A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as first-line treatment for advanced colorectal cancer: A Japanese experience

Purpose

This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin in combination with levofolinate and infusion 5-fluorouracil (FOLFOX4) as first-line therapy for Japanese patients with unresectable metastatic colorectal cancer.

Methods

Sixty consecutive patients with histologically confirmed advanced or metastatic colorectal cancer were enrolled in the study. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred.

Results

Two patients were ineligible. Toxicity was evaluated in 60 patients, who had received a part or all of the protocol therapy. A partial response was observed in 20 patients. The overall response rate was 34.5% (95% CI, 22.5%?C48.1%) and the tumor control rate (partial response + stable disease) was 82.8%. The median progression-free survival was 6.9 months (95% CI, 5.1?C9.8 months), and the median overall survival was 31.5 months (95% CI, 18.1?C40.1 months). There were no toxicity-related deaths. Grade 3 or 4 neutropenia occurred in 48.3% of patients and often caused a delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 71.7% of patients.

Conclusion

The results showed good tolerability and efficacy for first-line FOLFOX4 in the treatment of patients with advanced colorectal cancer, indicating the promise of this regimen as first-line therapy for advanced colorectal cancer in the Japanese population.     

Chemotherapy-Associated Liver Injury in Patients with Colorectal Liver Metastases: A Systematic Review and Meta-analysis

Background

Chemotherapy-associated liver injury is a major cause for concern when treating patients with colorectal liver metastases. The aim of this review was to determine the pathological effect of specific chemotherapy regimens on the hepatic parenchyma as well as on surgical morbidity, mortality and overall survival.

Methods

A systematic review of the published literature and a meta-analysis were performed. For each of the variables under consideration, the effects of different chemotherapy regimens were determined by calculation of relative risks by a random-effects model.

Results

Hepatic parenchymal injury is regimen specific, with oxaliplatin-based regimens being associated with grade 2 or greater sinusoidal injury (number needed to harm 8; 95?% confidence interval [CI] 6.4?C13.6), whereas irinotecan-based regimens associated with steatohepatitis (number needed to harm 12; 95?% CI 7.8?C26). The use of bevacizumab alongside FOLFOX reduces the risk of grade 2 or greater sinusoidal injury (relative risk 0.34; 95?% CI 0.15?C0.75).

Conclusions

Chemotherapy before resection of colorectal liver metastases is associated with an increased risk of regimen-specific liver injury. This liver injury may have implications for the functional reserve of the liver for patients undergoing major hepatectomy for colorectal liver metastases.     

Circulating Tumor Cells and Prognosis of Patients with Resectable Colorectal Liver Metastases or Widespread Metastatic Colorectal Cancer: A Meta-Analysis

Background

We performed a systematic review and meta-analysis to investigate the prognostic value of tumor cells in blood (circulating tumor cells [CTCs]) or bone marrow (BM) (disseminated tumor cells) of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer (CRC).

Materials and Methods

The following databases were searched in May 2011: MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cochrane Library. Studies that investigated the association between tumor cells in blood or BM and long-term outcome in patients with metastatic CRC were included. We extracted hazard ratios (HRs) and confidence intervals (CIs) from the included studies and performed random-effects meta-analyses for survival outcomes.

Results

The literature search yielded 16 studies representing 1,491 patients. The results of 12 studies representing 1,329 patients were suitable for pooled analysis. The overall survival (HR, 2.47; 95 % CI 1.74–3.51) and progression-free survival (PFS) (HR, 2.07; 95 % CI 1.44–2.98) were worse in patients with CTCs. The subgroup of studies with more than 35 % CTC-positive patients was the only subgroup with a statistically significant worse PFS. All eight studies that performed multivariable analysis identified the detection of CTCs as an independent prognostic factor for survival.

Conclusion

The detection of CTCs in peripheral blood of patients with resectable colorectal liver metastases or widespread metastatic CRC is associated with disease progression and poor survival.     

Toxicity of Oxaliplatin Plus Fluorouracil/Leucovorin Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer: A Population-Based Study

Background

Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice.

Methods

Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan–Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model.

Results

There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68–2.41; p = 0.439).

Conclusions

Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients’ age alone, but consideration should be given to the capacity of patients to tolerate adverse events.     

Influence of Modern Systemic Therapies as Adjunct to Cytoreduction and Perioperative Intraperitoneal Chemotherapy for Patients With Colorectal Peritoneal Carcinomatosis: A Multicenter Study

Background

To evaluate the role of modern systemic therapies and its role as palliative or curative therapy for patients with colorectal peritoneal carcinomatosis with an emphasis on patient selection with the colorectal Peritoneal Surface Disease Severity Score (PSDSS).

Methods

From three specialized treatment centers, patients with colorectal peritoneal carcinomatosis were identified between December 1988 to December 2009 to receive best supportive care, standard, or modern systemic therapies. Intent was classified as palliative or curative (if treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy). Patients were stratified according to the PSDSS. Survival was estimated by the Kaplan–Meier method.

Results

Palliative and curative treatment achieved a median survival of 9 (95% confidence interval [95% CI] 5.9–12.8) and 38 (95% CI 30.2–45.2) months, respectively (P < 0.001). The type of chemotherapy in the palliative and curative group influenced outcome (P < 0.001, P = 0.011, respectively). In the palliative group, PSDSS I/II had a median survival of 24 (95% CI 15.6–32.6) and PSDSS III/IV had a median survival of 6 (95% CI 4.9–8.0) months (P < 0.001). In the curative group, PSDSS I/II had a median survival of 49 (95% CI 40.0–58.3) and PSDSS III/IV had a median survival of 31 (95% CI 20.4–40.9) months (P = 0.002).

Conclusions

Modern systemic therapies were associated with improved outcome in patients with colorectal peritoneal carcinomatosis treated systemically alone or with cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Preoperative evaluation with the PSDSS may improve patient selection and optimize outcomes.     

A Randomized Phase II Trial of Three Intensified Chemotherapy Regimens in First-Line Treatment of Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases. The METHEP Trial

Purpose

This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC).

Methods

Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25–30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS).

Results

A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively.

Conclusions

FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.     

Patterns of Care, Prognosis, and Survival in Patients with Metastatic Gastrointestinal Stromal Tumors (GIST) Refractory to First-Line Imatinib and Second-Line Sunitinib

Background

Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited.

Methods

Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed.

Results

The three most frequent drugs used in the 3rd-line setting were: nilotinib n?=?67 (29.5%), sorafenib n?=?55 (24.5%), and imatinib n?=?40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6?months [95% confidence interval (95% CI), 3.1?C4.1] and 9.2?months (95% CI, 7.5?C10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC.

Conclusion

In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.     

First-line vs second-line fulvestrant for hormone receptor-positive advanced breast cancer: A post-hoc analysis of the CONFIRM study

ObjectivesThe double-blind, phase III CONFIRM study (NCT00099437) evaluated fulvestrant 500 mg vs fulvestrant 250 mg in postmenopausal women with hormone receptor-positive locally advanced/metastatic breast cancer (LA/MBC). This post-hoc analysis investigated the efficacy and safety of fulvestrant given either first-line or second-line for advanced disease.Materials & methodsProgression-free survival (PFS) and overall survival (OS) with fulvestrant 500 mg vs fulvestrant 250 mg was evaluated using unadjusted log-rank tests in patients treated in the first- (progression during or within 12 months after completing adjuvant endocrine therapy; n = 387) and second-line (following endocrine therapy for LA/MBC; n = 343) settings.ResultsFirst-line fulvestrant 500 mg significantly prolonged PFS vs fulvestrant 250 mg (median PFS 5.6 vs 4.2 months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.64–1.00; p = .047). Median PFS was numerically greater with second-line fulvestrant 500 mg vs fulvestrant 250 mg (7.9 vs 6.3 months; HR 0.80; 95% CI 0.64–1.02; p = .068). At data cut-off (75.5% maturity), median OS with first-line fulvestrant 500 mg was 23.2 vs 22.1 months with fulvestrant 250 mg (HR 0.87; 95% CI 0.70–1.10; p = .251), and 29.2 vs 22.8 months, respectively, in the second-line (HR 0.75; 95% CI 0.58–0.96; p = .020). The safety profile was broadly comparable between dose groups and across treatment lines, and consistent with the overall patient population.ConclusionThe superiority of fulvestrant 500 mg over fulvestrant 250 mg in patients with LA/MBC in CONFIRM was consistent in both the first- and second-line settings for PFS, and numerically greater in both settings for OS.     

Cytoreduction and HIPEC in The Netherlands: Nationwide Long-term Outcome Following the Dutch Protocol

Purpose

This nationwide study evaluated results of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis of colorectal origin in the Netherlands following a national protocol.

Methods

In a multi-institutional study prospective databases of patients with peritoneal carcinomatosis (PC) from colorectal cancer and pseudomyxoma peritonei (PMP) treated according to the Dutch HIPEC protocol, a uniform approach for the CRS and HIPEC treatment, were reviewed. Primary end point was overall survival and secondary end points were surgical outcome and progression-free survival.

Results

Nine-hundred sixty patients were included; 660 patients (69 %) were affected by PC of colorectal carcinoma and the remaining suffered from PMP (31 %). In 767 procedures (80 %), macroscopic complete cytoreduction was achieved. Three-hundred and thirty one patients had grade III–V complications (34 %). Thirty-two patients died perioperatively (3 %). Median length of hospital stay was 16 days (range 0–166 days). Median follow-up period was 41 months (95 % confidence interval (CI), 36–46 months). Median progression-free survival was 15 months (95 % CI 13–17 months) for CRC patients and 53 months (95 % CI 40–66 months) for PMP patients. Overall median survival was 33 (95 % CI 28–38 months) months for CRC patients and 130 months (95 % CI 98–162 months) for PMP patients. Three- and five-year survival rates were 46 and 31 % respectively in case of CRC patients and 77 and 65 % respectively in case of PMP patients.

Conclusions

The results underline the safety and efficacy of cytoreduction and HIPEC for PC from CRC and PMP. It is assumed the uniform Dutch HIPEC protocol was beneficial.     

Multivisceral Resection in Colorectal Cancer: A Systematic Review

Background

The objective of this study was to critically evaluate current literature on outcomes following multivisceral resection (MVR) in colorectal cancer (CRC). Adequate surgical resection with clear margins is imperative in achieving long-term survival in colorectal cancer. Where there is adherence to or invasion of adjacent organs, (MVR) may be needed to achieve complete disease clearance.

Methods

A systematic review of MVR in CRC was performed. Pubmed/Medline and Cochrane databases were searched for English language articles from 1995 to 2012 using a predefined strategy. Retrieved abstracts were independently screened for relevance and data extracted from selected studies by 2 researchers. Results are reported as weighted means.

Results

Included were 22 studies comprising 1575 patients (87.0 % primary colorectal cancer; 13.0 % recurrent, 63.8 % rectal; 36.2 % colon). The most common organs resected were the bladder and reproductive organs. The perioperative mortality was 4.2 % with morbidity of 41.5 % (95 % CI, 40.8–42.2 %). The overall 5-year survival rate was 50.3 % (95 % CI, 49.9–50.8 %). Surgery for recurrence was associated with worse outcomes than primary tumors with 5-year survival 19.5 % (95 % CI, 17.8–21.1 %) for recurrent rectal cancer and primary rectal tumors 5-year overall survival 52.8 % (95 % CI, 52.0–53.8 %). R0 resection was the strongest factor associated with long-term survival.

Conclusions

Multivisceral resection provides the best possibility of long-term survival in locally advanced primary colorectal cancer in which a clear margin has been achieved.     

Hepatic Intra-Arterial Injection of Drug-Eluting Bead, Irinotecan (DEBIRI) in Unresectable Colorectal Liver Metastases Refractory to Systemic Chemotherapy: Results of Multi-Institutional Study

Introduction

Response rates and overall outcome for patients who have failed first-line and in some cases second-line chemotherapy are as low as 12% and 7 months, respectively. The aim of this study is to evaluate the efficacy of hepatic arterial sulfonate hydrogel microsphere (drug-eluting beads), irinotecan preloaded therapy (DEBIRI) in metastatic colorectal cancer refractory to systemic chemotherapy.

Methods

This was a multicenter multinational single-arm study of metastatic colorectal cancer patients who received DEBIRI after failing systemic chemotherapy from 10/2006 to 8/2008. Primary endpoints were safety, tolerance, tumor response rates, and overall survival.

Results

Fifty-five patients who had received prior systemic chemotherapy and who underwent a total of 99 DEBIRI treatments were reviewed. The median number of DEBIRI treatments was 2 (range 1–5), median treatment dose was 100 mg (range 100–200 mg), with total hepatic treatment of 200 mg (range 200–650 mg), with 86% of treatments performed as lobar infusion and 30% of patients treated with concurrent simultaneous chemotherapy. Adverse events occurred in 28% of patients with median grade of 2 (range 1–3) with no deaths at 30 days post procedure. Response rates were 66% at 6 months and 75% at 12 months. Overall survival in these patients was 19 months, with progression-free survival of 11 months.

Conclusions

Hepatic arterial drug-eluting bead, irinotecan (DEBIRI) was safe and effective in treatment of metastatic colorectal cancer (MCC) refractory to multiple lines of systemic chemotherapy. DEBIRI is an acceptable therapy for treatment of metastatic colorectal cancer to the liver.     

Role of Primary Tumor Resection Among Chemotherapy-Treated Patients with Synchronous Stage IV Colorectal Cancer: A Survival Analysis

Introduction

The benefit of an operation to remove the primary tumor among patients with synchronous stage IV colorectal cancer is controversial. This study analyzed the survival benefits associated with primary tumor resection among chemotherapy-treated stage IV colorectal cancer patients.

Methods

The study analyzed 11,716 chemotherapy-treated stage IV colorectal cancer patients in the California Cancer Registry between 1996 and 2007, with follow-up through 2009. Patients were stratified into operation and non-operation groups. Estimates of median overall and colorectal cancer-specific survival were generated.

Results

Patients undergoing operation compared to those who are not had higher median overall and colorectal cancer-specific survival, 21 versus 10 months (p?<?0.0001) and 22 versus 12 months (p?<?0.0001), respectively. Patients who were offered surgery but refused had decreased median overall and colorectal cancer-specific survival when compared to patients who underwent resection, 8 versus 21 months (p?<?0.001) and 7 versus 22 months (p?<?0.001), respectively. In multivariate regression models, patients who underwent resection of primary tumor had improved overall (hazard ratio (HR), 0.42; 95 % confidence interval (CI) 0.40–0.44, p?<?0.0001) and colorectal cancer-specific survival (HR, 0.43; 95 % CI, 0.41–0.45; p?<?0.0001).

Conclusion

Primary tumor resection is associated with improved survival among stage IV chemotherapy-treated colorectal cancer patients.     

The feasibility and potential benefit of preoperative chemotherapy for colorectal liver metastasis (CLM): a single-centered retrospective study

Purposes

The benefit of neo-adjuvant chemotherapy for liver-limited metastatic colorectal cancer is still controversial. This study defined the resectability regardless of the size and number of liver metastases, and attempted curative hepatic resection in all cases.

Methods

Sixty-four patients that tolerated chemotherapy were diagnosed with CLM (colorectal liver metastases) without extrahepatic metastase from January 2007 to November 2010, and received an oxaliplatin-based regimen. This study assessed the resectability after chemotherapy, and the patients were divided in two groups; the resected and unresected group. Sixteen patients underwent hepatic resection without chemotherapy.

Results

Thirty-five patients underwent surgical resection (resected group) and twenty-nine patients were considered unresectable (unresected group). All 35 patients in the resected group safely received oxaliplatin-based chemotherapy safely without serious adverse effects. No serious postoperative complications were observed. The median overall survival (MST) was significantly higher in the resected than in the unresected group (56.93 [95 % CI 38.13–75.73] and 25.07 months [95 % CI 17.87–32.26], respectively; P < 0.001). The median disease-free survival was 20.2 [95 % CI 8.82–31.65] months in the resected group.

Conclusion

Preoperative chemotherapy for CLM is well tolerated and does not increase postoperative complications. Curative surgery with preoperative chemotherapy has the potential to improve the overall survival in patients with CLM.     

The Treatment of Peritoneal Carcinomatosis of Colorectal Cancer with Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Peroperative Chemotherapy (HIPEC) with Oxaliplatin: A Belgian Multicentre Prospective Phase II Clinical Study

Background

Up to 25% of patients with metastatic colorectal cancer (CRC) present with peritoneal carcinomatosis (PC) as the only site of metastases. Complete cytoreductive surgery (CCRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) aims for locoregional disease control and long-term survival. Oxaliplatin is effective for treating advanced CRC. This study assesses the safety and efficacy of CCRS with HIPEC with oxaliplatin for patients with PC of CRC.

Methods

A Belgian prospective multicenter registry was performed to monitor perioperative morbidity and assess mortality, disease-free survival (DFS), and overall survival (OS).

Results

Forty-eight consecutive patients underwent CCRS (R0/1) with HIPEC (male/female ratio 17/31, median age 60?years, range 24?C76?years). Median PC index was 11 (range 1?C22). Median operation time was 460 (range 125?C840)?min, with a median blood loss of 475 (range 2?C6,000)?ml. Thirty-day mortality was 0%. Complication rate (any grade) was 52.1%. Anastomotic leakage occurred in 10.4% of patients, bleeding in 6.3%, and bowel perforation in 2.1%. Median hospital stay was 20 (range 5?C65) days. At median follow-up of 22.7 (range 3.2?C55.7) months, OS was 97.9% [95% confidence interval (CI) 86.1?C99.7] at 1?year and 88.7% (95% CI 73.6?C95.4) at 2?years. DFS at 1?year was 65.8% (95% CI 52.3?C76.2) and 45.5% (95% CI 34.3?C55.9) at 2?years. Median time until recurrence was 19.8?months (95% CI 12?Cupper limit not defined). Only after dichotomizing PC index was a significant difference in OS found between low and high PC index.

Conclusions

CCRS followed by HIPEC with oxaliplatin for PC from CRC can be implemented with acceptable morbidity. Long-term DFS and OS can be achieved in selected patients.     

A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival

Background

Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed.

Methods

A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data.

Results

There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P < 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858, P < 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P < 0.001), were less likely to have ≥2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P < 0.001). There was significant cross-study heterogeneity.

Conclusions

Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.     

The Role of Surgical Resection Following Imatinib Treatment in Patients with Recurrent or Metastatic Gastrointestinal Stromal Tumors: Results of Propensity Score Analyses

Background

Although benefits of surgical resection of residual gastrointestinal stromal tumors (GISTs) after imatinib therapy have been suggested, those benefits over imatinib alone have not been proven. We compared the clinical outcomes of surgical resection of residual lesions after imatinib treatment (S group) with imatinib treatment alone (NS group) in patients with recurrent or metastatic GISTs.

Methods

A total of 134 patients (42 in the S group, 92 in the NS group) with recurrent or metastatic GIST who had stable disease for more than 6 months after responding to imatinib were included.

Results

There were no statistically significant differences in the baseline characteristics of the S and NS groups except for age and number of peritoneal metastases. The median follow-up period was 58.9 months. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the S group compared with the NS group (median PFS: 87.7 vs. 42.8 months, p = 0.001; median OS: not reached vs. 88.8 months, p = 0.001). Multivariate analysis revealed that S group, female sex, KIT exon 11 mutations, and low initial tumor burden were associated with longer PFS, and S group and low initial tumor burden were associated with a longer OS. Even after applying inverse probability of treatment weighting adjustment, the S group demonstrated significantly better outcomes in terms of PFS (HR 2.326; 95 % confidence interval [CI] 1.034–5.236; p = 0.0412) and OS (HR 5.464; 95 % CI 1.460–20.408; p = 0.0117).

Conclusion

Surgical resection of residual lesions after disease control with imatinib is likely to be beneficial to patients with recurrent or metastatic GISTs.     

Irinotecan Drug-Eluting Beads in the Treatment of Chemo-Naive Unresectable Colorectal Liver Metastasis with Concomitant Systemic Fluorouracil and Oxaliplatin: Results of Pharmacokinetics and Phase I Trial

Purpose

The primary objective of this study is to evaluate the safety, tolerance, and pharmacokinetic profile of liver-directed therapy with drug-eluting beads irinotecan (DEBIRI) in combination with systemic modified FOLFOX in the treatment of unresectable liver metastases in chemotherapy-naive patients with colorectal cancer.

Design

DEBIRI, loaded with 100?mg irinotecan (100?C300???m beads), was administered via hepatic artery during the off week of FOLFOX therapy. Primary endpoints were safety, tolerance, systemic dose-limiting toxicities, and pharmacokinetics of systemic irinotecan and its active metabolite SN-38 at each infusion at 1-, 4-, and 24-h post-DEBIRI. Secondary endpoints were response rate and survival.

Results

The ten patients have undergone at least 12 cycles of FOLFOX in combination with at least two DEBIRI bead treatments during the patients?? off week. Pharmacokinetic data has demonstrated minimal detectable levels of irinotecan (18.6, 21, and 18.6?ng/ml) and SN-38 (1.06, 1.47, and 1.55?ng/ml) after the first, second, and third DEBIRI treatments, respectively. Currently, there has been only one severe device-related adverse event, a grade 3 hypertensive episode that required 1?day of observation in the hospital. The initial 9- and 12-month response rates have been 100?% (2 CR, 8 PR). Four (40?%) patients were successfully downstaged to resection and/or ablation with a median overall survival of 15.2?months.

Conclusion

Concomitant DEBIRI and FOLFOX±bevacizumab is safe, with a minimal adverse event rate, no dose-limiting toxicities, and enhanced overall response rate.     

Surgery Is an Essential Component of Multimodality Therapy for Patients with Locally Advanced Esophageal Adenocarcinoma

Background

Experience with neoadjuvant chemoradiation (CXRT) has raised questions regarding the additional benefit of surgery after locally advanced esophageal adenocarcinoma patients achieve a clinical response to CXRT. We sought to quantify the value of surgery by comparing the overall (OS) and disease-free survival (DFS) of trimodality-eligible patients treated with definitive CXRT vs. CXRT followed by esophagectomy.

Methods

We identified 143 clinical stage III esophageal adenocarcinoma patients that were eligible for trimodality therapy. All patients successfully completed neoadjuvant CXRT and were considered appropriate candidates for resection. Patients that were medically inoperable were excluded. Cox regression models were used to identify significant predictors of survival.

Results

Among the 143 patients eligible for surgery after completing CXRT, 114 underwent resection and 29 did not. Poorly differentiated tumors (HR?=?2.041, 95% CI?=?1.235–3.373) and surgical resection (HR?=?0.504, 95% CI?=?0.283–0.899) were the only independent predictors of OS. Patients treated with surgery had a 50 and 54 % risk reduction in overall and cancer-specific mortality, respectively. Median OS (41.2 vs. 20.3 months, p?=?0.012) and DFS (21.5 vs. 11.4 months, p?=?0.007) were significantly improved with the addition of surgery compared to definitive CXRT.

Conclusions

Surgery provides a significant survival benefit to trimodality-eligible esophageal adenocarcinoma patients with locally advanced disease.     

Retrospective Comparison of Triple-sequence Therapies in Metastatic Renal Cell Carcinoma

Background

The optimal sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been defined.

Objective

To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy.

Design, setting and participants

Retrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n = 62) or VEGFi-mTORi-rTKI (n = 41) at two German academic centers.

Intervention

Sequence of systemic targeted treatment.

Outcome measurements and statistical analysis

Response was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression.

Results and limitations

Sequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8–5.4), 4.1 mo (95% CI, 3.4–4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7–8.1) for mTORi treatment (p = 0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p = 0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4–37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4–52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases.

Conclusions

The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.     

Indeterminate Pulmonary Nodules at Colorectal Cancer Staging: A Systematic Review of Predictive Parameters for Malignancy

Background

This study aimed to estimate the prevalence of indeterminate pulmonary nodules and specific radiological and clinical characteristics that predict malignancy of these at initial staging chest computed tomography (CT) in patients with colorectal cancer. A considerable number of indeterminate pulmonary nodules, which cannot readily be classified as either benign or malignant, are detected at initial staging chest CT in colorectal cancer patients.

Methods

A systematic review based on a search in EMBASE, Medline, the Cochrane library and science citation index, PubMed databases, Google scholar, and relevant conference proceedings was performed in cooperation with the Cochrane Colorectal Cancer Group.

Results

A total of 2,799 studies were identified, of which 12 studies met the inclusion criteria. The studies primarily consisted of case series and included a total of 5,873 patients. Of these patients, 9 % (95 % confidence interval [95 % CI] 8.9–9.2 %) had indeterminate pulmonary nodules at chest CT, of which 10.8 % (95 % CI 10.3–11.2 %) turned out to be colorectal cancer metastases at follow-up. Generally, regional lymph node metastasis, and multiple numbers of indeterminate pulmonary nodules were reported to predict malignancy, whereas calcification of the nodules indicated benign lesions.

Conclusion

It was found that 1 in 100 colorectal cancer patients subjected to preoperative staging chest CT will have an indeterminate pulmonary nodule that proves to be metastatic disease. Such a low risk suggests that indeterminate pulmonary nodules should not cause further preoperative diagnostic workup or follow-up besides routine regimens.