Comparative analysis of perioperative intraperitoneal chemotherapy regimen in appendiceal and colorectal peritoneal carcinomatosis

Background

Perioperative intraperitoneal chemotherapy (PIC) is delivered by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). The relative survival benefits of each or both regimens are explored in this large series of patients undergoing cytoreduction at a single institution.

Methods

Patients with a complete (CCR0) or optimal (CCR1) cytoreduction who received intraperitoneal chemotherapy for appendiceal and colorectal peritoneal carcinomatosis were included for analysis. PIC regimens were delivered according to the treatment protocol. Standardized statistical analyses were performed.

Results

Of 262 patients, 98 patients (37%) had colorectal peritoneal carcinomatosis, 108 patients (41%) had low-grade pseudomyxoma peritonei and 56 patients (21%) had appendiceal peritoneal carcinomatosis. For pseudomyxoma peritonei, recurrence-free survival (RFS) did not vary with PIC regimen, 5-year survival was 86% in the HIPEC and EPIC group and 64% in the HIPEC or EPIC group (P = 0.070). For appendiceal peritoneal carcinomatosis, RFS and overall survival (OS) did not vary with PIC regimen. For colorectal peritoneal carcinomatosis, the median RFS was 33 months in the HIPEC and EPIC group, 19 months in the HIPEC alone group and 20 months in the EPIC alone group (P = 0.046). OS did not vary with PIC regimen.

Conclusion

From our experience, without compromising the perioperative morbidity and mortality, PIC consisting of HIPEC and EPIC appears to be associated with potential survival benefits of improved OS in pseudomyxoma peritonei and RFS in colorectal peritoneal carcinomatosis.     

Surgical Management of Colorectal Peritoneal Metastases: Treatment and Outcomes Compared with Hepatic Metastases

Purpose

The liver and peritoneum are common sites of colorectal metastases. Hepatectomy for colorectal liver metastases (CLM) is considered gold standard treatment. We attempt to compare the survival outcomes for CLM patients after hepatectomy to that of patients with colorectal peritoneal metastases (CPM) who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods

A retrospective review of patients with CPM and CLM who underwent surgery between January 2003 and May 2011 was performed. The overall (OS) and disease-free survivals (DFS) were compared.

Results

There were 22 patients with CPM who underwent CRS and HIPEC and 186 patients who underwent hepatectomy for CLM. Patients with CPM had a 3-year OS of 39 % and DFS of 27.7 %. CLM patients showed a 3-year OS of 58.5 % and a DFS of 28.8 %. Most recurrences for CPM occurred within 2 years, while CLM patients continue to develop systemic recurrences over 3 years, showing a gradual decline in DFS and OS during this period of time.

Conclusion

Our results show that CRS and HIPEC for CPM confer good OS and DFS rates and that the DFS after CRS and HIPEC is comparable to that after hepatectomy for CLM.     

A retrospective analysis of early CA19-9 change in salvage chemotherapy for refractory pancreatic cancer

Purpose

In salvage chemotherapy for refractory pancreatic cancer, early assessment is important to avoid unnecessary toxicities from ineffective chemotherapy. Early CA19-9 change after the first course as a prognostic factor was evaluated in this setting.

Methods

Patients receiving salvage chemotherapy were retrospectively studied. CA19-9 was measured prior to and after the first course. Cox regression analysis was performed for prognostic factors for progression-free survival (PFS) and overall survival (OS), using the landmark method defined as a day of CA19-9 measurement after the first course.

Results

A total of 239 salvage regimens were given in 167 patients. Median PFS and OS were 2.7 and 6.1 months, respectively. Median pretreatment CA19-9 was 2,362 U/mL, and median CA19-9 change after the first course was 17.8 % increase. CA19-9 change was associated with tumor response, and PFS was 1.7 versus 3.5 months and OS was 3.9 and 8.6 months in patients with ≥50 % versus <50 % increase. In the multivariate analyses, CA19-9 increase ≥50 % was prognostic of both PFS and OS (HR 2.28 and 2.50, p < 0.001, respectively).

Conclusion

CA19-9 change after the first course was prognostic of PFS and OS in refractory pancreatic cancer. Early discontinuation should be considered given the palliative setting.     

Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs?

Background

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have demonstrated some dramatic response rate and prolonged progression-free survival (PFS) in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, PFS and overall survival (OS) among those patients who were treated with EGFR TKIs are inconsistent and unpredictable. In this study, we evaluated predictors of clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs.

Methods

A total of 148 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated with either erlotinib or gefitinib as a first-line (n = 10) and a second-line or more treatment (n = 138) were retrospectively reviewed.

Results

The median follow-up duration was 21.9 months (range, 1.1–62.5). The median PFS and OS for a total 148 patients were 10.6 months (95 % CI 9.0–12.2) and 21.8 months (95 % CI 18.5–25.1), respectively. The survival outcomes were similar between the first-line and second-line or more line of treatment of EGFR TKIs (P = 0.512 for PFS, P = 0.699 for OS). Although a high number of metastasis sites (3–6 vs. 1–2) were associated with shorter PFS and OS (median PFS 9.9 vs. 11.9 months, P = 0.019; median OS 16.4 vs. 22.2 months, P = 0.021, respectively) in univariate analysis, but not in multivariate analysis. According to the clinical and molecular markers by multivariate analysis, there were no significant differences in PFS. When PFS was dichotomized by median 11 months for 105 patients treated with EGFR TKIs as second-line therapy, no significant differences in any clinical or molecular features were found between longer PFS and shorter PFS groups.

Conclusions

Despite the inconsistencies in PFS among EGFR mutant patients treated with EGFR TKIs, no significant differences of clinical features were noted, thereby suggesting a need for more understanding of the heterogeneity of underlying biology.     

A retrospective study of S-1 and oxaliplatin combination chemotherapy in patients with refractory pancreatic cancer

Purpose

The aim of this study was to evaluate S-1 and oxaliplatin combination chemotherapy (SOX) in patients with refractory pancreatic cancer (PC).

Methods

Consecutive patients with advanced PC refractory to gemcitabine who were treated with oral S-1 (80 mg/m²) on days 1–14 and intravenous oxaliplatin (100 mg/m²) on day 1 every 3 weeks were studied retrospectively. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety.

Results

Between March 2009 and October 2011, 30 patients were treated with SOX, with a median of two courses (range 1–8). The ORR and DCR were 10.0 and 50.0 %, respectively. Median PFS and OS were 3.4 months (95 % confidence interval [CI] 1.3–5.3) and 5.0 months (95 % CI 3.4–7.4), respectively. The median PFS and OS were 5.6 and 9.1 months in patients receiving S-1 and oxaliplatin as a second-line treatment. Major grade 3 or 4 adverse events included neutropenia (10.0 %), anemia (3.3 %), and diarrhea (6.7 %).

Conclusions

SOX was well tolerated and moderately effective in patients with refractory PC.     

Erlotinib in patients with advanced lung squamous cell carcinoma

Purpose

Erlotinib had proved efficacy in patients with advanced non-small cell lung cancer, especially adenocarcinoma. The aim of this study was to evaluate the efficacy of erlotinib in patients with advanced lung squamous cell carcinoma (LSQC).

Methods

We retrospectively reviewed medical records and serial chest images of consecutive patients who were diagnosed with advanced LSQC and had been treated with erlotinib monotherapy. The primary objective was to evaluate the treatment efficacy and to correlate with patients’ clinical characteristics.

Results

Totally 55 patients were analyzed (42 men and 13 women, median age of 71 years). In 37 patients who had measurable lesions, 6 had partial response and 13 had stable disease, yielding an overall response rate of 16.2 % and disease control rate of 51.4 %. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 2.0 months (95 % confidence interval, 1.5–2.4 months) and 10.4 months (95 % confidence interval, 0.6–20.2 months), respectively. The PFS and OS were significantly longer in patients who had good clinical response (either the tumor achieved partial response or the patients had disease controlled for more than 6 months) than those who did not (median PFS, 13.0 vs. 1.6 months; median OS, 28.3 vs. 4.9 months; both P values <0.01). Patients who never smoked seemed to have better clinical response and longer survival than those who had smoking history (P = 0.077 and 0.086, respectively).

Conclusions

Erlotinib could provide some clinical benefit to patients with advanced LSQC.     

Predictive factors for the efficacy of cetuximab plus chemotherapy as salvage therapy in metastatic gastric cancer patients

Purpose

We performed a retrospective study to evaluate the efficacy of cetuximab plus chemotherapy in metastatic gastric cancer (MGC) patients previously treated with chemotherapy and to investigate potential predictors of treatment efficacy in those patients.

Methods

Thirty-two patients with MGC were included in this study. Cetuximab was delivered, often combined with irinotecan-based chemotherapy. Thirty patients were analyzed for K-ras mutations via direct sequencing of the tumor DNA.

Results

Patients were heavily pretreated with a median number of three previous lines of palliative chemotherapy (56% of the patients were refractory to all of the following drugs: fluoropyrimidines, cisplatin, irinotecan, oxaliplatin, and docetaxel) and 53% of the patients displayed poor performance status. Of 28 response-assessable patients, the overall response rate to cetuximab plus chemotherapy was 3.6% [95% confidence interval (CI) 0–10.5%] and the disease control rate was 28.6%. The median progression-free survival (PFS) was 1.7 months (95% CI 1.3–2.1 months), and the median overall survival (OS) was 3.2 months (95% CI 1.4–5.0 months). Multivariate analyses revealed that skin rash and performance status were significantly associated with PFS and OS. The presence of a K-ras mutation (13.3%) was not associated with either PFS or OS.

Conclusion

Our study suggests that MGC patients with good performance status and skin rash benefit most from salvage cetuximab combined with chemotherapy, even in heavily pretreated status.     

A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme

Background

Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM).

Objectives

To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM.

Patients and methods

Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150–200 mg/m²/day on days 1–5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1–28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%.

Results

Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32–84); median Karnofsky performance status was 80% (range 60–100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3–4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12–38%]. The median time to progression is 15 weeks (95% C.I. 10–20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome.

Conclusion

This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.     

Preoperative platelet–lymphocyte ratio is an independent prognostic marker and superior to carcinoembryonic antigen in colorectal peritoneal carcinomatosis patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Objective

The aim of this study was to examine the prognostic significance of preoperative inflammatory-based indices, platelet–lymphocyte ratio (PLR), neutrophil–lymphocyte ratio (NLR), and carcinoembryonic antigen (CEA) in predicting overall survival (OS) in patients with colorectal peritoneal carcinomatosis (CPC) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods

Sixty patients with pathologically confirmed CPC treated with CRS and HIPEC between 2003 and 2015 were included. Levels of preoperative PLR, NLR, and CEA were recorded. Univariate and multivariate analyses were conducted to identify prognostic factors associated with OS.

Results

Median OS was 36 months (95% CI, 26.6–45.4) and 5-year OS was 40.5% (95% CI, 27.3–51.6%). Preoperative PLR (p = 0.034) and CEA (p = 0.036) were found to be significant prognostic markers of OS, whereas NLR did not affect OS. PLR remained significant on multivariate analysis (hazard ratio, 1.035; 95% CI, 1.027–1.043; p < 0.001).

Conclusion

Our study indicates that preoperative PLR may be used as a prognostic marker in CPC patients undergoing CRS and HIPEC and could be useful in the preoperative setting when selecting patients for surgery. The subset of patients with PLR > 300 have a median OS of 5 months (95% CI, 0–24.6 months), indicating that CRS and HIPEC may not be superior to systemic chemotherapy in this subset of patients.

     

Prognostic significance of circulating tumor cells in advanced non-small cell lung cancer patients treated with docetaxel and gemcitabine

Purpose

To evaluate the association in the change of circulating tumor cell (CTC) levels and clinical outcomes (PFS and OS) in patients with advanced non-small cell lung cancer (NSCLC) treated homogenously with docetaxel and gemcitabine administered every 2 weeks.

Methods

We prospectively evaluated 37 patients for CTC levels at baseline and after 2 months of chemotherapy (before third cycle). Detection was carried out with the CellSearch system.

Results

Nine of the 37 patients (24 %) had ≥2 CTCs at the baseline determination. Median progression-free survival (PFS) was 4.3 months (95 % CI 2.5–8.3) for patients with CTC 0–1 as compared to 9.4 months (95 % CI 1.2–12.2) for those with CTC ≥2 (p = 0.3506). Median overall survival (OS) was 8.1 (95 % CI 2.8–16.3) and 12.2 (95 % CI 1.4–12.2) months for patients with 0–1 CTCs and ≥2 CTCs, respectively (p = 0.7639). Patients with a second CTC quantification were classified as: group 1, CTC = 0–1 at baseline and CTC = 0–1 after second chemotherapy cycle (18 patients); group 2, CTC ≥2 at baseline and CTC = 0–1 after second determination (5 patients). Median PFS was 7.7 and 9.9 months for group 1 and group 2, respectively (p = 0.4467).

Conclusions

CTCs ≥2 at baseline were detected only in 24 % of this group of patients with advanced NSCLC and poor performance status. No significant differences in PFS and OS between patients with or without CTCs at baseline were observed.     

FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study

Purpose

The purpose of this multicenter phase II study was to evaluate the efficacy and safety of a combination of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) plus bevacizumab as first-line chemotherapy in Japanese patients with metastatic colorectal cancer.

Methods

Patients with metastatic colorectal cancer were eligible for enrollment. On day 1 of a 14-day cycle, patients received bevacizumab 5 mg/kg, irinotecan 150 mg/m², and l-leucovorin 200 mg/m² as an intravenous infusion, followed by 5-FU 400 mg/m² as an intravenous bolus and then 5-FU 2,400 mg/m² as an 46-h intravenous infusion. This treatment cycle was repeated. The primary endpoint was progression-free survival (PFS).

Results

We enrolled 40 patients, but one withdrew consent before starting treatment. The remaining 39 patients received a total of 509 cycles of FOLFIRI plus bevacizumab (median 11 per patient; range 1–30). The median PFS was 11.5 months, the median overall survival (OS) was 22.0 months, and the 1-year OS rate was 81.8 %. All 39 patients had adverse events. Grade 3 or 4 neutropenia and stomatitis occurred in 21 (53.9 %) and 4 (10.3 %) patients, respectively.

Conclusion

Our results suggest that FOLFIRI plus bevacizumab is a clinically effective regimen with a manageable toxicity profile as first-line chemotherapy in patients with metastatic colorectal cancer.     

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology)

Purpose

The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC.

Methods

Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint.

Results

Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3–24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %.

Conclusions

Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.     

Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis

Purpose

ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients.

Methods

One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G.

Results

With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485).

Conclusions

There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.     

An open-label single-arm,phase II trial of zalutumumab,a human monoclonal anti-EGFR antibody,in patients with platinum-refractory squamous cell carcinoma of the head and neck

Purpose

Treatment options for patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) are limited. The purpose of this study was to assess the efficacy and safety of zalutumumab in platinum-refractory R/M SCCHN.

Methods

Patients with platinum-refractory R/M SCCHN were enrolled if they had performance status of 0–2, age ≥18 years and adequate organ function. Patients received weekly infusions of zalutumumab individually titrated to a grade 2 skin rash. Primary objective was overall survival (OS), and secondary objectives were efficacy and safety. A subgroup analysis of OS and progression-free survival (PFS) was conducted for various demographic, disease-related and molecular factors.

Results

Ninety patients were enrolled. Twenty-three percent of patients had performance status (PS) 2 and 74 % had distant metastases. Median OS was 5.3 months (95 % CI [4.1, 7.1]), and median PFS was 2.1 months (95 % CI [2.0, 2.6]). Subgroup analysis by ECOG PS revealed median OS of 6.3 months for PS = 0–1 and 2.5 months for PS = 2. Objective response rate was 5.7 %, and disease control rate was 39.8 %. Grade 3–4 adverse events related to zalutumumab were observed in 19 % of patients and included skin rash (5 %), hypomagnesemia (4 %) and pneumonitis (1 %). The frequency of all-cause grade 3–4 AEs was 62 % and included infections (14 %), gastrointestinal disorders (12 %) and hypokalemia (6 %). Two deaths were deemed related to zalutumumab [ClinicalTrials.gov Identifier: NCT00542308].

Conclusions

Zalutumumab showed reasonable efficacy in platinum-refractory R/M SCCHN patients, and dose titration based on skin rash evaluation was feasible.     

Reduced-dose docetaxel for castration-resistant prostate cancer has no inferior impact on overall survival in Japanese patients

Background

In clinical practice, an adapted regimen with dose reduction is applied to castration-resistant prostate cancer (CRPC) treated with docetaxel because of its toxicity. However, there are few reports on the impact of dose reduction on survival.

Methods

Fifty-seven patients with CRPC treated with first-line docetaxel in a single institution from 2005 to 2008 were evaluated retrospectively.

Results

The median follow-up period was 20.5 months. Twenty-eight patients (49 %) received a standard 60 mg/m² regimen (SR), and 29 patients (51 %) received an adapted regimen (AR) with dose reduction. There was no difference in their baseline characteristics. The prostate-specific antigen response rates were not significantly different between the SR and AR groups (50 vs. 62 %, p = 0.36). Progression-free survival (PFS) and overall survival (OS) were also not significantly different between the groups (PFS 5.3 vs. 7.3 months, p = 0.39; OS 26.4 vs. 27.1 months, p = 0.53, respectively). No significant difference in the incidence of grade 3 or 4 adverse events was noted between the groups (89 vs. 83 %, p = 0.70). In multivariate analysis, hemoglobin and alkaline phosphatase were significant predictive factors for OS (hazard ratios 2.81 and 2.39, p = 0.012 and 0.024, respectively).

Conclusions

A reduced-dose regimen of docetaxel has no inferior impact on OS. Further studies on the optimal dose of docetaxel for Japanese patients are required.     

Combination chemotherapy with S-1 plus cisplatin for gastric cancer that recurs after adjuvant chemotherapy with S-1: multi-institutional retrospective analysis

Background

It is unclear whether S-1 plus cisplatin is effective for patients with recurrent gastric cancer after adjuvant S-1 chemotherapy.

Methods

We retrospectively evaluated the efficacy of S-1 plus cisplatin in patients whose gastric cancer recurred after adjuvant S-1 chemotherapy.

Results

In the 52 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 8.1?months, and the median recurrence-free interval (RFI) since the last administration of adjuvant S-1 was 6.4?months. Among the 36 patients with measurable lesions, 7 achieved a complete or partial response, and 13 were evaluated as having stable disease, for an overall response rate of 19.4% and a disease control rate of 55.6%. For all patients, the median progression-free survival (PFS) was 4.8?months, and the median overall survival (OS) was 12.2?months. Compared with patients with an RFI of <6?months (n?=?25), patients with an RFI of ≥6?months (n?=?27) had a significantly higher response rate (5.0 vs. 37.5%, respectively), longer PFS (2.3 vs. 6.2?months, respectively), and longer overall survival (7.3 vs. 16.6?months, respectively). According to a multivariate Cox model including performance status (PS) and reason for discontinuation of adjuvant S-1, an RFI of 6?months was still significantly associated with PFS and OS.

Conclusions

S-1 plus cisplatin is effective for patients with gastric cancer that recurs after adjuvant S-1 chemotherapy, especially for those with an RFI of ≥6?months.     

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial

Backgrounds

In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294).

Methods

HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m² bid for 14 days plus cisplatin 80 mg/m² on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety.

Results

Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6–5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0–17.7) and ORR was 8/30 (26.7%) (95% CI 14.2–44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%).

Conclusions

XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1.

Trial registration

NCT01412294.

     

A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis

Purpose

Gastric cancer with para-aortic lymph node (PAN) involvement is regarded as advanced disease, and only chemotherapy is recommended from the guidelines. In unresectable cases, neoadjuvant chemotherapy could prolong survival if conversion to resectability could be achieved.

Methods

The study was a single-arm phase II trial. Patients who were diagnosed with gastric cancer and PAN involvement (Stations No. 16a2/16b1) were treated with capecitabine and oxaliplatin combination chemotherapy every 3 weeks for a maximum of six cycles. After every two cycles, abdominal computed tomographic scans were repeated to evaluate the response, and surgery was performed at the physician^’s discretion in patients with sufficient tumor response, followed by chemotherapy with the same regimen to complete a total of six cycles. The primary end point was the response rate of the preoperative chemotherapy. The secondary end points were R0 resection rate, progression-free survival (PFS), overall survival (OS), and adverse events.

Results

A total of 48 patients were enrolled. The response rate of the first-line chemotherapy was 49.0 %, and the clinical benefit response was 85.1 %. After a median of four cycles of chemotherapy, 28 patients received surgery (58.3 %). The median PFS and OS of all patients were 10.0 and 29.8 months, respectively. Patients in the surgery group had much longer PFS (18.1 vs. 5.6 mo, P = 0.001) and OS (not reached vs. 12.5 mo, P = 0.016) compared with those in the non-surgery group.

Conclusions

For gastric cancer patients with PAN involvement, neoadjuvant chemotherapy with XELOX demonstrated a good response rate, and a sufficient R0 resection rate, with acceptable toxicities. Further study is needed to confirm the effectiveness of this regimen.     

A phase II study of oxaliplatin in combination with leucovorin and fluorouracil as first-line chemotherapy in patients with metastatic squamous cell carcinoma of esophagus

Purpose

Squamous cell carcinoma is the main histological subtype of esophageal cancer in the east Asia. Oxaliplatin and fluorouracil are active agents for esophageal carcinoma. The aim of this phase II study was to evaluate the efficacy and safety of oxaliplatin, fluorouracil and leucovorin in patients with metastatic esophageal squamous cell carcinoma (ESCC).

Methods

Patients with metastatic ESCC and Eastern Cooperative Oncology Group performance score of 0–2 who had not received prior systemic chemotherapy for metastatic disease were enrolled. Oxaliplatin, 100 mg/m², was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin, 400 mg/m² i.v., was administered as a 2-h infusion followed by fluorouracil (400 mg/m²) i.v. bolus immediately followed by fluorouracil (2,400 mg/m²) as a 46-h continuous infusion on days 1 and 2. Chemotherapy was repeated every 14 days.

Results

Between October 2008 and September 2011, fifty-six patients, with a median age of 59 years, were enrolled in this study. The overall response rate was 23.2 % with a disease control rate of 67.9 %. The median progression-free survival (PFS) was 4.4 months, and the median overall survival (OS) was 7.7 months. Median PFS was significantly longer in patients without liver metastasis than those with liver metastasis (5.4 vs 2.4 months, P = 0.003). Partial response was associated with longer PFS (7.2 vs 2.7 months, P = 0.023) and OS (11.3 vs 7.1 months, P = 0.028). Significant difference in OS was noted between those age >65 and ≤65 years of age (7.9 vs 3.3 months, P = 0.033). Grade 3/4 neutropenia, leucopenia, anemia and thrombocytopenia occurred in 35.7, 28.6, 10.7 and 10.7 % of patients, respectively. The most common non-hematologic toxicities were fatigue, mucositis, nausea/vomiting and peripheral neuropathy, all of which were moderate, reversible and did not require a dose reduction.

Conclusions

Chemotherapy with oxaliplatin, leucovorin and fluorouracil showed moderate antitumor activity in metastatic ESCC and was well tolerated with acceptable myelosuppression, infrequent and reversible non-hematologic toxicities in patients with ESCC.