified as greater than or equal to Grade 2. By univariate analysis, body weight loss, tumour length, Stage IV, response to treatment and all DVH parameters proved to be significant factors for the development of RP (p < 0.05). By multivariate analysis, Stage IV and all dosimetric factors were independent predictive factors for the development of symptomatic RP (p < 0.05). Recursive partitioning analysis indicated that V10 values of 24.8% or more and Stage IV were associated with higher development of RP (odds ratio 6.53).
Our study demonstrated that severe RP was also developed in patients treated with the minimal radiation field. Stage IV and the dosimetric factors were identified as independent predictive factors for symptomatic RP in oesophageal cancer patients treated with CRT without prophylactic nodal irradiation.
The British journal of radiology 01/2012; 85(1014):813-8. DOI:10.1259/bjr/13604628 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To retrospectively compare docetaxel (DTX) with paclitaxel (PTX) with regard to efficacy and safety in advanced or recurrent esophageal cancer patients who previously received platinum-based chemotherapy.
We retrospectively analyzed 124 advanced or recurrent esophageal cancer patients who had received platinum-based chemotherapy and then received DTX or PTX from April 2006 to November 2010.
Eighty-six patients (69.4%) received DTX and 38 patients (30.6%) received PTX monotherapy. Due to toxicity, dose reduction was needed in 36.0 and 27.8% of patients and treatment was discontinued in 10.5 and 2.6% of patients receiving DTX and PTX, respectively. The objective response (25.7 vs. 10.3%, p = 0.03) and disease control rates (60.0 vs. 34.6%, p = 0.01) were higher in the PTX group than in the DTX group, respectively. There were no significant differences in median progression-free survival (2.1 vs. 3.5 months) and overall survival (6.1 vs. 7.2 months) between the DTX and PTX groups, respectively. Grade 3-4 neutropenia (48.8 vs. 21.1%, p = 0.003) and febrile neutropenia (20.9 vs. 5.3%, p = 0.029) were more frequent in the DTX patients than in the PTX patients, respectively.
Although the efficacy of DTX and PTX for advanced or recurrent esophageal cancer patients after platinum-based chemotherapy was not significantly different in terms of survival, PTX was a more feasible treatment. PTX provided similar efficacy to DTX with less febrile neutropenia.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to evaluate the efficacy of docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy for locally advanced borderline-resectable T4 esophageal cancer.
We retrospectively analyzed data regarding thirty patients with borderline-resectable T4 tumor who received either DCF or cisplatin plus 5-fluorouracil (FP) as induction chemotherapy.
The overall response rate was significantly better for the DCF group than the FP group. In the DCF group, 6/16 patients achieved a grade 2 histological post-chemotherapeutic effect after treatment, compared to 1/14 in FP group. Except for myelotoxicity, no other significant differences in toxicity were observed during induction chemotherapy between groups. The DCF regimen did not result in increased postoperative complications compared to the FP regimen. Postoperative recurrence or distant metastasis was observed in 7/10 of FP patients and 5/12 of DCF patients.
DCF induction chemotherapy may be an option for conversion therapy of initially unresectable, locally advanced esophageal cancer.
Anticancer research 10/2011; 31(10):3535-41. · 1.83 Impact Factor