Phase II study of cetuximab with irinotecan for KRAS wild-type colorectal cancer in Japanese patients.

AIM: Cetuximab improves the prognosis for wild-type KRAS metastatic colorectal cancer (MCRC). We evaluated the safety and efficacy of cetuximab in combination with irinotecan in Japanese patients with wild-type KRAS MCRC refractory to irinotecan, oxaliplatin and fluoropyrimidines. METHODS: Cetuximab was administered initially at a dose of 400 mg/m2 , followed by weekly infusions at 250 mg/m2 . Irinotecan was administered every 2 weeks at 150 mg/m2 . Primary endpoint was the incidence of grade 3/4 adverse events; secondary endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), time to treatment failure (TTF), and TTF for irinotecan. RESULTS: Thirty-four patients were enrolled. Grade 3 or 4 toxicities were leucopenia (11.8%), neutropenia (23.5%), anemia (11.8%), fatigue (2.9%), anorexia (2.9%), diarrhea (14.7%) and hypomagnesemia (5.9%). Skin toxicities were as follows (any grade/grade 3): acne (94.2/8.8%), rash (55.9/0%), nail changes (75.5/8.8%) and hand-foot syndrome (55.9/5.9%). Median PFS was 6.0 months (95%CI; 4.7-7.4). Median OS was 12.9 months (95%CI; 10.0-15.9). RR was 26.4%. Median TTF was 5.1 months and median TTF for irinotecan was 5.0 months (95%CI; 4.3-5.6). CONCLUSION: Cetuximab with irinotecan therapy was well tolerated in Japanese patients with wild-type KRAS colorectal cancer refractory to irinotecan, oxaliplatin and fluoropyrimidine, thus demonstrating the feasibility of their usage.

Efficacy of Prophylactic G-CSF in Patients Receiving FOLFIRINOX: A Preliminary Retrospective Study.

OBJECTIVE: Recent guidelines have adopted an incidence of febrile neutropenia (FN) threshold of 20% for the use of prophylactic granulocyte colony-stimulating factor (G-CSF). In a Japanese phase II study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) for Japanese patients with advanced pancreatic cancer, the incidence of FN and severe neutropenia were 24.7% and 77.8%, respectively, without G-CSF prophylaxis. The aim of this retrospective study was to investigate the incidence of FN or severe neutropenia induced by full-dose FOLFIRINOX administration with G-CSF prophylaxis during the first cycle of treatment. METHODS: Patients with advanced pancreatic cancer who received FOLFIRINOX with G-CSF prophylaxis during the first cycle of treatment from January 2014 to August 2014 were investigated and the frequency of adverse events during the first cycle was measured. RESULTS: Among seven patients who received FOLFIRINOX, six patients met the eligibility criteria. The patient characteristics were as follows: median age (range), 57 (50-66); men/women, 3/3; performance status 0/1, 2/4. Grade 3/4 hematological adverse events were as follows: leukopenia in 33% of the patients, neutropenia in 33% of the patients, thrombocytopenia in 33% of the patients and FN in 17% of the patients. One patient was heterozygous for the UGT1A1*6 and UGT1A1*28 polymorphisms and experienced FN. Grade3/4 non-hematological adverse events were as follows: anorexia in 33% of the cases and nausea in 50% of the cases. CONCLUSION: Although the present study was retrospective and small, the simultaneous administration of G-CSF might be effective for the prevention of severe neutropenia and FN in patients treated with FOLFIRINOX.

[A Case of Esophageal Neuroendocrine Carcinoma for Which Irinotecan and Cisplatin Combination Therapy Was Effective].

A 72-year-old previously healthy man visited our hospital with complaints of hoarseness and dysphagia. Computed tomography showed wall thickening of the thoracic esophagus; invasion to the left main bronchus, aorta, and right supraclavicular lymph nodes (LNs); right recurrent nerve LNs; and cardiac LN swelling. Esophagogastroduodenoscopy revealed an elevated tumor in the middle thoracic esophagus, which was similar to a submucosal tumor and had a longitudinal ulcer at its center. Pathologicexamination showed a tumor with a high N/C ratio, and immunohistochemical staining showed the tumor was CD56 and NSE positive, with a Ki-67 index >80%. We diagnosed esophageal neuroendocrine carcinoma (NEC), cT4N3M0, Stage IVa. We started chemotherapy with irinotecan and cisplatin (IP therapy) according to a regimen for small-cell lung cancer. After 3 courses of chemotherapy, the primary lesion and the LN swelling had almost disappeared. Esophageal NEC is relatively rare disease, so there are no standard established treatments. We report a case of esophageal NEC for which IP therapy was effective with the relevant literature cited.

The feasibility of a short bevacizumab infusion in patients with metastatic colorectal cancer.

BACKGROUND: Typically, bevacizumab is initially infused for 90 min, then for 60 min, and subsequently for 30 min. The objective of the present study was to evaluate the safety profile of a short infusion of bevacizumab in Japanese colorectal cancer patients. PATIENTS AND METHODS: The records of 58 patients who received bevacizumab (5 mg/kg) from June 2010 to September 2010 were reviewed. Bevacizumab was administered for 30 min at the first time. If patients had no infusion reaction, the infusion time was shortened to 10 min. RESULTS: None of the 58 patients who received bevacizumab experienced an infusion reaction (95% confidence interval 0-6.2). The only serious adverse event related to bevacizumab infusion was grade 3 proteinuria in 2 patients. CONCLUSION: Short infusion of bevacizumab for 30 min the first time and 10 min is safe and feasible.

Impact of adding cisplatin to S-1 in elderly patients with advanced gastric cancer.

PURPOSE: We retrospectively examined the efficacy and safety of S-1 alone or S-1 plus cisplatin (SP) for elderly patients with advanced gastric cancer because the benefit of adding cisplatin in these patients still remains unclear. PATIENTS AND METHODS: Among 175 patients aged 70 years or older who received S-1 alone or SP as a first-line therapy between April 2000 and November 2010 at our institution, 104 patients who met eligibility criteria were examined. We investigated safety and efficacy of S-1 and SP. RESULTS: Among these 104 patients, 73 patients received S-1 and 31 patients received SP. The median age was 75 years in the S-1 group and 74 years in the SP group. The response rate was 26.3 % in the S-1 group and 44.0 % in the SP group. Major grade 3 or higher adverse events were observed as follows (S-1 vs. SP): nausea (1.4 vs. 16.1 %), anorexia (16.4 vs. 41.9 %), neutropenia (4.1 vs. 35.5 %), and febrile neutropenia (0 vs. 9.7 %). The median overall survival (OS) was 10.4 months in the S-1 group and 17.8 months in the SP group. Treatment of SP and histology of intestinal type were detected as independent, good prognostic factors in multivariate analysis. CONCLUSION: SP might improve OS with some added toxicity compared to S-1 alone in elderly patients with advanced gastric cancer.

Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer.

BACKGROUND/AIM: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. METHODS: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. RESULTS: The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. CONCLUSION: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

A retrospective analysis of periodontitis during bevacizumab treatment in metastatic colorectal cancer patients.

BACKGROUND: Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has showed clinical benefits in patients with metastatic colorectal cancer. Periodontitis has been observed infrequently in bevacizumab-containing chemotherapy in clinical practice. The purpose of this study was to retrospectively investigate bevacizumab-related periodontitis in metastatic colorectal cancer patients. METHODS: From January 2008 to March 2010, 274 patients received bevacizumab-containing chemotherapy at the National Cancer Center Hospital in Tokyo. Patients who had consulted the dentist for periodontitis were included in the study. We examined the interval between the initiation of the first bevacizumab administration and the day of the consultation with the dentist. Periodontitis was evaluated before and after conservative therapy. RESULTS: Twenty-six patients (9.5 % of the 274 metastatic colorectal cancer patients) were included in this study. The median age was 60 years (range 30-79 years). Nineteen (73 %) patients had a good performance status of 0. The combination regimens used with bevacizumab were infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX, 53 %); infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI, 27 %); capecitabine + oxaliplatin (CapeOX, 8 %); S-1 + oxaliplatin (8 %); and S-1 + irinotecan (4 %). The median time from bevacizumab administration to the consultation with a dentist for periodontitis was 69 days (range 12-390 days), and the median number of bevacizumab administrations was 3.5 (range 1-25). After conservative therapy, 22 (85 %) patients with periodontitis showed an improvement. CONCLUSIONS: Periodontitis occurred frequently in patients receiving bevacizumab. The conservative therapy for periodontitis was very effective, and the prophylaxitic treatment was important.

[Comparison of chemotherapy side effects between elderly and young subjects].

UNLABELLED: With the aging of society, the number of elderly patients receiving chemotherapy has increased. Since organ function, particularly the liver and kidney function, is known to decrease with age, there is concern that severe side effects may develop in the elderly because of chemotherapy. It is a considerable challenge to establish safe, effective chemotherapy that enables elderly patients to maintain a favorable QOL. Therefore, we conducted a survey of the current status of chemotherapy side effects. METHODS: The subjects were patients enrolled in physician-led clinical trials between April 2006 and December 2010. A survey of the chemotherapy regimens used, PS, and, side effects(CTC-AE v3.0)was conducted to examine differences in the incidence and Grade of side effects between elderly and younger subjects(aged 65 years or older, and younger than 65 years, respectively). The subjects consisted of9 3 elderly and younger people, with mean ages of 70 and 59. 5 years, respectively. Myelosuppression of Grade 3, or more severe side effects in the elderly and younger subjects, was 22. 5% and 16. 3%, respectively. The incidence of side effects was slightly higher in the elderly than in the younger subjects. In general clinical practice, side effects are controlled by selecting regimens and adjusting doses for the elderly. However, in clinical trials in which the dosage is predetermined regardless of age, the elderly are more prone to develop side effects than young people. We compare and present the current status regarding the side effects, effectiveness, and contents of chemotherapy regimens.

Retroperitoneal fibrosis in a patient with gastric cancer manifested by lower extremity edema and hydrocele.

Herein we report a 57-year-old man with lower extremity edema and swelling in the scrotum who was found to have a periaortic soft tissue mass and hydronephrosis by computed tomography. With the most plausible diagnosis of retroperitoneal fibrosis, corticosteroid therapy was initiated; however, it did not improve his symptoms. Upper gastroscopy performed on day 20 post admission showed ulcerative regions with an irregular border and fusion of thickened rugae at the gastric angle; the diagnosis of gastric adenocarcinoma was confirmed histologically. It is important to always be aware of unrecognized malignancies that are accompanied by retroperitoneal fibrosis.

[Chemotherapy for gastrointestinal cancer in elderly patients].

Since elderly people have decreased renal function along with increased risks for complications of cardiac disorders such as hypertension and decreased physical strength, compared to in younger people, drug therapy for them is associated more with concern about drug-related toxicity. Therefore, dose reduction or discontinuation of drug administration is sometimes considered during earlier stages of therapy. On the other hand, there are some reports suggesting that as long as proper organ function is maintained, the elderly can be treated in the same way as younger people. However, given limited information and depending on the therapeutic goal of each patient, it should be carefully considered whether the same medicinal strategy used for younger patients is appropriate for treating elderly patients or not.

Second-line chemotherapy with irinotecan plus cisplatin after the failure of S-1 monotherapy for advanced gastric cancer.

BACKGROUND: For advanced gastric cancer (AGC), second-line chemotherapy after the failure of S-1 has not yet been established. The present study aimed to retrospectively evaluate the efficacy and safety of irinotecan plus cisplatin (IP) therapy after the failure of S-1 in patients with AGC. METHODS: The subjects included 87 patients with AGC who received IP therapy as second-line chemotherapy. Irinotecan (70 mg/m(2)) was administered by intravenous infusion followed by an intravenous infusion of cisplatin (80 mg/m(2)) on day 1. On day 15, irinotecan (70 mg/m(2)) alone was administered. The treatment was repeated every 4 weeks until disease progression, patient refusal, or severe adverse events. RESULTS: The median patient age was 62 years (range, 39-75 years), and the median number of treatment cycles was 3 (range, 1-9). Out of the 87 patients, 70 were assessable for clinical response. There were 2 complete responses and 18 partial responses. The overall response rate was 28.6% (95% confidence interval [CI], 18.4%-40.6%) and the disease control ratio was 70.0%. The median time to progression and median survival time from the first day of IP therapy were 4.3 months and 9.4 months, respectively. The 1-year survival rate was 34.6%. Severe (grade 3/4) leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 34%, 40%, 28%, and 8% of patients, respectively. Grade 3/4 nonhematologic toxicities included anorexia (17%), febrile neutropenia (10%), diarrhea (6%), fatigue (5%), nausea (2%), and elevated creatinine (1%). CONCLUSIONS: The combination of irinotecan plus cisplatin as second-line chemotherapy for AGC appears to be an effective and feasible treatment option after S-1 failure.

Evaluation of prognostic factors of esophageal squamous cell carcinoma (stage II-III) after concurrent chemoradiotherapy using biopsy specimens.

BACKGROUND: Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. METHODS: The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. RESULTS: The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. CONCLUSIONS: PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT.

[Weekly administration regimen of paclitaxel (PTX) in patient with inoperable or recurrent gastric cancer].

Paclitaxel is one of the new drugs against advanced/recurrent gastric cancer. We report its efficacy and toxicity with weekly administration for advanced/recurrent gastric cancer. We administered 26 patients (postoperative/non-operation=9/17) PTX 80 mg/m(2)by 1-hour intravenous infusion once a week for 3 weeks followed by one week rest. Median PTX administrations were 2.0 cycles (range:1-22). Characteristics of the patients were median age of 62 (range: 37-78) and PS 0/1/2:2/17/7, male/female:18/8. Over grade 3 toxicities did not occur. The overall response rate was 14.3%, and the non-PD rate was 66.8%. Median time to treatment failure was 61 days and median survival time was 221 days. These results suggest that weekly PTX has modest activity with a favorable toxicity profile in patients with advanced/recurrent gastric cancer, and so this regimen may thus might be recommended in an outpatient treatment setting.

[A case of gastric cancer with multiple liver metastases resistant to TS-1 responding to chemotherapy with paclitaxel plus doxifluridine].

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

[Principles of managing chemotherapy-induced nausea and vomiting].

Chemotherapy-induced nausea and vomiting (emesis) can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. For patients treated with emetogenic chemotherapy, it is very important to prevent nausea and vomiting completely. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by numerous factors, including: 1) the specific chemotherapeutic agents used; 2) their dosage; 3) the schedule and route of administration; and 4) individual patient variability. Approximately 70 to 80% of all cancer patients receiving chemotherapy experience emesis, whereas 10% to 44% experience anticipatory emesis. The following general principles are recommended. 1) A 5-HT3 receptor antagonist should be administered prior to each day's 1st dose of moderately or highly emetogenic chemotherapy. 2) Dexamethasone should be administered once daily either orally or intravenously for every day of moderately or highly-emetogenic chemotherapy and for 2-3 days after chemotherapy for regimens that are likely to cause significant delayed-emesis. 3) The most effective way to treat anticipatory nausea and/or vomiting is to prevent it by using optimal antiemetic therapy during every cycle of treatment.