mFOLFOX6 Therapy Research Articles

An autopsy case of alpha-fetoprotein-producing large duodenal adenocarcinoma.

We report an autopsy case of a large duodenal adenocarcinoma that produced alpha-fetoprotein (AFP). The patient was a man in his 70s with diabetes mellitus. He presented with epigastralgia and was referred to our hospital. Upper gastrointestinal endoscopy and abdominal computed tomography revealed a large tumor of 11cm in diameter in the descending limb of the duodenum. A tumor biopsy showed poorly differentiated adenocarcinoma. Although his carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were within the normal range, his AFP levels were significantly elevated (42,078.4ng/mL). Due to vascular invasion, curative resection was not feasible, and chemotherapy was chosen as the treatment option. After gastrojejunostomy was performed to enable oral intake, one cycle of modified leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) therapy was administered. However, it proved ineffective, and the patient's anorexia gradually worsened. Ultimately, he succumbed to the progression of cancer cachexia. Autopsy findings revealed a 14-cm-long duodenal carcinoma primarily located in the duodenal bulb, with direct invasion into the stomach, pancreas, and liver. A pathological examination confirmed a diagnosis of poorly differentiated adenocarcinoma with AFP production. Duodenal cancer is rare, and AFP-producing duodenal cancer is even rarer, with only 21 reported cases, including our own. We present this autopsy case of AFP-producing duodenal adenocarcinoma and review the cases reported in the relevant literature.

Histological transformation to signet-ring cell carcinoma in a patient with clinically aggressive poorly differentiated adenocarcinoma of the ascending colon after response to chemotherapy plus cetuximab: a case report

BackgroundAlteration of chemosensitivity or tumor aggressiveness in response to chemotherapy has been reported, and liquid biopsy assessment during chemotherapy for colorectal cancers has confirmed the acquisition of mutations in various oncogenes. However, the occurrence of histological transformation seems to be extremely rare in colorectal cancers, and the few existing case reports of this transformation are from lung cancer and breast cancer. In this report, we describe the histological transformation of clinically aggressive scirrhous-type poorly differentiated adenocarcinoma of the ascending colon to signet-ring cell carcinoma in almost all recurrent tumors that were confirmed by autopsy after response to chemotherapy plus cetuximab.Case presentationA 59-year-old woman visited our hospital with whole abdominal pain and body weight loss and was diagnosed with scirrhous-type poorly differentiated adenocarcinoma of the ascending colon with aggressive lymph node metastases. The intrinsic chemosensitivity of the tumors was evident upon initiation of mFOLFOX6 plus cetuximab therapy, and right hemicolectomy was performed, and the tumor obviously remained in the peripancreatic area, paraaortic region, or other retroperitoneal areas. The ascending colon tumors mainly consisted of poorly differentiated adenocarcinoma and were not associated with signet-ring cell components except for minute clusters in a few lymphatic emboli in the main tumor. Chemotherapy was continued, and metastases were eliminated at 8 months after the operation; this response was maintained for an additional 4 months. Discontinuation of chemotherapy plus cetuximab resulted in immediate tumor recurrence and rapid expansion, and the patient died of the recurrent tumor 1 year and 2 months after the operation. Autopsy specimens revealed that almost all of the recurrent tumors exhibited transformation and consisted of signet-ring cell histology.ConclusionThis case might suggest that various oncogene mutations or epigenetic changes resulting from chemotherapy, especially regimens that include cetuximab, contribute to the transformation of non-signet-ring cell colorectal carcinoma to signet-ring cell carcinoma histology and can promote the aggressive clinical progression characteristic of signet-ring cell carcinoma.

Conversion surgery for microsatellite instability-high gastric cancer with a complete pathological response to pembrolizumab: a case report

BackgroundImmune checkpoint inhibitors are reportedly effective in treating microsatellite instability (MSI)-high gastric cancer. There are a few case reports of conversion surgery (CS) with nivolumab but none with pembrolizumab. Herein, we describe a patient with MSI-high gastric cancer who was successfully treated with pembrolizumab and underwent CS with a pathological complete response.Case presentationA 69-year-old man was diagnosed with stage III gastric cancer (T3N2M0) based on contrast-enhanced computed tomography, which revealed a neoplastic lesion and enlarged perigastric lymph nodes in the gastric lesser curvature. The anterior superior lymph node of the common hepatic artery (CHA) was determined to be unresectable due to invasion of the pancreatic head and CHA. Histopathologically, the biopsied tissue showed moderately differentiated adenocarcinoma, then determined to be MSI-high. After three courses of mFOLFOX6 therapy, the patient was diagnosed with progressive disease. Since one course of paclitaxel plus ramucirumab therapy caused grade 3 fatigue, his second-line therapy was switched to pembrolizumab monotherapy. After three courses, the primary tumor and perigastric lymph nodes had shrunk, and it was determined as a partial response. The anterior superior lymph node of the CHA became resectable based on the improvement of infiltration of the pancreatic head and CHA due to shrinkage of the lymph node. Tumor markers remained low; hence, distal gastrectomy plus D2 lymphadenectomy was performed at the end of six courses. Anterior superior lymph node of the CHA was confirmed by intraoperative ultrasonography, and the resection was completed safely. The gross examination of the resected specimen revealed an ulcer scar at the primary tumor site. The histopathological examination showed no viable tumor cell remnants in the primary tumor, which had a grade 3 histological response, and resection margins were negative. The lymph nodes showed mucus retention only in the anterior superior lymph node of the CHA, indicating the presence of metastasis, but no viable tumor cells remained. The patient commenced 6 months of adjuvant pembrolizumab monotherapy 3 months after surgery. Twenty months after surgery, there was no evidence of recurrence.ConclusionsConversion surgery following pembrolizumab monotherapy has a potential utility for the treatment of MSI-high gastric cancer.

Nucleic Acid Metabolizing Enzyme Levels Predict Chemotherapy Effects in Advanced and Recurrent Colorectal Cancer.

Background:Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) predict the effects of fluoropyrimidine. However, the effects of FOLFOX therapy from the perspective of fluorouracil plus leucovorin (FL) remain underexplored. Hence, the relationship between mFOLFOX6 therapy (mFOLFOX6) and therapeutic efficacy was evaluated in patients with advanced/recurrent colorectal cancer (CRC). Methods:Correlations between TS and DPD and primary and metastatic lesions in recurrent CRC were analyzed. Univariate and multivariate analyses of TS and DPD in combination with response rate (RR), progression-free survival (PFS), and overall survival (OS) were performed. Results:A positive correlation between DPD and primary and metastatic lesions; correlations between TS and RR, DPD and RR, and PFS and OS; and significant differences for RR and DPD and TS, PFS and DPD, and OS and DPD were obtained. Conclusion:Nucleic acid metabolizing enzymes in primary lesions can be used to predict mFOLFOX6 efficacy in patients with recurrent CRC.

Risk factors of mFOLFOX6-induced hyperammonemia in patients with colorectal cancer: an observational study.

FOLFOX therapy, a standard treatment for colorectal cancer (CRC), causes a rare, but serious adverse event, hyperammonemia. However, the risk factors of hyperammonemia remain unknown. We examined 74 patients who received mFOLFOX6 therapy with or without biologics for CRC between April 2013 and March 2018 in Yaizu City Hospital. Clinicopathological factors were retrospectively reviewed in association with hyperammonemia, and risk factors of hyperammonemia during mFOLFOX6 therapy were analyzed in 32 patients with the available data. Seven patients developed hyperammonemia, with onset exclusively on day 2 or 3 in the first cycle of therapy. They were treated with branched chain amino acid administration and hydration; however, one patient with stage G4 chronic kidney disease (CKD) died. By multivariate analysis, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was independently associated with hyperammonemia during FOLFOX therapy (odds ratio: 9.0, p = 0.040). Reduced eGFR is considered a risk factor of developing hyperammonemia during FOLFOX therapy. Serum ammonia levels should be monitored especially during the first cycle of FOLFOX therapy in patients with CKD stage G3 or higher.

Protective effect of the oral administration of cystine and theanine on oxaliplatin-induced peripheral neuropathy: a pilot randomized trial

BackgroundOxaliplatin, one of the key cytotoxic drugs for colorectal cancer, frequently causes peripheral neuropathy which leads to dose modification and decreased patients’ quality of life. However, prophylactic or therapeutic measures have not yet been established. Orally administered amino acids, cystine and theanine, promoted the synthesis of glutathione which was one of the potential candidates for preventing the neuropathy. The aim of this study was to determine whether daily oral administration of cystine and theanine attenuated oxaliplatin-induced peripheral neuropathy (OXLIPN).MethodsTwenty-eight colorectal cancer patients who received infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) therapy were randomly and evenly assigned to the cystine and theanine group and the control group. OXLIPN was assessed up to the sixth course using original 7-item questionnaire as well as Common Terminology Criteria for Adverse Events (CTCAE) grading scale.ResultsNeuropathy scores according to our original questionnaire were significantly smaller in the cystine and theanine group at the fourth (p = 0.026), fifth (p = 0.029), and sixth course (p = 0.038). Furthermore, significant differences were also observed in CTCAE neuropathy grades at the fourth (p = 0.037) and the sixth course (p = 0.017). There was one patient in each group who required dose reduction due to OXLIPN. Except for neurotoxicity, no significant differences were noted in the incidence of adverse events, and the total amount of administered oxaliplatin.ConclusionThe results demonstrated the daily oral administration of cystine and theanine attenuated OXLIPN.

JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer

PurposeAdjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer.MethodsTwelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated.ResultsOf the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2).ConclusionsAdjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.

Pathological complete response to mFOLFOX6 plus cetuximab therapy for unresectable colon cancer with multiple paraaortic lymph node metastases.

Pathological complete response is achievable with mFOLFOX6 plus cetuximab therapy for unresectable colorectal cancer with multiple paraaortic lymph node metastases (mCRC) despite right-sided colonic origin. A 62-year-old woman with synchronous paraaortic lymph node metastases of transverse colon cancer was treated with mFOLFOX6 plus cetuximab as first-line therapy. The tumor size was markedly decreased following 6 courses of chemotherapy, and all lymph node metastases had disappeared. The patient then underwent conventional right hemicolectomy with D3 lymph node dissection plus sampling excision of the paraaortic lymph nodes. The pathological diagnosis was a complete response. The patient is currently alive 5 years after surgery with no signs of recurrence. The present study reported the apparent effectiveness of conversion therapy (surgery) with combination treatment with mFOLFOX6 plus cetuximab and radical surgery. We hypothesized that patients with different types of mCRC of right-sided colon origin may be effectively treated with anti-EGFR monoclonal antibodies.

Effect of andecaliximab (anti-MMP9) on proteolysis of IL-7 in vitro, TCR diversity in mice, and serum IL-7 in gastric cancer patients in combination with chemotherapy.

101 Background: Andecaliximab (andeca) is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9). IL-7 selectively enhances the proliferation and survival of naïve, memory, and effector T-cells (but not regulatory T-cells) in the periphery. Previous clinical trials with systemic recombinant IL-7 therapy increased TCR diversity. In the disease setting, elevated circulating IL-7 may be due to a compensatory increase in IL-7 production as demonstrated in mice upon inhibition of IL-7 signaling. Methods: An in vitro screen, in which recombinant active human MMP9 was incubated with &gt; 140 human recombinant folded proteins, identified IL-7 as the most efficient substrate of MMP9. Results: IL-7 proteolysis occurred between A128:L129. IL-7 proteolysis altered the global protein structure, evidenced by a loss of cooperative unfolding observed with intact IL-7 (intrinsic fluorescence, Tm = 59.3o C). Mouse MMP9 proteolyzed mouse IL-7 in vitro. In the orthotopic syngeneic NeuT mouse model, MMP9 inhibition reduced tumor growth (p = 0.0005). In a 7-day NeuT study, anti-MMP9 alone improved TCR diversity (decreased clonality) within tumor-infiltrating T-cells (Dunnett’s p = 0.0083). Further, anti-MMP9 and anti-PDL1 co-treatment promoted an increase in CD3+ cells (p = 0.01), CD4+ T cells (p = 0.006), and CD8+ T cells (p = 0.013) concomitant with a decrease in tumor-associated CD25+ FoxP3+ regulatory T cells (p = 0.04) in the tumor. In gastric cancer patient serum, pro-MMP9 (p &lt; 0.0001), active MMP9 (p &lt; 0.0001), and IL-7 (p &lt; 0.0001) were higher than healthy controls. Serum IL-7 levels were normalized upon treatment with andeca plus mFOLFOX6 (N = 40; FDR-corrected p &lt; 0.001) in a Phase I gastric cancer study. Conclusions: MMP9 proteolyzed IL-7 in vitro. Specific MMP9 inhibition in a mouse tumor model improved TCR diversity. Andeca +mFOLFOX6 therapy normalized serum IL-7 levels, which could be due to andeca, chemotherapy, or disease resolution. The functional implications of IL-7 proteolysis by MMP9 in gastric cancer are currently under investigation.

Comparison between hypersensitivity reactions to cycles of modified FOLFOX6 and XELOX therapies in patients with colorectal cancer

PurposeAlthough hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) therapy are well-documented, few reports have compared different therapies in terms of HSR occurrence. In this study, we compared the frequency and pattern of HSRs to modified FOLFOX6 (mFOLFOX6; 5-fluorouracil, levofolinate calcium and L-OHP infusions) and XELOX (capecitabine and L-OHP) therapies, and sought to identify risk factors associated with HSRs.MethodsPatients who had received mFOLFOX6 or XELOX chemotherapeutic regimens for unresectable colon or rectal cancer or as adjuvant chemotherapy following colon cancer surgery between April 2012 and August 2015 were included. Potential correlation between treatment modalities (regimen, dosage and route of administration of L-OHP, and injection timing for dexamethasone administration) and HSRs was assessed.ResultsAmong the 240 patients included in the study, 136 had received mFOLFOX6 therapy and 104 had received XELOX therapy. Although the frequency of HSRs did not differ between the two groups, incidence of HSRs in the first cycle was higher in the XELOX therapy group. Treatment method or cumulative dosage was not identified as a risk factor for HSR; however, the incidence of ≥grade-2 HSR was higher in cases where the cumulative L-OHP dosage was ≥600 mg/m2 and in patients in whom dexamethasone was not co-infused with L-OHP.ConclusionAlthough HSR rates were comparable among patients treated with mFOLFOX6 and XELOX, HSRs tended to occur more frequently during the first cycle of XELOX therapy as compared to that with mFOLFOX6 therapy. Our findings warrant careful assessment of ≥grade-2 HSRs in patients who are prescribed cumulative L-OHP dosages of ≥600 mg/m2.

MFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)—Study Design and Rationale

BackgroundIn Japan, oxaliplatin (OXA)/5-fluorouracil (5-FU)/leucovorin (LV)—the mFOLFOX6 regimen—is the most frequently used first-line chemotherapy backbone for metastatic colorectal cancer. However, peripheral nerve disorders caused by OXA during mFOLFOX6 therapy can decrease patients' quality of life. OXA can be safely discontinued from a FOLFOX regimen after 6 cycles during first-line therapy. Also, for patients who discontinue OXA without having experienced peripheral nerve disorders, reintroducing OXA in the later stages of treatment could remain an option. Patients and MethodsThe study is a phase II, multicenter, open-label, parallel-group, randomized, controlled exploratory study comparing the efficacy and safety of mFOLFOX6 plus panitumumab and 5-FU/LV plus panitumumab in patients with chemotherapy-naïve, unresectable, advanced or recurrent colorectal carcinoma of RAS wild-type (SAPPHIRE; ClinicalTrials.gov identifier, NCT02337946). Eligible patients will receive 6 cycles of mFOLFOX6 plus panitumumab combination therapy, followed by 1:1 randomization to either further treatment with mFOLFOX6 plus panitumumab or discontinuation of OXA and treatment with 5-FU/LV plus panitumumab. Up to 100 randomized patients will receive treatment for approximately 12 months or until any of the criteria for treatment discontinuation have been met. The primary endpoint is progression-free survival rate at 9 months after the day of randomization. The secondary endpoints are progression-free survival, overall survival, response rate, and interval to treatment failure. Safety will be evaluated according to the incidence and severity of adverse events, including the incidence of peripheral nerve and skin disorders. Additional endpoints will include maintenance of performance status, continuation of OXA in the mFOLFOX6 plus panitumumab group, and continuation of panitumumab in both groups.

P-276 Safety and Efficacy of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Patients with Chemotherapy-Naïve Metastatic Colorectal Cancer (SAPPHIRE)

Background: In Japan, oxaliplatin/5-FU/leucovorin (mFOLFOX6) is the most frequent first-line chemotherapy backbone for metastatic colorectal cancer (mCRC). However, peripheral nerve disorders caused by oxaliplatin (OXA), part of mFOLFOX6 therapy, decrease patients’ quality of life. For patients who discontinue OXA after taking it for a certain period with no peripheral nerve disorders, OXA re-introduction at a later stage may be an option. This "stop and go" OXA approach with 5-FU/leucovorin maintenance was explored in OPTIMOX-1 study and showed similar efficacy as with continuous OXA administration. The present study evaluates the safety and efficacy of mFOLFOX6 plus panitumumab induction with 5-FU/leucovorin+ panitumumab maintenance in first line mCRC patients. Methods: This phase II, multi-center, open-label, randomized, controlled study was designed to evaluate efficacy and safety in patients with chemotherapy-naïve, unresectable, advanced/recurrent KRAS wild-type colorectal cancer after 6 cycles of mFOLFOX6 + panitumumab combination therapy and subsequently assigning them to a group continuing mFOLFOX6 + panitumumab combination therapy (Group A) and a group in which OXA is discontinued and 5-FU/LV + panitumumab combination therapy is provided (Group B). Eligible patients will be treated with 6 cycles of mFOLFOX6 + panitumumab combination therapy. Patients for whom continuation of mFOLFOX6 + panitumumab combination therapy is appropriate on the basis of examination before the 7th cycle and imaging after the 6th cycle will be randomly assigned to either Group A or Group B at a ratio of 1:1. After randomization, Group A or Group B treatment will be continued until the criteria for discontinuation of treatment are met. The primary efficacy endpoint is progression-free survival (PFS) 9 months after the day of randomization. Secondary endpoints include PFS, overall survival, response rate, and time to treatment failure. Safety will be evaluated based on the incidence of adverse events and their severity, including the incidences of peripheral nerve disorders and skin disorders. Enrollment began in September 2014 and 100 pts after randomization will be recruited. The final analysis will be carried out when patients have been followed up for ≥24 months. This Phase II has been planned in order to elucidate the appropriate option for the treatment of mCRC. Clinical trial information: NCT02337946

血液透析患者の大腸癌肝転移にmFOLFOX6+Bevacizumab療法が奏効した1例

血液透析患者の大腸癌肝転移にmFOLFOX6+Bevacizumab療法が奏効した1例

A case of metastatic carcinoma of anal fistula caused by implantation from rectal cancer.

This case involved an 80-year-old man who was seen for melena. Further testing revealed a tubular adenocarcinoma 50 mm in size in the rectum. In addition, an anal fistula was noted behind the anus along with induration. A biopsy of tissue from the external (secondary) opening of the fistula also revealed adenocarcinoma. Nodules suspected of being metastases were noted in both lung fields. The patient was diagnosed with rectal cancer, a cancer arising from an anal fistula, and a metastatic pulmonary tumor, and neoadjuvant chemotherapy was begun. A laparoscopic abdominoperineal resection was performed 34 days after 6 cycles of mFOLFOX-6 therapy. Based on pathology, the rectal cancer was diagnosed as moderately differentiated adenocarcinoma, and this adenocarcinoma had lymph node metastasis (yp T3N2aM1b). There was no communication between the rectal lesion and the anal fistula, and a moderately differentiated tubular adenocarcinoma resembling the rectal lesion was noted in the anal fistula. Immunohistochemical staining indicated that both the rectal lesion and anal fistula were cytokeratin 7 (CK7) (−) and cytokeratin 20 (CK20) (+), and the patient’s condition was diagnosed as implantation of rectal cancer in an anal fistula.In instances where an anal fistula develops in colon cancer, cancer implantation in that fistula must also be taken into account, and further testing should be performed prior to surgery.

Multicenter phase II trial of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer with a T3/T4 tumor FACT trial.

713 Background: The efficacy and safety of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer patients with a T3/T4 tumor is still unknown. Methods: Inclusion criteriain this study are as follows: Stage II/III (Ra/Rb) rectal cancer patients with a T3/T4 tumor. The primary endpoint is preoperative response rate, and the secondary endpoints are histological effect, R0 resection rate, pCR rate, down-staging rate, neoadjuvant therapy completion rate, toxicity, the incidence of postoperative complications, and 3-year disease-free survival. Computed tomography was performed after 4 courses of mFOLFOX6. Patients with disease progression (DP) underwent resection of the primary lesion, while those without DP received another 2 courses of treatment. Treatment was discontinued when resection was not possible in patients with DP. Results: Registered patients totaled 53 with a mean age of 60 (38–77). The number of patients with T3 and T4 tumors was 42 and 10, and patients at stages II and III were 10 and 42, respectively. One patient withdrew due to consent retraction. Median relative dose intensity of mFOLFOX6 therapy was 93.2% for L-OHP, 5-FU, and l-LV. Treatment completion was achieved in 96.2% and 84.6% for 4 and 6 courses, respectively, and withdrawal was due to patient’s discretion, not adverse events. Preoperative response rate was 51%. Surgery was performed in 78.8% of patients. Serious (grade ≥3) toxicity included neutropenia (n=5), leukopenia (n=1), thrombocytopenia (n=1), febrile neutropenia (n=1), nausea (n=1), vomiting (n=1), and peripheral neuropathy (n=2). The rates of R0 resection, pCR, and sphincter preservation were 91.0%, 10.3%, and 82.9%. The down staging rate was calculated as 2%. The median follow-up after surgery was 18.0 months. Median DFS was 17.3 months, and 1-year disease-free survival was 78.8%. Median OS was 22.0 months, and 1-year overall survival was 95.7%. Postoperative complications included suture failure (n=3), wound infection (n=2), pneumonia (n=1), and intestinal obstruction (n=1). Conclusions: Neoadjuvant chemotherapy using mFOLFOX6 is a safe and efficacious treatment option for rectal cancer, especially locally advanced disease. Clinical trial information: UMIN000006583.

MFOLFOX6療法中にたこつぼ型心筋症を発症した進行大腸癌の1例

mFOLFOX6療法中にたこつぼ型心筋症を発症した進行大腸癌の1例

589P - Multicenter Phase Ii Trial of Neoadjuvant Chemotherapy with Mfolfox6 for Stage Ii/Iii Rectal Cancer with a T3/T4 Tumor Fact Trial

ABSTRACT Aim: The efficacy and safety of neoadjuvant chemotherapy with modified FOLFOX6 (mFOLFOX6) for stage II/III rectal cancer patients with a T3/T4 tumor is still unknown. Methods: Inclusion criteria in this multicenter phase II study as follows; Stage II/III (Ra/Rb) rectal cancer patients with a T3/T4 tumor, aged 20–80 years old, Eastern Cooperative Oncology Group performance status of 0–1. A planned patient population set is 50. The primary endpoint is preoperative response rate, and the secondary endpoints are histological effect, R0 resection rate, pCR rate, down-staging rate, neoadjuvant therapy completion rate, toxicity, the incidence of postoperative complications, and 3-year disease-free survival. Computed tomography was performed after 4 courses of mFOLFOX6. Patients with disease progression (DP) underwent resection of the primary lesion, while those without DP received another 2 courses of treatment. Treatment was discontinued when resection was not possible in patients with DP. Results: Registered patients from August 2011 to July 2013 totaled 53 (male n = 41, female n = 12) with a mean age of 60 (38–77). The number of patients with T3 and T4 tumors was 42 and 10, and patients at stages II and III were 10 and 42, respectively. One patient withdrew due to consent retraction. Median relative dose intensity of mFOLFOX6 therapy was 93.2% for L-OHP, 5-FU, and l-LV. Treatment completion was achieved in 96.2% and 84.6% for 4 and 6 courses, respectively, and withdrawal was due to patient's discretion, not adverse events. Preoperative response rate was 51%. Surgery was performed in 78.8% of patients. Serious (grade ≥3) toxicity included neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The rates of R0 resection, pCR, and sphincter preservation were 91.0%, 10.3%, and 82.9%, respectively. The down staging rate was calculated as 2%. Postoperative complications included suture failure (n = 3), wound infection (n = 2), pneumonia (n = 1), and intestinal obstruction (n = 1). Conclusions: In a short period observation, neoadjuvant chemotherapy using mFOLFOX6 is a safe and efficacious treatment option for rectal cancer, especially locally advanced disease. Disclosure: All authors have declared no conflicts of interest.

Modified FOLFOX6 Chemotherapy in Patients with Metastatic Urachal Cancer

Background: To improve the prognosis of patients with urachal cancer and establish an effective chemotherapeutic regimen for distant metastases. Methods: We conducted a retrospective study to evaluate the efficacy and safety of a modified combination of 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) therapy in patients with metastatic urachal cancer. Results: Five patients were treated with mFOLFOX6. Their median age was 65 years (range 41-80). The median follow-up time was 42 months (range 18-46). Two of the 5 patients (40%) showed an objective response: 1 achieved a clinically complete response and 1 a partial response. The grade 3/4 toxicity associated with this regimen was primarily neutropenia, but febrile neutropenia was not observed. Oxaliplatin treatment was discontinued because of a grade 2 allergic reaction in 1 patient. Grade 2 peripheral sensory neuropathy caused by oxaliplatin was observed in 2 patients, and the OPTIMOX (stop and go) approach had to be adopted. Conclusions: mFOLFOX6 appears to be effective for the treatment of metastatic urachal cancer.

Neoadjuvant mFOLFOX6 for stage II/III rectal cancer patients with a T3/T4 tumor.

3554 Background: The efficacy and safety of neoadjuvant modified FOLFOX6 (mFOLFOX6) therapy in stage II/III rectal cancer patients with a T3/T4 tumor is yet to be determined. Methods: Stage II/III ...

The impact of dose reduction and time delay in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer.

631 Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p &lt; 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p &lt; 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p &lt; 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.