Caio Max S. Rocha Lima

Irinotecan Plus Gemcitabine Results in No Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate

PURPOSE This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. RESULTS In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. CONCLUSION IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.

Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy

PURPOSE Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor receptor and multiple other growth factor receptors. We assessed the safety and efficacy of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. PATIENTS AND METHODS Eighty-four patients were enrolled onto this two-stage phase II trial and were stratified by whether they had received prior bevacizumab (n = 43) or not (n = 41). Treatment comprised sunitinib 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. RESULTS By Response Evaluation Criteria in Solid Tumors criteria, one patient, who was in the prior bevacizumab cohort, achieved a partial response, and 13 patients (two in the prior bevacizumab cohort and 11 in the no prior bevacizumab cohort) achieved stable disease lasting > or = 22 weeks. Median time to progression in the prior bevacizumab and bevacizumab-naïve cohorts was 2.2 months (95% CI, 1.9 to 2.3 months) and 2.5 months (95% CI, 2.3 to 3.1 months), respectively, whereas median overall survival time was 7.1 months (95% CI, 4.9 to 10.6 months) and 10.2 months (95% CI, 8.2 to 15.3 months), respectively. The most common adverse events were fatigue, diarrhea, nausea, vomiting, and anorexia. Twenty-six patients (32%) required dose reduction to 37.5 mg/d, and one patient required dose reduction to 25 mg/d. CONCLUSION Sunitinib did not demonstrate a meaningful single-agent objective response rate in colorectal cancer refractory to standard chemotherapy. However, the mechanisms of action and acceptable safety profile of sunitinib warrant further study in combination with standard regimens for metastatic colorectal cancer.

Irinotecan Plus Gemcitabine Induces Both Radiographic and CA 19-9 Tumor Marker Responses in Patients With Previously Untreated Advanced Pancreatic Cancer

PURPOSE This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma.

PURPOSE Treatment of unresectable locally advanced pancreatic cancer (LAPC) usually includes chemotherapy and/or radiation therapy in an attempt to downstage these tumors to the extent of resectability, but outcomes remain poor. Irreversible electroporation (IRE) is an ablative modality that may be useful in this population. The aim of this study was to evaluate the safety of percutaneous IRE in patients with pancreatic adenocarcinoma. MATERIALS AND METHODS IRE was performed in patients with pancreatic cancer whose tumors remained unresectable after, or who were intolerant of, standard therapy. The procedures were all done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS Fifteen IRE procedures were performed in 14 patients (one was treated twice). Three patients had metastatic disease and 11 had LAPC. All patients had received chemotherapy previously, and 11 had received radiation. The median tumor size was 3.3 cm (range, 2.5-7 cm). Immediate and 24-hour postprocedural scans demonstrated patent vasculature in the treatment zone in all patients. Two patients underwent surgery 4 and 5 months after IRE, respectively. Both had margin-negative resections, and one had a pathologic complete response; both remain disease-free after 11 and 14 months, respectively. Complications included spontaneous pneumothorax during anesthesia (n = 1) and pancreatitis (n = 1), and both patients recovered completely. There were no deaths directly related to the procedure. All three patients with metastatic disease at IRE died from progression of their disease. CONCLUSIONS Percutaneous IRE for pancreatic adenocarcinoma is feasible and safe. A prospective trial is being planned.

A phase ii trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer

Objective:nab-Paclitaxel has been shown to disrupt pancreatic cancer stroma and was effective in combination with gemcitabine in a phase I/II trial. This study was designed to determine the efficacy of nab-paclitaxel monotherapy in previously treated pancreatic cancer patients. Methods:In this phase II trial, patients with advanced pancreatic cancer who progressed on gemcitabine-based therapy, received nab-paclitaxel 100 mg/m2 over 30 minutes on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was 6-month overall survival (OS). Secondary endpoints were response rate (by Response Evaluation Criteria In Solid Tumors), progression-free survival, safety, and toxicity profile. Results:Among 19 patients treated, the median age was 61 years, 9 (47%) were male patients and 18 (95%) had stage-IV disease. The primary endpoint of the study was reached with a 6-month OS of 58% [95% confidence interval (95% CI), 33%-76%] and an estimated median OS of 7.3 months (95% CI, 2.8-15.8 mo). The median progression-free survival was 1.7 months (95% CI, 1.5-3.5 mo). One patient had a confirmed partial response and 6 (32%) had stable disease as their best response. Nonhematological toxicities were generally mild with grades 1-2 nausea, anorexia, hypocalcemia, and vomiting occurring in 63%, 47%, 37%, and 26% of patients, respectively. Grades 3-4 neutropenia, neutropenic fever, and anemia occurred in 32%, 11%, and 11% of patients, respectively. Only 2 of 15 available tumors stained positive for secreted protein acid rich in cysteine, and neither of these patients benefited from the therapy. Conclusions:nab-Paclitaxel was well tolerated, and it demonstrated preliminary evidence of activity in a subset of patients who progressed on gemcitabine-based therapy.

5-Fluorouracil-Induced Coronary Vasospasm

BACKGROUND Cardiotoxicity is a rare but well-documented adverse effect of 5-fluorouracil (5-FU). The underlying cause of this side effect of 5-FU is uncertain. METHODS We present a case report of a 63-year-old man treated for metastatic colon cancer who experienced chest pain while being treated with the FOLFIRI regimen. This case report documents coronary artery spasm on catheterization observed with the continuous infusion of 5-FU. RESULTS Cardiac catheterization obtained within 36 hours of the onset of chest pain revealed marked coronary vasospasm in the obtuse marginal coronary artery and a right coronary artery with a critical obstructive atherosclerotic plaque. Electrocardiogram revealed the myocardium area associated with the event was diffuse rather than localized to the right coronary artery. CONCLUSIONS This observation supports the vasospastic hypothesis for 5-FU-induced angina. Although rare, this type of cardiotoxicity with 5-FU is a potentially lethal side effect. Therapy with 5-FU should be discontinued and patients should be promptly treated.

Metastatic Colorectal Cancer: Systemic Treatment in the New Millennium

BACKGROUND Colorectal cancer (CRC) is common in North America. Metastatic disease is present at diagnosis in 30% of the patients, and approximately half of early-stage patients will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic CRC. METHODS The authors review the results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer. RESULTS Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient. In randomized trials, capecitabine was equally effective to bolus 5-FU and LV in the management of metastatic CRC. CONCLUSIONS Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new era of drug development. Anti-angiogenesis drugs, tyrosine kinase inhibitors, and epidermal growth factor blockers are among this new generation of agents with encouraging preliminary data. Randomized trials will determine the impact of these newer agents on survival and quality of life of patients with metastatic CRC.

Phase II Trial of Paclitaxel–Topotecan–Etoposide Followed by Consolidation Chemoradiotherapy for Limited-Stage Small Cell Lung Cancer: CALGB 30002

Purpose: We sought to evaluate the activity and tolerance of the rationally designed sequence of paclitaxel–topotecan–etoposide, a nonplatinum regimen, as induction therapy for limited-stage small-cell lung cancer before combined chemo- and radiotherapy. Patients and Methods: Patients with measurable disease, performance status 0 to 2, no prior therapy, and adequate organ function were eligible. Paclitaxel (110 mg/m2, administered intravenously on day 1), topotecan (1.5 mg/m2, administered orally on days 2 to 4), and etoposide (160 mg/m2, administered orally on days 5 to 7 every 21 days), with filgrastim for two cycles, were followed by chest irradiation to 70 Gy (to postinduction tumor volume) concurrent with carboplatin (area under the curve of 5, administered intravenously on day 1) and etoposide (100 mg/m2 on days 1 to 3 every 21 days) without filgrastim for three cycles (five chemotherapy cycles total). We aimed to determine the response rates to induction and overall therapy, overall and failure-free survival, and toxicity. The primary statistical endpoint was to differentiate between complete response rates of 50 and 70% for the overall treatment program. Results: Between June 2001 and January 2003, 65 patients were enrolled, but one never started therapy, and one was ineligible. Patient characteristics included male/female, 27/36; white/black/other/unknown, 58/3/1/1; median age 62 (range, 38–78); performance status 0/1/2, 27/33/3. Induction chemotherapy resulted in six (10%) complete responses and 35 (56%) partial responses. Overall response to chemoradiotherapy included 27 (43%; 95% confidence interval [CI] 30–56%) complete responses and 24 (38%) partial responses. Median progression-free survival is 12 months (95% CI, 9–15 months). Median overall survival is 20 months (95% CI, 16–24 months). Frequent (>20%) grade 3/4 toxicities during all therapy included neutropenia, febrile neutropenia, anemia, thrombocytopenia, fatigue, and dysphagia. One patient died of febrile neutropenia, one died of febrile neutropenia and typhlitis, and one patient who declined transfusion for anemia died of cardiac ischemia. Conclusions: This treatment regimen has significant activity in limited-stage small-cell lung cancer but did not meet our prospectively defined criteria for further investigation in this setting. The addition of etoposide and the use of a sequenced administration schedule did not seem to improve overall activity beyond our prior experience with a topotecan–paclitaxel doublet.

Gefitinib (ZD1839) in Previously Treated Advanced Non-Small-Cell Lung Cancer: Experience From a Single Institution

BACKGROUND We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor. METHODS Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib. RESULTS The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. CONCLUSIONS In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.

Full dose neoadjuvant FOLFIRINOX is associated with prolonged survival in patients with locally advanced pancreatic adenocarcinoma

BACKGROUND The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. METHODS Between 2008 and 2013, 51 treatment-naïve patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. RESULTS A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2-29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8-45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. CONCLUSIONS FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.