A phase II study of capecitabine plus oxaliplatin (XELOX)

Background: Capecitabine and oxaliplatin are both effective and well-tolerated monotherapies for the treatment of advanced colorectal cancer (CRC). Oxaliplatin has also been shown to be very effective when combined with 5-FU/LV in the first-line setting. Aim of the Study: Assess the efficacy and safety of capecitabine plus oxaliplatin (XELOX) in patients with previously untreated advanced CRC. Methods: Fifty-three patients with measurable disease received capecitabine 1,000 mg/m² twice daily on d 1–14 and oxaliplatin 130 mg/m² on d 1, every 3 wk. Of these, 52 were evaluable for safety and 49 for antitumor response. Results: There was a low rate of grade 1/2 adverse events; grade 3/4 events included leukopenia (10%), neutropenia (6%), thrombocytopenia (2%), nausea/vomiting (4%), and diarrhea (4%). The overall response rate was 39% (95% CI, 25–54%) and median time to disease progression was 7.8 mo. Conclusions: XELOX is an active and well-tolerated first-line treatment for advanced CRC. Randomized phase III studies are ongoing to compare XELOX with FOLFOX in view of the comparable efficacy and safety but superior convenience of XELOX therapy.     

Retrospective Comparison of CAPOX and FOLFOX Dose Intensity,Toxicity, and Clinical Outcomes in the Treatment of Metastatic Colon Cancer

Purpose

The treatment of metastatic colon cancer (mCC) utilizes either combination therapies or sequential monotherapy followed by combination therapy in subsequent lines of treatment. Patients often receive therapy consisting of oxaliplatin with intravenous 5-fluoruacil (5-FU) (FOLFOX) or oral capecitabine (CAPOX). A retrospective analysis was performed comparing median dose intensity (MDI), overall survival (OS), progression-free survival (PFS), and toxicity profiles of these two regimens in mCC.

Methods

One hundred twenty-two mCC patients (pts) received either FOLFOX6 (n?=?46) or CAPOX (n?=?76). Age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis were balanced between groups. MDI was compared by calculating a percent of target dose achieved in the average cycle for each patient and taking the median of this value.

Results

Oxaliplatin MDI trended towards being lower in those treated with CAPOX compared to FOLFOX (87.5 vs 93 %, p?=?0.0874), and capecitabine (CA) MDI was significantly lower than 5-FU (82.0 vs 100 %, p?<?0.0001). There was a trend to more dose-limiting toxicities (DLTs) in pts treated with CAPOX (68.42 vs 54.35 %, p?=?0.1268), and grade?≥?2 toxicities were more frequent in CAPOX-treated pts (38.16 vs 15.22 % of patients, p?=?0.0079). Survival analysis demonstrated trends towards improved median OS (9.86 vs 7.46 months, p?=?0.1183) and median PFS (4.34 vs 3.33 months, p?=?0.1674) with CAPOX. In multivariate analysis, CAPOX was associated with improved OS (p?=?0.0156, hazard ratio (HR) 0.559) and disease-free survival (DFS) (p?=?0.0094, HR 0.549).

Conclusions

Patients treated with CAPOX received lower doses of oxaliplatin and fluoropyrimidine compared to FOLFOX and had toxicities of higher grade but did not have worsened clinical outcomes.     

Chemoradiotherapy in the Management of Locally Advanced Squamous Cell Carcinoma Esophagus: Is Surgical Resection Required?

Purpose

The present study aims to evaluate benefit of adding surgery to chemoradiotherapy alone in management of carcinoma esophagus.

Methods

We retrospectively analyzed 45 eligible patients of squamous cell esophageal carcinoma which were enrolled from February 2008 to April 2009. All patients were treated with chemoradiotherapy (50.40 Gy with 40 mg/m² of weekly cisplatin). Tumor response was assessed after 6 weeks of treatment. Patients with resectable disease were subjected to surgical resection (arm A) and remaining was kept on regular clinical follow-up (arm B). Overall survival (OS) was selected as the primary endpoint. The secondary end points were disease-free survival (DFS) and clinical toxicities.

Results

Median follow-up was 13.6 months. Pathological complete response was seen in 60.9 % patients in arm A. In arm B, 77.3 % patients attained radiological complete response (p?=?0.194). The median OS was 16.4 and 19.1 months (p?=?0.388) and median DFS was 5.8 and 4.1 months (p?=?0.347) in arm A and B, respectively. The 2-year survival probability was 39.1 and 36.4 % (p?=?0.387) in arm A and B, respectively. The recurrence probability was 56.5 % (SE?=?5.6 %) and 45.5 % (SE?=?4.2 %) (p?=?0.328) in arm A and B, respectively. The probability of loco regional recurrence was more in arm B than in arm A (p?=?0.002).

Conclusions

The study suggests that there is no difference in clinical toxicity profiles or survival outcomes with either definitive chemoradiotherapy or chemoradiation followed by surgery in management of locally advanced esophageal cancer.     

Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma

Background

The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation.

Methods

This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66?Gy (66?Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60?Gy or twice daily to a total dose of 59.2?Gy (60?Gy RT).

Results

A total of 133 patients received standard 60?Gy RT, while 23 received 66?Gy RT. Patients in the 66?Gy RT group were younger (p?<? 0.001), whereas concomitant temozolomide use was more frequent in the 60?Gy RT group (p?<? 0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66?Gy RT arm versus the 60?Gy RT arm (12.2 versus 7.6?months, p?=?0.011), and this translated to an improved OS (18.8 versus 15.3?months, p?=?0.012). A multivariate analysis revealed a strong association of 66?Gy RT with a prolonged time to ICR (hazard ratio?=?0.498, p?=?0.01) and OS (hazard ratio?=?0.451, p?=?0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p?=?0.008, OS p?=?0.007) and propensity-scored matched pairing (ICR p?=?0.099, OS p?=?0.023).

Conclusion

Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.

     

Splenomegaly in FOLFOX-naïve stage IV or recurrent colorectal cancer patients due to chemotherapy-associated hepatotoxicity can be predicted by the aspartate aminotransferase to platelet ratio before chemotherapy

Background

Chemotherapy-associated hepatotoxicity is a common cause of postoperative complications after major hepatectomy. Splenomegaly may indicate portal hypertension due to chemotherapy. To identify chemotherapy-na?ve patients with liver damage, the splenic volume (SV) and aspartate aminotransferase to platelet ratio (APR) were investigated.

Methods

Seventy-one patients receiving FOLFIRI, FOLFOX, or FOLFOX plus bevacizumab as first-line chemotherapy were included in this study. The SV measurement was performed by helical computed tomography volumetry, and the SV index (SVI) was calculated during 6 cycles of chemotherapy. The APR was used as an indicator of liver injury and the APR index (APRI) was calculated.

Results

The SVI and APRI were significantly higher in the FOLFOX group than in the FOLFIRI group. In the FOLFOX group, the maximum APR during FOLFOX administration was significantly higher in the subjects with SVI?≥??30% than in those with SVI?p?p?Conclusion Splenomegaly due to FOLFOX-associated hepatotoxicity can be predicted if the APR before FOLFOX is 0.17 or higher.     

Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients

Purpose

FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples.

Patients and methods

Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method.

Results

We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively.

Conclusion

The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.     

A randomised phase II trial of two sequential schedules of docetaxel and cisplatin followed by gemcitabine in patients with advanced non-small-cell lung cancer

Purpose

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).

Methods

Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75?mg/m² cisplatin plus 75?mg/m² docetaxel, both administered on day 1 every 21?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm A), or three cycles of 25?mg/m² cisplatin plus 25?mg/m² docetaxel on days 1, 8 and 15 every 28?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm B).

Results

Of the evaluable patients, 61% in arm A (n?=?41) and 36% (n?=?44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3?months in arm A, respectively, 3.1 and 7.7?months in arm B. Grade 3?C4 adverse events were more common in arm A. Grade 3?C4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B).

Conclusions

Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).     

Preoperative Platelet Count Associates with Survival and Distant Metastasis in Surgically Resected Colorectal Cancer Patients

Objective

Platelets have been implicated in cancer metastasis and prognosis. No population-based study has been reported as to whether preoperative platelet count directly predicts metastatic recurrence of colorectal cancer (CRC) patients.

Design

Using a well-characterized cohort of 1,513 surgically resected CRC patients, we assessed the predictive roles of preoperative platelet count in overall survival, overall recurrence, as well as locoregional and distant metastatic recurrences.

Results

Patients with clinically high platelet count (≥400?×?10⁹/L) measured within 1 month before surgery had a significantly unfavorable survival (hazard ratio [HR]?=?1.66, 95 % confidence interval [CI] 1.34–2.05, P?=?2.6?×?10^?6, P _{log rank}?=?1.1?×?10^?11) and recurrence (HR?=?1.90, 1.24–2.93, P?=?0.003, P _{log rank}?=?0.003). The association of platelet count with recurrence was evident only in patients with metastatic (HR?=?2.81, 1.67–4.74, P?=?1.1?×?10^?4, P _{log rank}?=?2.6?×?10^?6) but not locoregional recurrence (HR?=?0.59, 95 % CI 0.21–1.68, P?=?0.325, P _{log rank}?=?0.152). The findings were internally validated through bootstrap resampling (P?<?0.01 at 98.6 % of resampling). Consistently, platelet count was significantly higher in deceased than living patients (P?<?0.0001) and in patients with metastatic recurrence than locoregional (P?=?0.004) or nonrecurrent patients (P?<?0.0001). Time-dependent modeling indicated that the increased risks for death and metastasis associated with elevated preoperative platelet counts persisted up to 5 years after surgery.

Conclusion

Our data demonstrated that clinically high level of preoperative platelets was an independent predictor of CRC survival and metastasis. As an important component of the routinely tested complete blood count panel, platelet count may be a cost-effective and noninvasive marker for CRC prognosis and a potential intervention target to prevent metastatic recurrence.     

Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients

Purpose

The aim of this study is to evaluate the effect of excision repair cross-complementation group 1 (ERCC1) expression on treatment outcomes in advanced biliary tract adenocarcinoma (ABTA) patients treated with platinum-based chemotherapy.

Methods

One hundred and six patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions in South Korea between January 2002 and September 2008. Of 106 patients, 93 were assessed by immunohistochemistry from tissue specimens. Sixty-five patients were treated with cisplatin-based regimens and the other 28 treated with oxaliplatin-based ones.

Results

For total study population, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between ERCC1-negative and ERCC1-positive patients, respectively (4.2 vs. 2.9?months, p?=?0.116; 7.0 vs. 7.8?months, p?=?0.143). In patients treated with cisplatin-based regimens, median PFS and OS were significantly longer in ERCC1-negative group than in ERCC1-positive group, respectively (4.6 vs. 1.9?months, p?=?0.014; 9.1 vs. 7.9?months, p?=?0.017). Disease control rate (DCR) was better in patients with ERCC1 negative than in patients with ERCC1 positive (p?=?0.048). On the other hand, in patients treated with oxaliplatin-containing regimens, median PFS and OS tended to be longer in ERCC1-positive group, but these did not reach statistical significances. Response rate was better in patients with ERCC1 positive (p?=?0.005).

Conclusions

ERCC1 shows a significant prognostic value in ABTA patients treated with cisplatin. A survival benefit was observed in ERCC1-negative patients from cisplatin-containing chemotherapy but not from oxaliplatin-containing ones. The action mechanism of ERCC1 on cisplatin may be different from that on oxaliplatin.     

益气健脾汤联合FOLFOX4方案治疗结直肠癌术后患者的临床研究

Objective

The aim of the study was to observe the clinical efficacy with Yiqi Jianpi decoction combination with FOLFOX4 for the postoperative patients of colorectal cancer (CRC).

Methods

Eighty-five patients were randomly divided into two groups. The treated group (n = 41) received Yiqi Jianpi decoction combined with FOLFOX4 chemotherapy and the control group (n = 44) received FLOFOX4 chemotherapy alone. A treatment course of 6 months was applied to both groups.

Results

The life quality, symptomatic improvement and adverse side effects reducing in the treated group were better than those of the control group.

Conclusion

Yiqi Jianpi decoction combination with FOLFOX4 chemotherapy is effective in the treatment of the postoperative patients with colorectal cancer.     

Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer

Background

Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC.

Methods

The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks.

Results

Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P?=?0.02) and overall (median: 16.6 vs 23.2 months; P?=?0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P?=?0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients.

Conclusions

Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.

     

A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity

Background

This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer.

Methods

Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 3 consecutive weeks every 4?weeks) or a 3-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 2 consecutive weeks every 3?weeks). The primary endpoint was the compliance rate during the first 8?weeks between the two groups.

Results

A total of 90 patients were enrolled. The compliance rate during the first 8?weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p?=?0.92), median progression free survival was 112 and 114?days (p?=?0.82), and median overall survival was 206 and 250?days (p?=?0.84), respectively. Grade 3?? neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p?=?0.82). In contrast, thrombocytopenia (platelet count <70000/mm3) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p?=?0.008). The mean received dose intensity was equal: 588 and 550?mg/m2/week (p?=?0.14).

Conclusions

The 3-week schedule of gemcitabine did not improve the compliance rate during 8?weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. Clinical trial registration number: UMIN ID 974.     

Impact of Preoperative and Postoperative FOLFOX Chemotherapies in Patients with Resectable Colorectal Liver Metastasis

Purpose

Whether the survival benefit of perioperative FOLFOX in patients with liver metastases of colorectal cancer (LMCRC) is provided by preoperative chemotherapy (CT), postoperative CT, or both remains unclear. This study aimed to evaluate, in patients with resectable LMCRC, the survival impact of preoperative and postoperative separately.

Methods

Between 2000 and 2010, the 179 patients (126 men, age 61?±?11 years) with initially resectable LMCRC, who underwent liver resection (LR) and were offered pre- and/or postoperative FOLFOX were included. Twenty-four (13 %) patients did not receive CT, 27(15 %) patients received only preoperative CT, 71 (40 %) patients received only postoperative CT, and 57 (32 %) patients received both pre- and postoperative CT.

Results

Operative morbidity and mortality rates were 19 and 0.6 %, respectively. At 1, 3, and 5 years, OS and DFS rates were 97, 66, 46 and 60, 32, and 24 %, respectively. Postoperative FOLFOX was an independent predictor of increased OS (HR?=?0.55 [95 % CI, 0.35–0.87] p?=?0.01) and DFS (HR?=?0.54 [0.36–0.82] p?=?0.0017), whereas the synchronous onset of the metastasis and the presence of radiographically occult liver metastases were independent predictors of poorer OS. Alternatively, preoperative FOLFOX had no significant influence on OS (HR?=?0.96 [0.57–1.60] p?=?0.83) or DFS (HR?=?1.05 [0.66–1.66] p?=?0.87).

Conclusions

The survival benefit of FOLFOX in patients with resectable LMCRC may be provided by postoperative rather than preoperative administration.     

Modified FOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study

Background

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.

Methods

Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).

Results

Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9?months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).

Conclusion

The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.     

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer

Purpose

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer.

Methods

Patients received continuous, once-daily oral doses of cediranib 20?mg in combination with either cisplatin (60?mg/m² iv day 1) plus S-1 (40?C60?mg bid, days 1?C21) every 5?weeks for a maximum of eight cycles [Arm A]; or cisplatin (80?mg/m² iv, day 1) plus capecitabine (1,000?mg/m² bid, days 1?C14) every 3?weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21?days of cycle 1.

Results

Fourteen patients (Arm A, n?=?6; Arm B, n?=?8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n?=?13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n?=?1; Arm B, n?=?2) partial responses that were ongoing at data cut-off.

Conclusions

Cediranib 20?mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.     

Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)

Background

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.

Patients and Methods

We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman’s rank correlation coefficient.

Results

In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p?=?0.0003; 42.8 vs. 9.0 months, HR 0.40, p?=?0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r _s?=?0.314, p?=?0.027) as well as post-progression survival (PPS) (r _s?=?0.366, p?=?0.017). Interestingly, DpR was moderately associated with OS and PPS (r _s?=?0.587, r _s?=?0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities.

Conclusions

Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

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Phase I pharmacokinetic study of chronomodulated dose-intensified combination of capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer

Purpose

To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC).

Methods

Patients (N?=?18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100?mg/m² on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000?mg) once daily taken at 2400 hours on days 1?C5. Each cycle lasted 14?days.

Results

The MTD of capecitabine was 4,500?mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3?%, and median overall survival was 16.3?months (95?% CI: 11.2?C18.2?months). The maximum plasma concentration (C _max) and area under plasma concentration?Ctime curve from time 0 to infinity (AUC_[0?C??]) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity.

Conclusions

Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.     

Prognostic Significance of Matrix Metalloproteinase-9 (MMP-9) in Stage II Colorectal Carcinoma

Background

Approximately 30% of all colorectal cancer patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well-established that a subgroup of patients with stage II is at high risk for recurrence within their life time and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of matrix metalloproteinase-9 (MMP-9) as a predictor of disease outcome in a series of 202 stage II colorectal cancer (CRC) patients with long-term follow-up.

Methods

The present study comprises a series of 202 patients who underwent bowel resection for stage II CRC at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with MMP-9 antibody.

Results

Forty-eight percent of all CRC samples were positive for MMP-9. There was no significant correlation between MMP-9 expression and age, depth of invasion, and lymph node status. However, MMP-9 expression was significantly related to histological grade (p?=?0.03) and location of the tumor (p?=?0.01), therefore, being lower in high-grade tumors and most intense in carcinomas of the descending colon and rectum. Tumors with high MMP-9 expression showed a higher recurrence rate than tumors with low expression (p?=?0.02). MMP-9 negative tumors had a more favorable disease-free survival (DFS) than those expressing MMP-9 (p?=?0.03). The same was true with disease-specific survival (DSS; p?=?0.02) as well, high expression of MMP-9 being associated with shorter survival rates. In multivariate (Cox) survival analysis, MMP-9 expression proved to be an independent predictor of DFS, but not DSS, which was predicted by age and sex only.

Conclusion

Quantification of MMP-9 expression seems to provide valuable prognostic information in stage II CRC, particularly, in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.     

High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin

Background

Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective.

Methods

A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8?mg and granisetron 3?mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50?mg orally, followed by dexamethasone 20?mg, granisetron 3?mg, and famotidine 20?mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts.

Results

A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P?=?0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2.

Conclusion

Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.     

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.