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ABSTRACT: PURPOSE: To assess the efficacy of 2 different approaches to neoadjuvant chemoradiation for distal rectal cancers. METHODS AND MATERIALS: One hundred six patients with T3/T4 distal rectal cancers were randomized in a phase 2 study. Patients received either continuous venous infusion (CVI) of 5-Fluorouracil (5-FU), 225 mg/m(2) per day, 7 days per week plus pelvic hyperfractionated radiation (HRT), 45.6 Gy at 1.2 Gy twice daily plus a boost of 9.6 to 14.4 Gy for T3 or T4 cancers (Arm 1), or CVI of 5-FU, 225 mg/m(2) per day, Monday to Friday, plus irinotecan, 50 mg/m(2) once weekly × 4, plus pelvic radiation therapy (RT), 45 Gy at 1.8 Gy per day and a boost of 5.4 Gy for T3 and 9 Gy for T4 cancers (Arm 2). Surgery was performed 4 to 10 weeks later. RESULTS: All eligible patients (n=103) are included in this analysis; 2 ineligible patients were excluded, and 1 patient withdrew consent. Ninety-eight of 103 patients (95%) underwent resection. Four patients did not undergo surgery for either disease progression or patient refusal, and 1 patient died during induction chemotherapy. The median time of follow-up was 6.4 years in Arm 1 and 7.0 years in Arm 2. The pathological complete response (pCR) rates were 30% in Arm 1 and 26% in Arm 2. Locoregional recurrence rates were 16% in Arm 1 and 17% in Arm 2. Five-year survival rates were 61% and 75% and Disease-specific survival rates were 78% and 85% for Arm1 and Arm 2, respectively. Five second primaries occurred in patients on Arm 1, and 1 second primary occurred in Arm 2. CONCLUSIONS: High rates of disease-specific survival were seen in each arm. Overall survival appears affected by the development of unrelated second cancers. The high pCR rates with 5-FU and higher dose radiation in T4 cancers provide opportunity for increased R0 resections and improved survival.
International journal of radiation oncology, biology, physics 03/2013; · 4.59 Impact Factor
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Stuart J Wong,
Kathryn Winter,
Neal J Meropol,
Pramila Rani Anne,
Lisa Kachnic,
Asif Rashid,
James C Watson, Edith Mitchell,
Jondavid Pollock,
Robert Jeffrey Lee,
Michael Haddock,
Beth A Erickson,
Christopher G Willett
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ABSTRACT: To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study.
Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m(2)/d Mondays through Friday) and irinotecan (50 mg/m(2) weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m(2)/d Monday through Friday) and oxaliplatin (50 mg/m(2) weekly in five doses) (Arm 2). Surgery was performed 4-8 weeks after chemoRT, and adjuvant chemotherapy 4-6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm.
A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint-the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively.
Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).
International journal of radiation oncology, biology, physics 07/2011; 82(4):1367-75. · 4.59 Impact Factor
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ABSTRACT: The use of induction chemoradiotherapy followed by surgery has been widely used for the treatment of esophageal cancer. The presumed risk of increased postoperative morbidity and mortality with this regimen has led to reluctance to offer this therapy to elderly patients. We compared the perioperative morbidity and mortality of patients 70 years old and older with those of patients younger than 70 who received CRT followed by esophagectomy and sought to identify preoperative risk factors that may predict higher risk of postoperative death or complications.
We identified 260 patients who underwent preoperative chemoradiotherapy followed by esophagectomy. The association of age with postoperative death and complications was evaluated. The Charlson index, prior cardiac history, and diabetes were identified as preoperative risk factors and were evaluated as potential confounders or effect modifiers.
Cardiac disease and the Charlson index were potential modifiers of the effect of age on length of hospital stay (p = 0.08 and p = 0.07, respectively) and postoperative complications (p = 0.1 and p = 0.2) but were not statistically significant. There was a slight nonsignificant decrease in the risk of death in elderly patients after adjustment for the Charlson index (p = 0.2).
No significant differences were detected with respect to morbidity and mortality in elderly patients. The presence of cardiac disease, higher scores on the Charlson index, or diabetes did not significantly influence length of stay, postoperative complications, or postoperative death. Given the potential to improve outcomes, this regimen should not be discounted in elderly patients.
International journal of radiation oncology, biology, physics 11/2010; 80(5):1372-6. · 4.59 Impact Factor
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ABSTRACT: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is approved as monotherapy for the treatment of metastatic colorectal cancer. We evaluated the association of tumor EGFR expression levels with outcomes in patients with chemorefractory metastatic colorectal cancer.
Two phase II, multicenter, single-arm, open-label studies enrolled chemorefractory patients with tumors expressing low/negative (1-9%/<1%; Low/Negative EGFR study) or high (> or =10%; High EGFR study) levels of EGFR. Patients received panitumumab 6 mg/kg every two weeks until disease progression or intolerance. End points included objective response rate (per response evaluation criteria in solid tumors), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses by tumor KRAS status were carried out.
A total of 203 patients (Low/Negative EGFR) and 185 patients (High EGFR) enrolled in the studies. The overall response rate was 5.7% [95% confidence interval (95% CI), 2.6-10.5] in patients with low/negative EGFR and 4.2% (95% CI, 1.6-9.0) in patients with high EGFR; the response rate at week 16 was 4% in both studies (all partial responses). Median PFS times were 8.1 weeks (95% CI, 7.1-12.6), 8.1 weeks (95% CI, 7.4-11.1), and 7.3 weeks (95% CI, 7.1-7.6) in patients with negative, low, and high levels of EGFR expression, respectively. PFS and OS were longer in patients with wild-type KRAS than those with mutant KRAS. As expected, most adverse events were skin related.
These studies confirm previous reports that tumor EGFR expression levels are not associated with efficacy with an anti-EGFR antibody and that anti-EGFR antibody therapy should be limited to those patients whose tumors express wild-type KRAS.
Clinical Cancer Research 03/2010; 16(7):2205-13. · 7.74 Impact Factor
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ABSTRACT: Esophageal carcinoma is an aggressive disease that is often treated with neoadjuvant therapy followed by surgical resection. Diabetes mellitus (DM) has been associated with reduced efficacy of chemoradiation (CRT) in other gastrointestinal cancers. The goal of this study was to determine if DM affects response to neoadjuvant CRT in the management of gastroesophageal carcinoma.
We retrospectively reviewed the esophageal cancer patient databases and subsequently analyzed those patients who received neoadjuvant CRT followed by surgical resection at two institutions, Thomas Jefferson University (TJUH) and Fox Chase Cancer Center (FCCC). Comparative analyses of rates of pathologic complete response rate (pCR) and pathologic downstaging in DM patients versus non-DM patients was performed.
Two hundred sixty patients were included in the study; 36 patients had DM and 224 were non-diabetics. The average age of the patients was 61 years (range 24-84 years). The overall pCR was 26%. The pCR rate was 19% and 27% for patients with DM and without DM, respectively (P = 0.31). Pathologic downstaging occurred in 39% of study patients, including of 33% of DM patients and 40% of non-DM patients (P = 0.42).
Although the current analysis does not demonstrate a significant reduction in pCR rates or pathologic downstaging in patients with DM, the observed trend suggests that a potential difference may be observed with a larger patient population. Further studies are warranted to evaluate the influence of DM on the effectiveness of neoadjuvant CRT in esophageal cancer.
Journal of Surgical Oncology 10/2009; 101(1):43-6. · 2.10 Impact Factor
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Elizabeth Poplin,
Yang Feng,
Jordan Berlin,
Mace L Rothenberg,
Howard Hochster, Edith Mitchell,
Steven Alberts,
Peter O'Dwyer,
Daniel Haller,
Paul Catalano,
David Cella,
Al Bowen Benson
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ABSTRACT: Single-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m(2)/30 minutes versus GEM FDR 1,500 mg/m(2)/150 minutes or GEM 1,000 mg/m(2)/100 minutes/day 1 plus oxaliplatin 100 mg/m(2)/day 2 every 14 days (GEMOX).
This trial included patients with metastatic or locally advanced pancreatic cancer, normal organ function, and performance status of 0 to 2. The study was designed to detect a 33% difference in median survival (hazard ratio [HR] < or = 0.75 for either of the experimental arms) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons.
Eight hundred thirty-two patients were enrolled. The median survival and 1-year survival were 4.9 months (95% CI, 4.5 to 5.6) and 16% for GEM, 6.2 months (95% CI, 5.4 to 6.9), and 21% for GEM FDR (HR, 0.83; stratified log-rank P = .04), and 5.7 months (95% CI, 4.9 to 6.5) and 21% for GEMOX (HR, 0.88; stratified log-rank P = .22). Neither of these differences met the prespecified criteria for significance. Survival was 9.2 months for patients with locally advanced disease, and 5.4 months for those with metastatic disease. Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR. GEMOX caused higher rates of nausea, vomiting, and neuropathy.
Neither GEM FDR nor GEMOX resulted in substantially improved survival or symptom benefit over standard GEM in patients with advanced pancreatic cancer.
Journal of Clinical Oncology 09/2009; 27(23):3778-85. · 18.37 Impact Factor
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ABSTRACT: Irinotecan-based chemotherapy regimens are 1 option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib [BICC-C]) cohort.
In period 1, 430 previously untreated patients with mCRC were randomized in a 3-by-2 design to receive irinotecan plus infusional 5-fluorouracil, and leucovorin (FOLFIRI), irinotecan plus bolus 5-fluorouracil/leucovorin (mIFL), and irinotecan plus oral capecitabine (CapeIRI). In period 2, an additional 117 patients were randomized to receive FOLFIRI or mIFL and bevacizumab. In both periods patients were also randomized to a double-blind treatment with celecoxib or placebo. A secondary analysis was conducted examining the safety and efficacy of these regimens in elderly (age >70 years) versus nonelderly (age <or=70 years) patients.
In period 1, 19.5% of patients were elderly, compared with 24.8% in period 2. Rates of grade 3 and higher toxicity did not differ significantly between age groups in either period by treatment arm, with the exception of asthenia in the FOLFIRI and CapeIRI arms (P = .05 and P = .03, respectively) and dehydration in the CapeIRI arm in period 1 (P = .02). Overall progression-free survival for FOLFIRI in both periods was not statistically different by age. Objective responses and overall survival did not differ by patient age within treatment arms and periods.
Irinotecan/fluoropyrimidine combinations are well tolerated in the elderly population, with similar efficacy to that found in nonelderly patients in first-line mCRC.
Cancer 05/2009; 115(12):2617-29. · 4.77 Impact Factor
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George P Kim,
Daniel J Sargent,
Michelle R Mahoney,
Kendrith M Rowland,
Philip A Philip, Edith Mitchell,
Abraham P Mathews,
Tom R Fitch,
Richard M Goldberg,
Steven R Alberts,
Henry C Pitot
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ABSTRACT: The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated.
Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m(2) every 3 weeks) or arm B (FOLFOX4).
A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias.
In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.
Journal of Clinical Oncology 05/2009; 27(17):2848-54. · 18.37 Impact Factor
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J Randolph Hecht, Edith Mitchell,
Tarek Chidiac,
Carroll Scroggin,
Christopher Hagenstad,
David Spigel,
John Marshall,
Allen Cohn,
David McCollum,
Philip Stella,
Robert Deeter,
Seta Shahin,
Rafael G Amado
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ABSTRACT: Panitumumab, a fully human antibody targeting the epidermal growth factor receptor, is active in patients with metastatic colorectal cancer (mCRC). This trial evaluated panitumumab added to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment for mCRC.
Patients were randomly assigned within each chemotherapy cohort to bevacizumab and chemotherapy with or without panitumumab 6 mg/kg every 2 weeks. The primary end point was progression-free survival (PFS) within the oxaliplatin cohort. Tumor assessments were performed every 12 weeks and reviewed centrally.
A total of 823 and 230 patients were randomly assigned to the oxaliplatin and irinotecan cohorts, respectively. Panitumumab was discontinued after a planned interim analysis of 812 oxaliplatin patients showed worse efficacy in the panitumumab arm. In the final analysis, median PFS was 10.0 and 11.4 months for the panitumumab and control arms, respectively (HR, 1.27; 95% CI, 1.06 to 1.52); median survival was 19.4 months and 24.5 months for the panitumumab and control arms, respectively. Grade 3/4 adverse events in the oxaliplatin cohort (panitumumab v control) included skin toxicity (36% v 1%), diarrhea (24% v 13%), infections (19% v 10%), and pulmonary embolism (6% v 4%). Increased toxicity without evidence of improved efficacy was observed in the panitumumab arm of the irinotecan cohort. KRAS analyses showed adverse outcomes for the panitumumab arm in both wild-type and mutant groups.
The addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy results in increased toxicity and decreased PFS. These combinations are not recommended for the treatment of mCRC in clinical practice.
Journal of Clinical Oncology 01/2009; 27(5):672-80. · 18.37 Impact Factor
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Steven J Cohen,
Cornelis J A Punt,
Nicholas Iannotti,
Bruce H Saidman,
Kert D Sabbath,
Nashat Y Gabrail,
Joel Picus,
Michael Morse, Edith Mitchell,
M Craig Miller,
Gerald V Doyle,
Henk Tissing,
Leon W M M Terstappen,
Neal J Meropol
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ABSTRACT: As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC.
In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique.
Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P < .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors.
The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.
Journal of Clinical Oncology 07/2008; 26(19):3213-21. · 18.37 Impact Factor
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ABSTRACT: Identifying predictive biomarkers is important to optimally treat patients. This analysis evaluated the association of K-ras, BRAF, and PIK3CA gene mutations with tumor resistance to panitumumab alone.
From 3 phase II panitumumab metastatic colorectal cancer (mCRC) studies, 62 of 533 patient samples were available. Mutations were identified from genomic DNA by sequencing.
Of the 62 samples, 24 (38.7%) harbored a K-ras mutation, and 38 (61.3%) were wild type. In the wild-type K-ras group, 11% of patients had a partial response (PR), 53% had stable disease (SD), and 37% had progressive disease (PD). In the mutant K-ras group, 21% of patients had SD, and 79% of patients had PD; there were no responses. The absence of a K-ras mutation was associated with response to panitumumab (PR vs. SD vs. PD; P = .0028). The hazard ratio for wild-type versus mutant K-ras was 0.4 (95% CI, 0.2-0.7) for progression-free survival and 0.5 (95% CI, 0.3-0.9) for overall survival. Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation.
These data suggest that patients with mCRC with activating K-ras mutations are less likely to respond to panitumumab alone. The small sample size limits us from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.
Clinical Colorectal Cancer 06/2008; 7(3):184-90. · 1.68 Impact Factor
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Charles S Fuchs,
John Marshall, Edith Mitchell,
Rafal Wierzbicki,
Vinod Ganju,
Mark Jeffery,
Joseph Schulz,
Donald Richards,
Raoudha Soufi-Mahjoubi,
Benjamin Wang,
José Barrueco
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ABSTRACT: This phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI).
A total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity.
Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev.
FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.
Journal of Clinical Oncology 11/2007; 25(30):4779-86. · 18.37 Impact Factor
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ABSTRACT: To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.
Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.
An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.
These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.
Journal of Clinical Oncology 10/2006; 24(25):4069-77. · 18.37 Impact Factor
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ABSTRACT: To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a randomized phase II study
Patients with clinical T3/T4 distal rectal cancers were randomly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection. Patients were randomly assigned to receive continuous venous infusion (CVI) fluorouracil (FU) 225 mg/m2 per day, 7 days per week, plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid (arm 1) or CVI FU 225 mg/m2 per day Monday to Friday, 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day (arm 2). Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy. The primary end point of this study was pathologic complete response (pCR). Secondary end points included acute and late normal tissue morbidity.
A total of 106 patients were entered onto the study, with 103 assessable for response. The overall resectability rate was 93%. The median time to surgery was 7 weeks. Tumor downstaging was observed in 78% of patients in both arms. The pCR rate for all assessable patients was 26% in each arm. For patients who had surgery, the pCR rate was also the same (28%) in both arms. Acute and late toxicity was also similar. Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13% and 38% in arm 1 and 12% and 45% in arm 2, respectively.
Although the overall complete response rate and toxicity seems similar in both arms, this is the first multi-institutional study to establish a relatively high (28%) pCR rate after neoadjuvant therapy.
Journal of Clinical Oncology 03/2006; 24(4):650-5. · 18.37 Impact Factor
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ABSTRACT: As genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations is increasingly integrated into the clinical management of high-risk women, it will be important to understand barriers and motivations for genetic counseling among women from underserved minority groups to ensure equitable access to these services. Therefore, the purpose of this review was to synthesize literature on knowledge and attitudes about genetic counseling and testing for inherited breast cancer risk in African Americans. We also review studies that evaluated genetic testing intentions in this population. We conducted a search of the PubMed database to identify studies related to BRCA1/2 testing in African Americans that were published between 1995 and 2003. Overall, studies have evaluated ethnic differences in knowledge and attitudes about genetic testing or have compared African American and Caucasian women in terms of genetic testing intentions. These studies have shown that knowledge about breast cancer genetics and exposure to information about the availability of testing is low among African Americans, whereas expectations about the benefits of genetic testing are endorsed highly. However, much less is known about the psychological and behavioral impact of genetic testing for BRCA1/2 mutations in African Americans. Additional research is needed to understand barriers and motivations for participating in genetic testing for inherited cancer risk in African Americans. The lack of studies on psychological functioning, cancer surveillance, and preventive behaviors following testing is a significant void; however, for these studies to be conducted, greater access to genetic counseling and testing in African Americans will be needed.
Cancer Investigation 02/2005; 23(4):285-95. · 1.85 Impact Factor
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Brigitte Birebent, Edith Mitchell,
Nese Akis,
Weiping Li,
Rajasekharan Somasundaram,
Enkhtsetseg Purev,
Diane Hoey,
Michael Mastrangelo,
Henry Maguire,
David T Harris,
Sridhar Nair,
Dewei Cai,
Tianqian Zhang,
Dorothee M Herlyn
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ABSTRACT: Monoclonal rat anti-idiotypic antibody (Ab2) BR3E4 mimicking the colorectal carcinoma (CRC)-associated epitope CO17-1A induced antigen-specific humoral and cellular immune responses in mice and rabbits. Ab2 BR3E4 was administered in a phase I trial to CRC patients either as intact IgG or as F(ab')(2) coupled to keyhole limpet hemocyanin (KLH). There was a trend for the F(ab')(2)-KLH-immunized patients to show higher immune response rates (18/21 and 5/15 patients with anti-anti-idiotypic antibodies and T cells, respectively) than the IgG-immunized patients (15/23 and 3/15 patients positive). Clinical responses were rare in these patients with liver metastases.
Vaccine 05/2003; 21(15):1601-12. · 3.77 Impact Factor
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ABSTRACT: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity.
Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45-54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28-56 days) and Group B (10-week to 14-week interval; 67-97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Student's t-test were calculated.
Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant.
Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.
Diseases of the Colon & Rectum 05/2003; 46(4):448-53. · 3.13 Impact Factor
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ABSTRACT: PURPOSE: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity.
METHODS: Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45–54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28–56 days) and Group B (10-week to 14-week interval; 67–97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Students t-test were calculated.
RESULTS: Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant.
CONCLUSIONS: Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.
Diseases of the Colon & Rectum 03/2003; 46(4):448-453. · 3.13 Impact Factor
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Cancer chemotherapy and biological response modifiers 02/2003; 21:287-98.
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Brigitte Birebent,
Takashi Koido, Edith Mitchell,
Weiping Li,
Rajasekharan Somasundaram,
Enkhtsetseg Purev,
Diane Hoey,
Michael Mastrangelo,
Henry Maguire,
David T. Harris,
Sridhar Nair,
Dewei Cai,
Dorothee Herlyn
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ABSTRACT: The colorectal carcinoma (CRC)-associated CO17-1A/GA733 antigen (Ag) has been the target of a phase II/III randomized trial of passive immunotherapy with monoclonal antibody CO17-1A (Abl), and phase I active immunotherapy trials with polyclonal anti-idiotypic antibodies (Ab2) mimicking the CO17-1A or GA733 epitope of the Ag. However, monoclonal rat Ab2 BR3E4 directed against Ab1 CO17-1A was superior to polyclonal Ab2 in inducing antigen-specific Immoral and cellular immune responses in mice and rabbits. Various forms of Ab2 BR3E4, i.e., BR3E4-F(ab')2 precipitated with aluminum-hydroxide (alum), BR3E4-F(ab')2 cou pled to KLH and precipitated or non-precipitated with alum, and BR3E4-IgG in alum or incomplete Freund's adjuvant were compared for their capacity to induce in rabbits anti-anti-idiotypic antibodies (Ab3) that specifically bind to the CO17-1A Ag. BR3E4-F(ab')2 coupled to KLH and precipitated with alum was shown to induce the highest Ab3 titers, followed by Ab2 BR3E4-IgG in alum. Therefore Ab2 BR3E4 as intact IgG (IgG group) or as F(ab')2 coupled to KLH (KLH group), was ad ministered in a phase I trial to 45 patients with CRC, stage Dukes'D (UICC stage IV), with the goal to modulate patients' immune responses to their tumors. Fiteen of 23 patients in the IgG group developed Ab3 binding specifically to Ab2, and in four of these patients the Ab3 also, specifically bound to Ag-positive CRC cells. Lymphoproliferative responses to Ab2 and/or GA733-2E Ag stimulation were observed in three of these developed Ab3 and the Ab3 bound specifically to CRC cells in eight patients. Five of the 15 KLH group patients tested developed lymphoproferative responses to Ab2 and/or Ga733-2E Ag. Thus, there was a trend for the KLH group demonstrating higher immune response rates than the IgG group. Clinical responses were rare in these patients with liver metestases.
Journal of Cancer Research and Clinical Oncology 09/2001; 127:R27-R33. · 2.56 Impact Factor
