173 results on '"Scott Wadler"'
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2. Newer Clinical Strategies for Combining Interferon and Cytotoxic Agents Against Solid Tumours and Hematological Malignancies
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Scott Wadler
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Infectious and parasitic diseases ,RC109-216 - Abstract
The role of interferons in the treatment of cancer continues to evolve. Despite limited single agent activity against solid tumours, interferons now appear to have an important role as modulators of the activity of a variety of cytotoxic drugs. Clinical benefits have been observed for combinations of interferons and alkylating agents against low grade lymphomas, interferons and dacarbazine against malignant melanoma, and interferons and 5-fluorouracil against gastrointestinal and genitourinary malignancies. Further progress will depend on a grealer understanding of the biology of the interaction.
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- 1994
- Full Text
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3. A Phase I Study of the Chinese Herbal Medicine PHY906 as a Modulator of Irinotecan-based Chemotherapy in Patients with Advanced Colorectal Cancer
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Tahmun Su, Mark O'Rourke, M. Sitki Copur, Zaoli Jiang, Edward Chu, Shwu-Huey Liu, Robert Tilton, Yung-Chi Cheng, Shivaani Kummar, Michal G. Rose, Joe Stephenson, Scott Wadler, and Wayne Brenckman
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Leucovorin ,Irinotecan ,Mice ,Double-Blind Method ,Pharmacokinetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Aged ,Chemotherapy ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Gastroenterology ,Middle Aged ,IFL Regimen ,medicine.disease ,digestive system diseases ,Clinical trial ,Regimen ,Tolerability ,Camptothecin ,Female ,Fluorouracil ,Colorectal Neoplasms ,business ,Drugs, Chinese Herbal ,Half-Life ,Phytotherapy ,medicine.drug - Abstract
PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38.
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- 2011
4. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
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Scott Wadler, Franco M. Muggia, Anne Hamilton, Leonard Liebes, D. Fry, Mark A. Rosenthal, Anna C. Pavlick, Jennifer Wu, Ruth Oratz, John D. Roberts, Michelle Carr, Anthony J. Murgo, K. Farrell, and Howard S. Hochster
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Adult ,Male ,Cancer Research ,Maximum Tolerated Dose ,Bryostatin 1 ,Antineoplastic Agents ,Toxicology ,Article ,Neoplasms ,medicine ,Humans ,Pharmacology (medical) ,Protein kinase A ,Cytotoxicity ,Protein Kinase C ,Protein kinase C ,Aged ,Aged, 80 and over ,Pharmacology ,Cisplatin ,Kinase ,business.industry ,Melanoma ,Cancer ,Middle Aged ,Bryostatins ,medicine.disease ,Oncology ,Immunology ,Cancer research ,Female ,business ,medicine.drug - Abstract
Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence.Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles.Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo.Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.
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- 2009
5. Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan
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David L, Grinblatt, Daohai, Yu, Vera, Hars, James W, Vardiman, Bayard L, Powell, Sreenivasa, Nattam, Lewis R, Silverman, Carlos, de Castro, Richard M, Stone, Clara D, Bloomfield, Richard A, Larson, and Scott, Wadler
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Administration, Oral ,Chronic myelomonocytic leukemia ,Gastroenterology ,Drug Administration Schedule ,Article ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Cytopenia ,business.industry ,Myelodysplastic syndromes ,Cancer ,Middle Aged ,medicine.disease ,Surgery ,Oncology ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,Absolute neutrophil count ,Female ,Topotecan ,business ,Refractory cytopenia with multilineage dysplasia ,medicine.drug - Abstract
BACKGROUD: The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS). METHODS: Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count
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- 2008
6. Impact of Body Mass Index and Weight Change After Treatment on Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From Cancer and Leukemia Group B 89803
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Jeffrey A, Meyerhardt, Donna, Niedzwiecki, Donna, Hollis, Leonard B, Saltz, Robert J, Mayer, Heidi, Nelson, Renaud, Whittom, Alexander, Hantel, James, Thomas, Charles S, Fuchs, and Scott, Wadler
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Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Overweight ,Gastroenterology ,Body Mass Index ,Cohort Studies ,Recurrence ,Internal medicine ,Gastrointestinal Cancer ,medicine ,Humans ,Obesity ,Prospective Studies ,Risk factor ,Prospective cohort study ,Aged ,business.industry ,Weight change ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Surgery ,Treatment Outcome ,Oncology ,Chemotherapy, Adjuvant ,Colonic Neoplasms ,Body Composition ,Female ,medicine.symptom ,business ,Body mass index - Abstract
Purpose Obesity is a risk factor for the development of colon cancer. However, the influence of body mass index (BMI) on the outcome of patients with established colon cancer remains uncertain. Moreover, the impact of change in body habitus after diagnosis has not been studied. Patients and Methods We conducted a prospective, observational study of 1,053 patients who had stage III colon cancer and who were enrolled on a randomized trial of adjuvant chemotherapy. Patients reported on height and weight during and 6 months after adjuvant chemotherapy. Patients were observed for cancer recurrence or death. Results In this cohort of patients with stage III cancer, 35% of patients were overweight (BMI, 25 to 29.9 kg/m2), and 34% were obese (BMI ≥ 30 kg/m2). Increased BMI was not significantly associated with a higher risk of colon cancer recurrence or death (P trend = .54). Compared with normal-weight patients (BMI, 21 to 24.9 kg/m2), the multivariate hazard ratio for disease-free survival was 1.00 (95% CI, 0.72 to 1.40) for patients with class I obesity (BMI, 30 to 34.9 kg/m2) and 1.24 (95% CI, 0.84 to 1.83) for those with class II to III obesity (BMI ≥ 35 kg/m2) after analysis was adjusted for tumor-related prognostic factors, physical activity, tobacco history, performance status, age, and sex. Similarly, after analysis was controlled for BMI, weight change (either loss or gain) during the time period between ongoing adjuvant therapy and 6 months after completion of therapy did not significantly impact on cancer recurrence and/or mortality. Conclusion Neither BMI nor weight change was significantly associated with an increased risk of cancer recurrence and death in patients with colon cancer.
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- 2008
7. Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III
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Gary L. Goldberg, Mark H. Einstein, Robert D. Burk, Carolyn D. Runowicz, Howard Streicher, Scott Wadler, Anna S. Kadish, and Mimi Kim
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Adult ,Oncology ,medicine.medical_specialty ,Chaperonins ,Papillomavirus E7 Proteins ,Recombinant Fusion Proteins ,Uterine Cervical Neoplasms ,Rate ratio ,Cervical intraepithelial neoplasia ,Cancer Vaccines ,Article ,law.invention ,Cohort Studies ,Bacterial Proteins ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Cervix ,HspE7 ,business.industry ,Obstetrics and Gynecology ,Chaperonin 60 ,Oncogene Proteins, Viral ,Uterine Cervical Dysplasia ,medicine.disease ,medicine.anatomical_structure ,Immunology ,Cohort ,Female ,business ,Progressive disease ,Cohort study - Abstract
Objectives. SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III. Methods. HIV (−) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 μg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of > 50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR. Results. Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p = 0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0.95–6.19, p = 0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p = 0.04 using Wilcoxon rank sum test). Conclusions. HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.
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- 2007
8. Targeted Therapy in Colorectal Cancer
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Scott Wadler
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Oncology ,medicine.medical_specialty ,Bevacizumab ,Cetuximab ,biology ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Gastroenterology ,medicine.disease ,Targeted therapy ,Internal medicine ,Monoclonal ,medicine ,Adjuvant therapy ,biology.protein ,Panitumumab ,Epidermal growth factor receptor ,business ,medicine.drug - Abstract
Adjuvant therapy can reduce the risk of disease recurrence in patients with stage II-IV colorectal cancer. Recently, 3 monoclonal antibodies have been shown to improve clinical outcome in this group of patients. Bevacizumab is an antiangiogenesis agent that has been shown in clinical and preclinical models to reverse the effects of proangiogenic molecules. Bevacizumab is active in the adjuvant setting and in the treatment of metastatic disease. Cetuximab is targeted to the epidermal growth factor receptor. Panitumumab is a fully human immunoglobulin G2 antibody that also binds to the epidermal growth factor receptor. Combination therapies of monoclonal therapies and chemotherapy have resulted in better clinical outcomes than with either modality alone.
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- 2007
9. Phase I/II Study of Preoperative Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy in Patients With Locally Advanced Rectal Cancer: Cancer and Leukemia Group B 89901
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Richard M. Goldberg, Brent E. Mediema, Robert J. Mayer, Donna Niedzwiecki, Donna Hollis, Scott Wadler, David P. Ryan, and Joel E. Tepper
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Adult ,Diarrhea ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Organoplatinum Compounds ,Colorectal cancer ,medicine.medical_treatment ,Adenocarcinoma ,Drug Administration Schedule ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Rectal Adenocarcinoma ,Humans ,Infusions, Intravenous ,Neoadjuvant therapy ,Aged ,Chemotherapy ,Rectal Neoplasms ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Neoadjuvant Therapy ,Oxaliplatin ,Surgery ,Radiation therapy ,Treatment Outcome ,Chemotherapy, Adjuvant ,Fluorouracil ,Female ,Radiotherapy, Adjuvant ,business ,medicine.drug - Abstract
Purpose The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma. Patients and Methods Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m2 intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m2. Results Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m2. At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response. Conclusion In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.
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- 2006
10. Phase II trial of thalidomide for advanced and recurrent gynecologic sarcoma: A brief communication from the New York Phase II consortium
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Paul J. Christos, D. Yi Shin Kuo, Abbie L. Fields, Gary L. Goldberg, Anthony J. Murgo, Stephanie V. Blank, Scott Wadler, Carolyn D. Runowicz, and Patrick F. Timmins
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medicine.medical_specialty ,Metastatic/Recurrent ,Constipation ,Genital Neoplasms, Female ,medicine.medical_treatment ,Administration, Oral ,Carcinosarcoma ,Internal medicine ,medicine ,Humans ,Chemotherapy ,Performance status ,business.industry ,Obstetrics and Gynecology ,Sarcoma ,medicine.disease ,Thalidomide ,Surgery ,Radiation therapy ,Treatment Outcome ,Oncology ,Ambulatory ,Female ,Neoplasm Recurrence, Local ,medicine.symptom ,business ,medicine.drug - Abstract
To define the efficacy of thalidomide on the overall survival of patients with metastatic recurrent gynecologic sarcomas.All patients with sarcoma or carcinosarcoma of gynecologic origin and documented recurrence or persistence of disease after appropriate surgery, radiation therapy and/or chemotherapy were recruited to the study. All patients were ambulatory and had measurable disease that could be documented on CT scan. Patients were started on 200 mg/day of thalidomide orally every night and escalated by 100-200 mg every 7 to 14 days. The length of the treatment was separated into 2 cycles with the first 84 days defined as the first cycle and the next 56 days as the second cycle. Common Toxicity Criteria were used to record toxicities. Because thalidomide was postulated to induce cytostasis, the end-points were progression-free and overall survival in this mixed group of patients.Seventeen patients were enrolled. The drug was not well tolerated because of constipation, fatigue, worsening performance status, drowsiness and sleepiness. The total dosage of medication given to each patient ranged from 3200 mg to 40,500 mg. The maximum dosage reached in each patient ranged from 300 mg to 750 mg, with the total time of treatment ranging from 13 to 99 days. All patients had progression of disease with a median progression-free survival time of 1.84 months (CI 1.54-2.79 months) and a median overall survival of 6.64 months.Thalidomide has no activity in patients with advanced or recurrent gynecologic sarcomas and was not well-tolerated. The overall survival was7 months. The progression-free survival was3 months, and, since the therapy was not tolerated well, we unanimously decided to close the study at this point. Despite the poor result, we still believe in the strategy of anti-angiogenesis and will continue to pursue other potential treatment options using the same concept.
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- 2006
11. Recommended Guidelines for the Treatment of Cancer Treatment-Induced Diarrhea
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Everett E. Vokes, Al B. Benson, Richard McCallum, Jaffer A. Ajani, Robert B. Catalano, Thomas M. O'Dorisio, Edith P. Mitchell, Steven M. Kornblau, Constance Engelking, James A. Martenson, and Scott Wadler
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Diarrhea ,Cancer Research ,Loperamide ,medicine.medical_specialty ,medicine.medical_treatment ,MEDLINE ,Antineoplastic Agents ,Neoplasms ,medicine ,Humans ,Antidiarrheals ,Intensive care medicine ,Radiotherapy ,business.industry ,Cancer ,Guideline ,medicine.disease ,Anti-Bacterial Agents ,Surgery ,Radiation therapy ,Irinotecan ,Oncology ,Fluorouracil ,medicine.symptom ,business ,Algorithms ,medicine.drug - Abstract
Purpose To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. Methods An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. Results A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. Conclusion With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.
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- 2004
12. Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion
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Della Makower, Scott Wadler, Karen Fehn, Paula Lambert, Mario Sznol, and Caroline Clairmont
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Adult ,Male ,Thiosemicarbazones ,Cancer Research ,Ribonucleotide ,Maximum Tolerated Dose ,Pyridines ,Nausea ,Ribonucleotide reductase inhibitor ,Pharmacology ,Reductase ,Neutropenia ,Drug Administration Schedule ,chemistry.chemical_compound ,Pharmacokinetics ,Risk Factors ,Neoplasms ,medicine ,Humans ,Prospective Studies ,Enzyme Inhibitors ,Infusions, Intravenous ,Aged ,Hyperbilirubinemia ,Uremia ,business.industry ,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone ,Middle Aged ,medicine.disease ,Oncology ,chemistry ,Asthenia ,Vomiting ,Female ,medicine.symptom ,business - Abstract
Purpose 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer. Patients and Methods Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients. Results Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m2/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m2/d but administered every 2 weeks. At 120 mg/m2/d, three of seven patients had dose-limiting but reversible asthenia, hyperbilirubinemia, and azotemia or acidosis; however, in the case of renal and hepatic adverse events, the events were related to pre-existing borderline abnormal organ function. Therefore, the recommended phase II dose for 3-AP administered by 96-hour IV infusion is 120 mg/m2/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg/m2, with substantial inter-patient variability. There was no correlation between dose and clearance (R2 = 0.0137). There were no objective responses, but there was prolonged stabilization of disease or decreases in serum tumor markers associated with stable disease in four patients. Conclusion The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.
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- 2004
13. A phase II trial of interleukin-12 in patients with advanced cervical cancer: clinical and immunologic correlates
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Helen L Frederickson, Donna E. Levy, Gloria Y.F. Ho, Anna S. Kadish, Edie Weller, Scott Wadler, Yuexian Wang, Robert D. Burk, and Carla I. Falkson
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Cervical cancer ,Oncology ,medicine.medical_specialty ,Chemotherapy ,Performance status ,business.industry ,medicine.medical_treatment ,HPV infection ,Obstetrics and Gynecology ,Immunopotentiator ,medicine.disease ,Clinical trial ,Regimen ,Internal medicine ,medicine ,business ,Lymphoproliferative response - Abstract
Purpose . The ability to mount lymphoproliferative responses to peptides derived from the human papillomavirus (HPV) E6 and E7 oncoproteins has been associated with regression of dysplastic lesions of the uterine cervix and loss of associated HPV infection. Interleukin-12 (IL-12) is a potent immunopotentiator of T-cell function, and has been shown in phase I clinical trials to be tolerable. Experimental design . Patients were required to have measurable metastatic, recurrent or inoperable cervical carcinoma. Patients could have had one prior adjuvant regimen and one prior regimen for advanced disease. Treatment consisted of IL-12 administered at 250 ng/kg IV as a rapid push in the outpatient setting daily × 5 every 21 days. Whole blood samples were acquired twice before treatment then approximately every 3 weeks to assess lymphoproliferative response in vitro to HPV type 16 (HPV 16) E4, E6, and E7 peptides. These responses were correlated with demographics and with clinical outcome. Results . Thirty-four patients were enrolled; 29 were evaluable. Over half had received cisplatin-based chemotherapy. The most common serious toxicities were hematologic or hepatic, and all were reversible. There was one partial responder (3%). The median survival was 6.5 months (95% CI: 5.8, 11.5 months). Eighteen of 29 eligible patients had evaluable laboratory data both pre- and post-therapy. There was a statistically significant increase in lymphoproliferative responses for HPV 16 E4, E6, and E7 peptides ( P = 0.020, 0.020, 0.043). There was a significant association between change in lymphoproliferative response to HPV 16 E6 peptides and number of cycles of treatment administered ( P = 0.048). There was no correlation between change in lymphoproliferative response to any peptide with age, performance status, race, prior chemotherapy, time from diagnosis to treatment, or with overall survival. Conclusions . IL-12 treatment was associated with improved lymphoproliferative responses to HPV 16 E4, E6, and E7 peptides. This is the first clinical trial to demonstrate induction of cell-mediated immune (CMI) responses to specific antigens (peptides) following treatment with IL-12 in women with cervical cancer. This improvement in immune response was not associated with enhanced objective response or survival.
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- 2004
14. Biweekly 72-Hour 9-Aminocamptothecin Infusion As Second-Line Therapy for Ovarian Carcinoma: Phase II Study of the New York Gynecologic Oncology Group and the Eastern Cooperative Oncology Group
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John Mandeli, Franco M. Muggia, Robert C. Wallach, John J. Wright, James Speyer, Joan Sorich, Elizabeth R. Plimack, Howard S. Hochster, Scott Wadler, and Carolyn D. Runowicz
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Adult ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Phases of clinical research ,Antineoplastic Agents ,Gynecologic oncology ,Gastroenterology ,Drug Administration Schedule ,Ovarian carcinoma ,Internal medicine ,medicine ,Humans ,Infusions, Intravenous ,Aged ,Aged, 80 and over ,Ovarian Neoplasms ,Response rate (survey) ,business.industry ,Carcinoma ,Anemia ,Middle Aged ,Thrombocytopenia ,Surgery ,Clinical trial ,Regimen ,Treatment Outcome ,Oncology ,Ambulatory ,Disease Progression ,Camptothecin ,Female ,Aminocamptothecin ,business - Abstract
Purpose To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. Patients and Methods Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 μg/m2/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. Results Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). Conclusion This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted.
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- 2004
15. Thalidomide for advanced hepatocellular carcinoma
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Scott Wadler
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Oncology ,Thalidomide ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Hepatocellular carcinoma ,medicine ,medicine.disease ,business ,medicine.drug - Published
- 2004
16. Phase III Trial of Paclitaxel at Two Dose Levels, the Higher Dose Accompanied by Filgrastim at Two Dose Levels in Platinum-Pretreated Epithelial Ovarian Cancer: An Intergroup Study
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George A. Omura, Gregory Spiegel, Hervy E. Averette, Susan G. Arbuck, Katherine Y. Look, Scott Wadler, Harry J. Long, James E. Delmore, and Mark F. Brady
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Filgrastim ,Paclitaxel ,medicine.medical_treatment ,Urology ,Platinum Compounds ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Survival analysis ,Aged ,Proportional Hazards Models ,Ovarian Neoplasms ,Chemotherapy ,Taxane ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,medicine.disease ,Survival Analysis ,Recombinant Proteins ,Granulocyte colony-stimulating factor ,Logistic Models ,Endocrinology ,Oncology ,chemistry ,Disease Progression ,Female ,Neoplasm Recurrence, Local ,business ,Ovarian cancer ,medicine.drug - Abstract
Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 μg/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-μg/kg and 10-μg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 μg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.
- Published
- 2003
17. Topotecan Is an Active Agent in the First-Line Treatment of Metastatic or Recurrent Endometrial Carcinoma: Eastern Cooperative Oncology Group Study E3E93
- Author
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Sarah T. Lincoln, Gamini S. Soori, Donna E. Levy, Julian C. Schink, Scott Wadler, and Gary L. Goldberg
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,ECOG Performance Status ,Antineoplastic Agents ,Internal medicine ,medicine ,Carcinoma ,Humans ,Prospective Studies ,Neoplasm Metastasis ,Prior Radiation Therapy ,Survival rate ,Aged ,Aged, 80 and over ,Chemotherapy ,business.industry ,Middle Aged ,medicine.disease ,United States ,Endometrial Neoplasms ,Survival Rate ,Clinical trial ,Radiation therapy ,Female ,Topotecan ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose: To determine the clinical activity and the toxicity profile of the topoisomerase-I inhibitor, topotecan, in women with recurrent or advanced endometrial carcinoma. Patients and Methods: A prospective, phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG). Patients had histologically confirmed advanced or recurrent endometrial carcinoma, measurable disease, no prior cytotoxic therapy, an ECOG performance status of 0 to 2, and evidence of disease progression while on progestins or after radiation therapy. Topotecan was administered at 1.5 mg/m2 (or 1.2 mg/m2 for patients with prior pelvic radiation) intravenously daily for 5 days every 3 weeks. Results: A total of 44 patients were enrolled; 42 were eligible. The study was suspended because of unexpected toxicities, primarily sepsis and bleeding. After toxicity review, the study was reopened using lower doses of topotecan (1.0 mg/m2 or 0.8 mg/m2 for patients with prior radiation therapy). In addition, prophylactic use of growth factors was allowed after the first cycle, and patients with performance status of 2 were excluded. The major toxicities were hematologic and gastrointestinal. Among the 40 assessable patients, there were three (7.5%) complete responders and five partial responders (12.5%), for an overall response rate of 20%. The median duration of response was 8.0 months and of overall survival was 6.5 months. Conclusion: Topotecan is an active agent for the treatment of advanced endometrial carcinoma. At the doses and schedules initially used, toxicities were unacceptable; however, at the modified doses, toxicities were acceptable and clinical activity was preserved.
- Published
- 2003
18. Phase II Trial of Intravenous CI-1042 in Patients With Metastatic Colorectal Cancer
- Author
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Mary Varterasian, Charles Omer, Evanthia Galanis, Scott Wadler, Al B. Benson, Oday Hamid, Paul Bycott, Robert C. Hackman, J. Randolph Hecht, Anthony F. Shields, and Margaret Uprichard
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Nausea ,Colorectal cancer ,medicine.medical_treatment ,Phases of clinical research ,Rectum ,Antineoplastic Agents ,Gastroenterology ,Drug Administration Schedule ,Adenoviridae ,Internal medicine ,medicine ,Humans ,Tissue Distribution ,Treatment Failure ,Antigens, Viral ,Aged ,Chemotherapy ,business.industry ,Viral Vaccines ,Middle Aged ,medicine.disease ,Surgery ,Clinical trial ,medicine.anatomical_structure ,Oncology ,Toxicity ,Disease Progression ,Female ,Autopsy ,medicine.symptom ,Colorectal Neoplasms ,business ,Progressive disease - Abstract
Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 × 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.
- Published
- 2003
19. Combined Intraperitoneal and Intravenous Chemotherapy for Women With Optimally Debulked Ovarian Cancer: Results From an Intergroup Phase II Trial
- Author
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Sharon P. Wilczynski, Mace L. Rothenberg, David S. Alberts, Scott Wadler, Patricia S. Braly, P.Y. Liu, Caroline Jiang, Edward V. Hannigan, Maurie Markman, and Gavin Stuart
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,medicine.medical_treatment ,Urology ,Ovary ,Adenocarcinoma ,Disease-Free Survival ,chemistry.chemical_compound ,Administration, Rectal ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Infusions, Parenteral ,Infusions, Intravenous ,Survival rate ,Aged ,Ovarian Neoplasms ,Stage III Ovarian Cancer ,Cisplatin ,Chemotherapy ,business.industry ,Drug Tolerance ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Oncology ,chemistry ,Female ,Ovarian cancer ,business ,medicine.drug - Abstract
Purpose: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. Patients and Methods: Treatment consisted of paclitaxel 135 mg/m2 IV over 24 hours on days 1 to 2, cisplatin 100 mg/m2 IP on day 2, and paclitaxel 60 mg/m2 IP on day 8 administered every 21 days for six cycles. Results: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. Conclusion: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.
- Published
- 2003
20. A Pilot Study of Edrecolomab (Panorex, 17-1A Antibody) and Capecitabine in Patients with Advanced or Metastatic Adenocarcinoma
- Author
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Della F. Makower, M. J. Versola, Karen Fehn, Paul Wissel, Sridhar Mani, Scott Wadler, Joseph A. Sparano, and Leon Landau
- Subjects
Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Leukopenia ,Combination therapy ,business.industry ,medicine.medical_treatment ,Edrecolomab ,General Medicine ,medicine.disease ,Loading dose ,Gastroenterology ,Surgery ,Capecitabine ,Oncology ,Fluorouracil ,Internal medicine ,medicine ,Adenocarcinoma ,medicine.symptom ,business ,medicine.drug - Abstract
Edrecolomab (Panorex) is a monoclonal antibody directed against the 17-1A antigen located on the cell surfaces of carcinomas. Clinical activity has been seen in colon and breast cancer. This trial investigated the feasibility of combining edrecolomab with the oral fluoropyrimidine capecitabine (Xeloda). Patients received a loading dose of edrecolomab 500 mg intravenously (i.v.) on day--14, followed 2 weeks later by 100 mg i.v. every 28 days (day 1). Capecitabine was administered to single-patient cohorts at escalating doses of 1500, 2000, and 2500 mg/m2/day in two equally divided doses for 14 of 21 days, beginning on day 1. Additional patients were enrolled at the 2500 mg/m2/day dose level to better define the toxicities of combination therapy. Toxicity assessment was the primary endpoint. Twenty seven patients with advanced or metastatic adenocarcinoma were enrolled on this study: 20 were evaluable for toxicity and 18 for response. The most common toxicities were elevated liver enzymes, diarrhea, and hand-foot syndrome. In cycle 1, grade 3 hand-foot syndrome was seen in two patients, and grade 3 diarrhea in one patient. Grade 2 toxicities included diarrhea, hand-foot syndrome, anemia, leukopenia, and transaminitis. Cumulative hand-foot syndrome was observed in four patients treated beyond two cycles. Three patients had edrecolomab infusion reactions during the course of treatment. One complete response and two partial responses were seen. Nine patients had disease stabilization lasting a median of 17.5 weeks (range 14.5-28+). Edrecolomab and capecitabine may be safely given in combination to patients with advanced or metastatic adenocarcinoma. Clinical activity is seen in this heavily pretreated patient population.
- Published
- 2003
21. Systemic treatment of advanced colorectal cancer: Incorporating new agents into the therapeutic strategy
- Author
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Scott Wadler
- Subjects
Gastroenterology ,Surgery - Published
- 2002
22. Randomized Phase II Trial of Embolization Therapy Versus Chemoembolization Therapy in Previously Treated Patients with Colorectal Carcinoma Metastatic to the Liver
- Author
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Alla M. Rozenblit, Ron Kaleya, Marci Jagust, Curtis W. Bakal, Abdissa Negassa, Scott Wadler, Jacov Cynamon, and Huda S. Salman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Rectum ,Adenocarcinoma ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Hepatic artery embolization ,Prospective Studies ,Embolization ,Chemoembolization, Therapeutic ,Aged ,Aged, 80 and over ,business.industry ,Liver Neoplasms ,Gastroenterology ,Cancer ,Middle Aged ,medicine.disease ,Embolization, Therapeutic ,Surgery ,Survival Rate ,medicine.anatomical_structure ,Oncology ,Toxicity ,Female ,Polyvinyls ,Fluorouracil ,Interferons ,Colorectal Neoplasms ,business ,Artery - Abstract
Locoregional therapies are useful in treating patients with colorectal cancer metastatic to the liver. A prospective randomized phase II trial of hepatic artery embolization versus hepatic artery chemoembolization was conducted to evaluate the response rates and toxicities of these therapies in the second-line setting. Patients were required to have biopsy-proven adenocarcinoma of the colon or rectum metastatic to the liver, with the liver as the sole or predominant site of metastatic disease. All patients had measurable disease and had failed at least one prior systemic chemotherapy treatment for metastatic disease. Patients were randomized to receive either embolization therapy with polyvinyl alcohol foam (Ivalon®) administered as a single agent or chemoembolization using polyvinyl alcohol foam mixed with 750 mg/m2 of 5-fluorouracil and 9 million units of interferon. Drugs and embolic material were administered via the hepatic artery as a slurry with polyvinyl alcohol foam. Fifty eligible patients were enrolled. There were 24 patients in the chemoembolization arm and 26 in the embolization arm. Sixty-four percent of patients in both treatment arms had the liver as the sole metastatic site. The most common National Cancer Institute common toxicity criteria grade 3/4 toxicities were diarrhea (17%) and hepatic toxicity (8%). There was 1 (4%) treatment-related mortality due to a hepatic abscess. Four patients (15.4%) treated with embolization had a partial response (PR), and 5 patients (20.8%) treated with chemoembolization had a PR. The median survival for all patients was 11 months (95% confidence interval [CI], 8–15 months). Survival in patients with extrahepatic disease was 8 months (95% CI, 6- 10 months). Survival in patients with liver-only metastases was 15 months (95% CI, 10–17 months). Embolization of the liver as second-line therapy in patients with liver-predominant metastases is safe and effective. Median survivals are comparable to other second-line therapies.
- Published
- 2002
23. SU9516, a cyclin-dependent kinase 2 inhibitor, promotes accumulation of high molecular weight E2F complexes in human colon carcinoma cells
- Author
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Scott Wadler, Maureen E. Lane, and Bo Yu
- Subjects
Indoles ,Cyclin E ,Cyclin D ,Cyclin A ,Cyclin B ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Retinoblastoma Protein ,Biochemistry ,Cyclin D1 ,E2F2 Transcription Factor ,Cyclin-dependent kinase ,Cyclins ,CDC2-CDC28 Kinases ,Humans ,Cells, Cultured ,Pharmacology ,E2F5 Transcription Factor ,biology ,Cyclin-Dependent Kinase 2 ,Imidazoles ,Intracellular Signaling Peptides and Proteins ,Cyclin-Dependent Kinases ,E2F Transcription Factors ,DNA-Binding Proteins ,Molecular Weight ,E2F3 Transcription Factor ,Colonic Neoplasms ,biology.protein ,Cancer research ,Cyclin-dependent kinase complex ,biological phenomena, cell phenomena, and immunity ,Carrier Proteins ,HT29 Cells ,E2F1 Transcription Factor ,Cyclin A2 ,Transcription Factors - Abstract
The E2F family plays a critical role in the expression of genes required for entry into and progression through S phase. E2F-mediated transcription is repressed by the tumor suppressor retinoblastoma protein (pRb), which results in sequestration of E2F in a multiprotein complex that includes pRb. Derepression of E2F results from a series of complex phosphorylation events mediated by cyclin D/cdk4 and cyclin E/cdk2. We have employed a novel 3-substituted indolinone compound, 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), which selectively inhibits cdk2 activity (Lane et al., Cancer Res 2001;61:6170-7) to investigate these events. Electrophoretic mobility gel shift assays were performed on SU9516-treated and -untreated HT-29, SW480, and RKO human colon cancer cell extracts. Treatment with 5 microM SU9516 prevented dissociation of pRb from E2F1 in all cell lines (HT-29>RKO>SW480). Treatment effects were time-dependent, demonstrating greater inhibition at 48 hr versus 24hr in HT-29 cells. Furthermore, E2F species were sequestered in complexes with p107, p130, DP-1, and cyclins A and E. After a 24-hr treatment with 5 microM SU9516, cyclin D1 and cdk2 levels decreased by 10-60%. These findings delineate a previously undescribed mechanism for SU9516-mediated cell growth arrest through down-regulation of cyclin D1, inhibition of cdk2 levels and activity, and pan-sequestration of E2F.
- Published
- 2002
24. Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days
- Author
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Joan Sorich, Chung Chiang, Milan Potmesil, Maitreyee Hazarika, Leonard Liebes, Howard S. Hochster, Anne Hamilton, Elliot Newman, Franco M. Muggia, Scott Wadler, and Gila Hornreich
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents ,Neutropenia ,Peripheral blood mononuclear cell ,Gastroenterology ,Drug Administration Schedule ,Peritoneal cavity ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Aged ,Pharmacology ,biology ,business.industry ,Topoisomerase ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Oncology ,Toxicity ,biology.protein ,Camptothecin ,Female ,Aminocamptothecin ,business ,Progressive disease - Abstract
We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m(2) in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m(2) was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (+/-SD) was 11.5 (+/-3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.
- Published
- 2002
25. Randomized Phase II Trial of Either Fluorouracil, Parenteral Hydroxyurea, Interferon-??t-2a, and Filgrastim or Doxorubicin/Docetaxel in Patients with Advanced Gastric Cancer with Quality-of-Life Assessment
- Author
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David Cella, Paul J. Catalano, Scott Wadler, Avi I. Einzig, Al B. Benson, and Carlos Brain
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Filgrastim ,medicine.disease ,Antimetabolite ,Granulocyte colony-stimulating factor ,Regimen ,Docetaxel ,Fluorouracil ,Internal medicine ,medicine ,business ,Stomach cancer ,medicine.drug - Abstract
PURPOSE The Eastern Cooperative Oncology Group conducted a randomized phase II trial to determine the objective response rates, toxicities, and overall survival and to assess effects on quality of life for two combination regimens in patients with advanced gastric cancer. PATIENTS AND METHODS All patients had biopsy-proven, untreated metastatic gastric cancer with measurable disease. The FHIG arm employed infusional fluorouracil (F), 2.6 g/m2, given intravenously over 24 hours once per week for 6 weeks; infusional hydroxyurea (H), 4.3g/m2, given intravenously over 24 hours once per week for 6 weeks; and interferon-a-2a (I), 9 MU given subcutaneously three times per week, once perweekfor6weeks. The AD arm employed doxorubicin (A), 50 mg/m2, and docetaxel (D), 75 mg/m2, both given intravenously every 21 days. Quality of life was measured by the FACT-Fatigue scale and a novel questionnaire assessing interferon-mediated fatigue. RESULTS Twenty-nine patients were enrolled; 23 were eligible and evaluable. Twelve were enrolled on FHIG and 11 on AD. The major grade ≥ 3 toxicities were neuromotor (46%) in patients receiving FHIG and granulocytopenia (91%) in those receiving AD. There were two fatalities in the AD arm. There was one partial responder on FHIG (8.3%) and none on AD. The median survival was 6.6 months for FHIG and 10.1 months for AD. Quality-of-life analysis did not show substantial cumulative fatigue in patients treated with FHIG. CONCLUSIONS Neither regimen demonstrated enough activity to serve as a platform for the development of further clinical regimens against gastric carcinoma. A subset of patients receiving interferon was able to tolerate therapy without deterioration in quality of life.
- Published
- 2002
26. Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix
- Author
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Brij Sood, Gary L. Goldberg, Jonathan J. Beitler, H. Haynes, Scott Wadler, Abbie L. Fields, Patrick Anderson, Bhadrasain Vikram, and Carolyn D. Runowicz
- Subjects
Radiation-Sensitizing Agents ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Brachytherapy ,Urology ,Phases of clinical research ,Antineoplastic Agents ,Hydroxycarbamide ,medicine ,Humans ,Hydroxyurea ,Infusions, Parenteral ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,External beam radiotherapy ,Aged ,Aged, 80 and over ,Radiation ,business.industry ,Middle Aged ,Pelvic cavity ,Combined Modality Therapy ,Surgery ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,Epidermoid carcinoma ,Concomitant ,Uterine Neoplasms ,Carcinoma, Squamous Cell ,Female ,business ,medicine.drug - Abstract
Purpose : Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. Methods : This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. Results : At dose level 1 (0.25 mg/m2/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m2/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m2/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. Conclusions : The maximal tolerated dose of parenteral HU was 0.375 mg/m2/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.
- Published
- 2002
27. Report of a phase I evaluation of dose and schedule of interleukin-1 alpha and cyclophosphamide in patients with advanced tumors: An Eastern Cooperative Oncology Group study (PX990) and review of IL-1-based studies of hematopoietic reconstitution
- Author
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James A. Stewart, Scott Wadler, Michael B. Atkins, William Tester, Abraham Chachoua, Janice P. Dutcher, Donna Neuberg, and Lynn M. Schuchter
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Neutropenia ,Drug Administration Schedule ,Virology ,White blood cell ,Internal medicine ,Interleukin-1alpha ,Neoplasms ,medicine ,Humans ,Transplantation, Homologous ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Hematopoietic Stem Cell Transplantation ,Interleukin ,Research Reports ,Cell Biology ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Toxicity ,Disease Progression ,Chills ,Female ,Bone marrow ,medicine.symptom ,business ,medicine.drug - Abstract
Interleukin-1 (IL-1) is a cytokine critical to inflammation, immunological activation, response to infection, and bone marrow hematopoiesis. Cyclophosphamide downmodulates immune suppressor cells and is cytotoxic to a variety of tumors. A phase I trial of IL-1 and cyclophosphamide was conducted by the Eastern Cooperative Oncology Group. This study evaluated 3 dose levels and 3 schedules in patients with solid tumors. The goal was to evaluate the hematopoietic supportive care effect and possible antitumor effect. Toxicity was fever, chills, hypotension, nausea/emesis, hepatic, and neutropenia. Toxicity increased with dose increases of interleukin-1. Treatment at all dose levels resulted in significant increases in total white blood cell (WBC) counts above baseline. Nadir WBC and nadir absolute neutrophil counts were not significantly different by dose level of IL-1 or schedule of IL-1. Toxicity due to IL-1 at higher doses prohibited further evaluation of this agent for hematopoietic support, particularly in view of the activity and tolerability of more lineage-specific hematopoietic cytokines. Therapeutic interventions in the role of IL-1 in inflammatory conditions and cancer may be further informed by our definition of its clinical and biological effects in this evaluation of dose and schedule.
- Published
- 2014
28. Perspectives for cancer therapies with cdk2 inhibitors
- Author
-
Scott Wadler
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,DNA Replication ,Cancer Research ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Retinoblastoma Protein ,S Phase ,Cyclin-dependent kinase ,Cyclins ,CDC2-CDC28 Kinases ,medicine ,Humans ,Pharmacology (medical) ,Phosphorylation ,Cyclin-Dependent Kinase Inhibitor p16 ,Pharmacology ,Estradiol ,biology ,Kinase ,Cyclin-dependent kinase 4 ,Cyclin-Dependent Kinase 2 ,Cyclin-dependent kinase 2 ,G1 Phase ,Retinoblastoma protein ,Cancer ,medicine.disease ,Cytostasis ,Cyclin-Dependent Kinases ,E2F Transcription Factors ,Cell biology ,DNA-Binding Proteins ,Infectious Diseases ,Oncology ,biology.protein ,Cancer research ,Cyclin-Dependent Kinase-Activating Kinase ,Transcription Factors - Abstract
Modern anticancer strategies are designed against specific molecular targets with the goal of sparing normal, non-neoplastic tissues. Choosing specific molecular targets, however, is problematic. Cdk2 (Cyclin dependent kinase 2, cell division kinase 2, p33) is an important candidate target for therapeutic intervention. Phosphorylation of retinoblastoma protein (pRb) by Cdk2 is the penultimate step in the transition from G1 to S phase. Inhibition of this step could potentially result in inhibition of proliferation, cytostasis and possibly apoptosis in human tumors. Cdk2 also plays a critical role in the transition through S phase and the S to G2 transition as well. Inhibitors of the cyclin dependent kinases, such as flavopiridol and UCN-01, are currently in clinical trials. While demonstrating clinical activity, neither acts specifically against Cdk2. Other more specific Cdk2 inhibitors are currently in preclinical development. Further studies to explore the therapeutic worth of such agents are warranted.
- Published
- 2001
29. Stage 4 Squamous Cell Carcinoma of the Tongue in a Child: Complete Response to Chemoradiotherapy
- Author
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Scott Wadler, Jonathan J. Beitler, Sandeep Soni, Eva Radel, Ron Sattenberg, Richard V. Smith, and Morris Edelman
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Palatine Tonsil ,Submandibular Gland ,Trismus ,Nasopharynx ,medicine ,Carcinoma ,Mucositis ,Humans ,Hydroxyurea ,Neoplasm Invasiveness ,External beam radiotherapy ,Antineoplastic Agents, Alkylating ,business.industry ,Remission Induction ,medicine.disease ,Combined Modality Therapy ,Tongue Neoplasms ,Surgery ,Regimen ,Epidermoid carcinoma ,Concomitant ,Carcinoma, Squamous Cell ,Female ,Dose Fractionation, Radiation ,medicine.symptom ,business ,Chemoradiotherapy - Abstract
This report describes a complete response to a chemoradiotherapy regimen in a child with an advanced and unresectable squamous cell carcinoma of the tongue. An 8-year-old girl had stage 4 squamous cell carcinoma of the tongue (T4N2M0), causing severe trismus and dysphagia. She received hyperfractionated external beam radiotherapy (total 74.4 Gy) and concomitant intravenous infusion of hydroxyurea (0.313 mg/m2 per min) for 43 days. Grade 3 mucositis and myelosuppression were the main toxicities. There was marked symptomatic improvement, and the patient achieved a complete response. She is disease-free 24 months after treatment, and all the acute symptoms have resolved. The regimen was well tolerated with acceptable toxicity and led to a complete objective response. This regimen needs further evaluation to confirm its efficacy and to ascertain its long-term effects in children.
- Published
- 2001
30. N-Methylformamide in Advanced Squamous Cancer of the Uterine Cervix: An Eastern Cooperative Oncology Group Phase II Trial
- Author
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Peter H. Wiernik, Edie Weller, S B Kahn, Douglass C. Tormey, R Skeel, Scott Wadler, L Rajdev, and Z F Yu
- Subjects
Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,Drug Administration Schedule ,Internal medicine ,medicine ,Carcinoma ,Humans ,Pharmacology (medical) ,education ,Survival rate ,Aged ,Pharmacology ,Chemotherapy ,education.field_of_study ,Formamides ,business.industry ,Cell Differentiation ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Survival Rate ,Clinical trial ,Treatment Outcome ,Epidermoid carcinoma ,Carcinoma, Squamous Cell ,Vomiting ,Female ,medicine.symptom ,business - Abstract
Purpose: Preclinical and clinical data support the studyof polar-planar compounds such as N-Methylformamide (NMF) inadvanced squamous cell carcinoma of the uterine cervix (SCC).This phase II trial sought to determine the efficacy andtoxicities of NMF in patients with advanced SCC. Patientsand methods: Eligibility for this trial requiredbidimensionally measurable squamous or adenosquamous cellcancer of the uterine cervix incurable by surgery or radiationtherapy, ECOG performance status of ≤2, no prior NMF and nomore than one prior chemotherapy regimen. Patients receivedNMF at 2000 mg/m2 intravenously over 15–30 minutes days 1,8 and 15. The cycle was repeated every 42 days. A single doseescalation of 25%, 500 mg/m2 was made after the firstcycle if the toxicities did not exceed grade I for hepatictoxicity and grade II for nausea and vomiting. Results:From July 1987 through September 1998, 21 patients withadvanced squamous cell carcinoma of the uterine cervix wereentered on study. Two patients were ineligible because therewas no pretreatment SGOT on one and the other deterioratedprior to drug approval. Therefore, 19 patients were include inthe analysis of response and survival. Four were inevaluable,3 due to inappropriate tumor evaluation and I secondary tograde III vomiting, who went off study. These patients wereincluded in the denominator while computing the results. Therewere 2 deaths, one due to pulmonary hemorrhage fromperforation during central venous insertion and one due todisease. 30% (6/19) patients had toxicities, EasternCooperative Oncology Group (ECOG) grade III or higher and 2 ofthese patients suffered multiple grade III toxicities. Therewere no complete or partial responses. Conclusion: Inthis population, NMF in the dose and schedule employedexhibited no clinical activity.
- Published
- 2001
31. Fluorouracil Modulation in Colorectal Cancer: Lack of Improvement With N -Phosphonoacetyl- l -Aspartic Acid or Oral Leucovorin or Interferon, But Enhanced Therapeutic Index With Weekly 24-Hour Infusion Schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study
- Author
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Judith Manola, Daniel G. Haller, Al B. Benson, Scott Wadler, Louis M. Weiner, Louise Ryan, Frank H. Valone, Peter J. O'Dwyer, John Hines, Robert J. Mayer, and Susan G. Arbuck
- Subjects
Male ,Phosphonoacetic Acid ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Colorectal cancer ,medicine.medical_treatment ,Leucovorin ,Administration, Oral ,Alpha interferon ,Antineoplastic Agents ,Interferon alpha-2 ,Antimetabolite ,Gastroenterology ,Thymidylate synthase ,Oral administration ,Internal medicine ,medicine ,Humans ,Infusions, Intravenous ,Aged ,Aspartic Acid ,Chemotherapy ,biology ,business.industry ,Interferon-alpha ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Recombinant Proteins ,Surgery ,Oncology ,Fluorouracil ,biology.protein ,Female ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
- Published
- 2001
32. Interferon-mediated fatigue
- Author
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Della F. Makower, Scott Wadler, and Ummekalsoom R. Malik
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunotherapy ,Neuropsychiatry ,medicine.disease_cause ,Pathophysiology ,Autoimmunity ,Cytokine ,Internal medicine ,Immunopathology ,Immunology ,Etiology ,medicine ,Antidepressant ,business - Abstract
Fatigue is a common side effect of interferon (IFN) therapy, reported in 70-100% of patients treated with IFN. The etiology of IFN-mediated fatigue (IMF) is multifactorial, with endocrine failure, neuropsychiatric disturbance, autoimmunity, and cytokine dysregulation potentially being contributors. Thyroid dysfunction, associated with the development of autoantibodies, is seen in 8-20% of patients receiving IFN-alpha. IFN-alpha also suppresses the hypothalamic-pituitary-adrenal axis. In addition, IFN-alpha therapy leads to depression and cognitive slowing, and depressed patients are predisposed to develop fatigue. Clinical management of IMF is challenging because the syndrome is variable in onset and severity and the pathophysiology is poorly understood. Current management typically centers on dose reduction, but ancillary nonpharmacologic measures may help improve symptoms. Other strategies include antidepressant or anxiolytic therapy and treatment of coexisting hypothyroidism. Future studies utilizing IFN should include quantitative guidelines for grading and managing IMF.
- Published
- 2001
33. Downregulation of Cyclin D1 Alters cdk 4- and cdk 2-Specific Phosphorylation of Retinoblastoma Protein
- Author
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Richard G. Pestell, Scott Wadler, Bo Yu, Chris Albanese, and Maureen E. Lane
- Subjects
Transcriptional Activation ,Receptors, Steroid ,Cyclin E ,Cyclin D ,Blotting, Western ,Cyclin A ,Cyclin B ,Down-Regulation ,Protein Serine-Threonine Kinases ,Transfection ,Retinoblastoma Protein ,CDK-activating kinase ,Substrate Specificity ,Genes, Reporter ,Cyclin-dependent kinase ,Proto-Oncogene Proteins ,CDC2-CDC28 Kinases ,Tumor Cells, Cultured ,Humans ,Cyclin D1 ,RNA, Antisense ,RNA, Messenger ,Phosphorylation ,Molecular Biology ,biology ,Cyclin-Dependent Kinase 2 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Molecular biology ,Cyclin-Dependent Kinases ,Cell biology ,Gene Expression Regulation, Neoplastic ,Ecdysterone ,Colonic Neoplasms ,biology.protein ,biological phenomena, cell phenomena, and immunity ,Restriction point ,Cyclin A2 - Abstract
Progression of cells through the G1 phase of the cell cycle requires the assembly and activation of specific cyclin:cyclin-dependent kinase (cdk) complexes in a tightly regulated, sequential fashion. To more clearly define the temporal events leading to the G1/S transition, sequential changes in the expression of cyclin E and cdks 2, 4, and 6, as well as the phosphorylation of the retinoblastoma protein (pRb), were assayed in RA28 cells, a variant of human colon cancer RKO cells which were modified by transfection of an ecdysone-inducible antisense (AS) CD1 expression system. Induction of cyclin D1 antisense mRNA by the ecdysteroid, ponasterone A, resulted in a 55% decrease in cyclin D1 mRNA and a 58% decrease in CD1 protein levels. There was a 2.4-fold decrease in the ratio of hyperphosphorylated pRb (ppRb) to hypophosphorylated pRb, as well as a 60–75% decrease in cdk 2- and cdk 4-specific phosphorylated pRb proteins. Of interest, cyclin E-dependent phosphorylation (cdk2) decreased 2.5-fold at 3 h despite only a 30% decrease in cyclin E protein level. Levels of cdk 2, cdk 4, and cdk 6 decreased 40–70%, while levels of cyclin A and B were unaffected by induction of CD1 antisense. Induction of a CD1 antisense gene in a human colon cancer cell line resulted in rapid, concomitant changes in CD1 mRNA and protein, cyclin E, cdk2, cdk4, and cdk6, as well as the ratio of ppRb to pRb. In this system, growth regulatory events are tightly regulated and the perturbed expression of a single protein, CD1, rapidly alters expression of multiple regulatory proteins involved in the G1/S transition phase of cell cycle progression.
- Published
- 2000
34. Management of Cancer Treatment–Related Diarrhea
- Author
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Richard E. Champlin, Patrick J. Stiff, Joseph Rubin, Edith P. Mitchell, Michael Field, Constance Engelking, Everett E. Vokes, Al B. Benson, Robert B. Catalano, Steven M. Kornblau, Cindy Ippoliti, Scott Wadler, and Hillard M. Lazarus
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,MEDLINE ,Octreotide ,Cancer ,Disease ,medicine.disease ,Irinotecan ,Diarrhea ,Anesthesiology and Pain Medicine ,Graft-versus-host disease ,Immunology ,medicine ,Neurology (clinical) ,medicine.symptom ,Intensive care medicine ,business ,General Nursing ,medicine.drug - Abstract
The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID- and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.
- Published
- 2000
35. Phase I-II Study of 5-Fluorouracil, Recombinant Interferon α2a, and Cisplatin in Combination With External Beam Radiation Therapy Followed by Surgery in Patients With Locally Advanced Carcinoma of the Esophagus
- Author
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Margarita Camacho, Jonathan J. Beitler, Hilda Haynes, Snehal Damle, Ellen L. Wolf, and Scott Wadler
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,medicine.medical_treatment ,Population ,Adenocarcinoma ,Interferon alpha-2 ,Drug Administration Schedule ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,medicine ,Mucositis ,Humans ,Prospective Studies ,education ,Aged ,Cisplatin ,Chemotherapy ,education.field_of_study ,Esophageal disease ,business.industry ,Interferon-alpha ,Radiotherapy Dosage ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Recombinant Proteins ,Surgery ,Radiation therapy ,Oncology ,Carcinoma, Squamous Cell ,Feasibility Studies ,Female ,Fluorouracil ,business ,Progressive disease ,medicine.drug - Abstract
Multimodality therapy has been demonstrated to be superior to external beam radiation therapy and possibly surgery alone for the treatment of carcinoma of the esophagus. The combination of 5-fluorouracil (5-FU), cisplatin, and recombinant interferon alpha2a (IFN) has yielded 65% response rates in metastatic and regionally advanced carcinoma of the esophagus. A phase I-II study was performed to assess the feasibility of combining 5-FU, IFN, and cisplatin with external beam radiation therapy followed by surgery in potentially resectable patients. Eligibility included biopsy-proven stage II-III squamous cell or adenocarcinoma of the esophagus with no prior therapy. External beam radiation therapy was administered concurrently with chemotherapy beginning on day 1, 5 days per week, twice a day with 1.5 Gy/fraction to a total dose of 45 Gy. 5-FU was administered at 750 mg/m2 on days 1, 8, 15, 22, and 29 after the administration of IFN and cisplatin. IFN was given at a dose of 6 million units subcutaneously three times per week beginning on day 1. Dose levels I, II, and III of cisplatin were 25, 30, and 35 mg/m2 administered on days 1, 8, 15, 22, and 29. The sequence of administration was IFN followed by cisplatin followed immediately by 5-FU. Dose escalation between patient cohorts occurred if 0/3 or < or = 1/6 patients had dose-limiting toxicity, i.e., grade II-III toxicity attributable to cisplatin. A phase II trial was planned using the maximum tolerated dose of cisplatin determined from the phase I trial. Patients who successfully completed therapy underwent thoracic exploration to resect residual disease. Twelve patients were enrolled; all were eligible. The demographics of the population were median age, 60 years (range, 44-77); nine male and three female patients; nine squamous cell carcinoma, one adenocarcinoma, and two adenosquamous histology; stage II:III, 2:10. Grade 3-4 toxicities included granulocytopenia (12 patients), thrombocytopenia (six), anemia (three), infection (six), diarrhea (two), mucositis (two), and renal and hepatic toxicities (one). Five patients had a clinical complete response, among whom four underwent surgery. At surgery, one patient had no evidence of residual disease and three patients had microscopic disease only. Two patients had progressive disease and five could not complete the therapy because of toxicities. Two patients are alive and disease free at 25 and 23 months, respectively. This regimen, though active, demonstrated an unfavorable toxicity profile and cannot be recommended for further study.
- Published
- 1999
36. Krukenberg Tumors:Can Management Be Improved? 1
- Author
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Caroline S. Rickard, Frances McGill, Wilma Markus Greston, Scott Wadler, Diane B. Ritter, Ronald N. Kaleya, and Katherine A. O'Hanlan
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Obstetrics and Gynecology ,Oophorectomy ,Cancer ,medicine.disease ,Krukenberg tumor ,Surgery ,Metastasis ,Radiation therapy ,Reproductive Medicine ,Carcinoma ,medicine ,Radiology ,Gastrointestinal cancer ,business - Abstract
Objective: The Montefiore Medical Center experience with women with gastrointestinal (GI) cancer was reviewed to: (1) evaluate clinical parameters in patients with Krukenberg tumor (GI cancer metastatic to the ovaries) and (2) evaluate oophorectomy in GI cancer patients. Methods: (1) Charts of all female patients admitted between 1985 and 1996 with gastric or colon cancer were reviewed. Results: The frequency of Krukenberg tumor was 7/1,021 (0.7%). The median age at presentation was 39.5 years (range 35–80); 5 were premenopausal, 2 of whom were postpartum. Krukenberg tumor was significantly more common in the premenopausal patients with gastric cancer (p = 0.002), colon cancer (p = 0.001), and in both sites combined (p < 0.001). Our rate of pregnancy-associated Krukenberg tumors (28.6%) was significantly higher (p < 0.05) than that found in 4 of 5 large studies. The average survival of our 7 patients was 12.3 months (range 4 days to 26 months), with secondary debulking and chemotherapy offering 1 patient the longest longevity. Only 19/788 (2.4%) women had oophorectomy during their colon cancer surgery revealing 2 (10.5%) Krukenberg tumors, 6 (31.6%) benign solid or cystic ovarian tumors, and 11 (57.9%) normal or atrophic ovaries. Conclusions: Krukenberg tumors are rare. There is no uniformity of data reported in the literature. Krukenberg tumors were more common in premenopausal women with gastric or colon cancer compared to postmenopausal women. Our rate of pregnancy-associated Krukenberg tumors appeared to be higher compared to other studies. Prophylactic oophorectomy in pre- and postmenopausal women should be considered at the time of GI cancer surgery, and requires further study. A national registry combined with prospective, multisite studies are needed to gather data and evaluate treatment.
- Published
- 1999
37. A phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck
- Author
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Tamar Kotz, Allan Brook, H. Haynes, Jonathan J. Beitler, Maria Serrano, Astrid Quish, Richard V. Smith, Carl E. Silver, and Scott Wadler
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,Phases of clinical research ,Drug Administration Schedule ,Hydroxycarbamide ,medicine ,Humans ,Hydroxyurea ,Pharmacology (medical) ,Aged ,Neoplasm Staging ,Pharmacology ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Combined Modality Therapy ,Radiation therapy ,Oncology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Concomitant ,Injections, Intravenous ,Toxicity ,Carcinoma, Squamous Cell ,Dose Fractionation, Radiation ,Accelerated Radiation Therapy ,Nuclear medicine ,business ,medicine.drug - Abstract
Background: Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck. Methods: Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25–0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed. Results: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3–4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT. Conclusion: The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.
- Published
- 1998
38. Effects of a Hybrid Recombinant Human Alpha Interferon (A/D) on in vitro Cytotoxicity and in vivo Localization of Monoclonal Antibody L6-Cytosine Deaminase Conjugate in a Colon Cancer Model
- Author
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Adeline L. Markowitz, Kevin P. O'Boyle, Gillian M. Anthony, Scott Wadler, Kuldeep K. Bhargava, Peter D. Senter, and S. B. Chun
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Adenosine Deaminase ,Cell Survival ,medicine.drug_class ,Flucytosine ,Mice, Nude ,Alpha interferon ,Biology ,Monoclonal antibody ,Mice ,In vivo ,Immunotoxin ,Tumor Cells, Cultured ,Percent Injected Dose ,medicine ,Animals ,Humans ,Hemadsorption ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Viability assay ,Pharmacology ,Immunotoxins ,Cytosine deaminase ,Antibodies, Monoclonal ,General Medicine ,Molecular biology ,Recombinant Proteins ,Antibodies, Anti-Idiotypic ,Immunoconjugate ,Liver ,Oncology ,Colonic Neoplasms ,Interferon Type I ,Spleen - Abstract
L6 is an IgG2a murine monoclonal antibody which we have demonstrated binds well to HT29 human colon carcinoma cells by flow cytometry, whole cell ELISA, and mixed hemadsorption. In vitro cytotoxicity studies revealed that the monoclonal antibody L6-cytosine deaminase (L6-CD) immunoconjugate plus the nontoxic prodrug, 5-fluorocytosine (5-FC), is equivalent to 5-fluorouracil (5-FU) in its ability to kill HT29 cells. Human alpha-interferon (A/D) was able to enhance this cytotoxic effect. The I.C.50's revealed that very small amounts of L6-CD are needed for this cytotoxic effect (approximately, 5 pg/ml resulted in 50% viability). The limiting factor was the amount of 5-FC employed with L6-CD (3 microM yielded 50% cell viability). alpha-Interferon (A/D) lowered the requirement of 5-FC to 1 microM to achieve 50% cell lethality. In vivo biodistribution experiments indicated that 1 microgram of L6-CD is nonspecifically taken up by the liver and spleen and cleared rapidly from the blood. Significant localization of L6-CD to HT29 tumors occurred only when 99 micrograms of unlabeled L6-CD was added to 1 microgram of 125I-labeled immunoconjugate injected intravenously. Further augmentation of tumor/blood ratios without reduction in percent injected dose per gram of tumor was possible with the intravenous injection of 100 micrograms of anti-idiotypic monoclonal antibody 13B, 24 hours after L6-CD, which bound unreacted L6-CD and cleared it from the blood. The addition of 100,000 U of alpha-interferon (A/D) given intraperitoneally every day increased the clearance of L6-CD by the liver and spleen, but impaired tumor localization (percent injected dose per gram). These studies demonstrated that in vivo localization of the L6-CD conjugate to HT29 tumors could be optimized by injecting excess L6-CD followed by an equal amount of L6 anti-idiotype mAb 13B, 24 hours after L6-CD.
- Published
- 1998
39. Close or positive margins after surgical resection for the head and neck cancer patient: The addition of brachytherapy improves local control
- Author
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Carl E. Silver, Doracy P. Fontenla, Bhadrasain Vikram, Jonathan J. Beitler, Mary Katherine Hayes, Scott Wadler, Richard V. Smith, S. M. Deore, Astrid Quish, and Eduard Mullokandov
- Subjects
Surgical resection ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Radiography ,medicine.medical_treatment ,Brachytherapy ,Iodine Radioisotopes ,medicine ,Positive Margins ,Carcinoma ,Humans ,Radiology, Nuclear Medicine and imaging ,Radiation ,business.industry ,Head and neck cancer ,Radiotherapy Dosage ,medicine.disease ,Surgery ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,Head and Neck Neoplasms ,Tonsil ,Carcinoma, Squamous Cell ,Female ,Radiotherapy, Adjuvant ,business - Abstract
Purpose: Microscopically positive or close margins after surgical resection results in an approximately 21-26% local failure rate despite excellent postoperative external radiation therapy. We sought to demonstrate improved local control in head and neck cancer patients who had a resection with curative intent, and had unexpected, microscopically positive or close surgical margins. Methods and Materials: Twenty-nine patients with microscopically close or positive margins after curative surgery were given definitive, adjuvant external radiation therapy and 125 I brachytherapy. All 29 patients had squamous cell cancer and tonsil was the most common subsite within the head and neck region. After external radiation therapy and thorough discussions with the attending surgeon and pathologists, the slides, gross specimens, and appropriate radiographs were reviewed and a target volume was determined. The target volume was the region of the margin in question and varied in size based on the surgery and pathologic results. Once the target volume was identified the patient was taken back to the operating room for insertion of 125 I seeds. Activity implanted (range 2.9-21.5 millicuries) was designed to administer a cumulative lifetime dose of 120-160 Gy. Results: Twenty-nine patients were followed for a median of 26 months (range 5-86 months). Two-year actuarial local control was 92%. Conclusion: 125 I, after external radiation therapy, is an excellent method to improve local control in the subset of patients with unexpectedly unsatisfactory margins.
- Published
- 1998
40. Measurement of deoxyuridine triphosphate and thymidine triphosphate in the extracts of thymidylate synthase-inhibited cells using a modified DNA polymerase assay
- Author
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Hong yang Zhang, Robert D. Ladner, Scott Wadler, Edward L. Schwartz, and Robert W. Horowitz
- Subjects
Antimetabolites, Antineoplastic ,DNA polymerase ,DNA-Directed DNA Polymerase ,Thiophenes ,Adenocarcinoma ,Biochemistry ,Thymidylate synthase ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Humans ,Thymine Nucleotides ,Enzyme Inhibitors ,Pyrophosphatases ,Thymidine triphosphate ,Polymerase ,Pharmacology ,chemistry.chemical_classification ,Deoxyuridine Triphosphate ,Dose-Response Relationship, Drug ,biology ,Templates, Genetic ,Thymidylate Synthase ,Molecular biology ,Kinetics ,Enzyme ,chemistry ,Enzyme inhibitor ,Colonic Neoplasms ,Quinazolines ,biology.protein ,Deoxyuracil Nucleotides ,Uracil nucleotide - Abstract
New inhibitors of the enzyme thymidylate synthase (TS) are now reaching clinical application. Alteration of the dUTP: dTTP ratio may be critical to TS inhibition-induced tumor cell death. The DNA polymerase assay with modification was used to rapidly and sensitively measure dUTP, dTTP, and dUTP:dTTP ratios in cell extracts of HT29 human colon carcinoma cells treated with the specific TS inhibitor ZD1694 [N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid]. These results revealed an increase in the dUTP:dTTP ratio at 2 hr after a 2-hr exposure to ZD1694 at concentrations of 0.05 to 0.2 microM with significant normalization at 16 hr after a 2-hr exposure despite evidence of continued TS inhibition. This assay is highly sensitive and reproducible for levels of dUTP and is less labor intensive than traditional assays.
- Published
- 1997
41. New Advances in Interferon Therapy of Cancer
- Author
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Edward L. Schwartz and Scott Wadler
- Subjects
Cancer Research ,Combination therapy ,business.industry ,Melanoma ,Cancer ,medicine.disease ,Non-Hodgkin's lymphoma ,Clinical trial ,Oncology ,Interferon ,Immunology ,Adjuvant therapy ,Cancer research ,Medicine ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Substantial increases in both the understanding of the cellular mechanisms of actions of interferon (IFN) and in its clinical use in cancer have occurred in recent years. The efficacy of interferon for the treatment of select malignancies has been established, and IFN-α and IFN-β have been approved by the Food and Drug Administration for multiple clinical indications. IFN-α increased median survival and relapse-free survival in patients with locally advanced melanoma when used as adjuvant therapy and had modest activity against advanced disease. In other tumors where studies indicated that IFN lacked direct therapeutic activity, clinical trials suggested that it increased the antitumor activity of cytotoxic chemotherapeutic agents when used in combination therapy. IFN has substantial activity in chronic myelogenous leukemia, increasing survival in patients in early chronic phase when compared with conventional chemotherapy, and has some activity in non-Hodgkin's lymphoma in combination with cytotoxic agents. Recent molecular and pharmacologic studies defining cellular receptor activation, signal transduction pathways, and biochemical modulating activities of interferon have yet to be fully incorporated into clinical development. Further preclinical advances along with the expanding identification of potentially clinically sensitive tumors make it likely that the use of IFN in cancer chemotherapy will continue to grow.
- Published
- 1997
42. An ECOG Phase II Study of Amonafide in Unresectable or Recurrent Carcinoma of the Head and Neck (PB390)
- Author
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Andrea N. Leaf, Scott Wadler, Donna Neuberg, Edward L. Schwartz, Janice P. Dutcher, George L. Adams, and Paul S. Ritch
- Subjects
Pharmacology ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Head and neck cancer ,Phases of clinical research ,Amonafide ,Urine ,medicine.disease ,Gastroenterology ,Oncology ,Pharmacokinetics ,Internal medicine ,Anesthesia ,Toxicity ,Carcinoma ,Medicine ,Pharmacology (medical) ,business - Abstract
The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m2, over two hours each day for five consecutive days every 21 days. There was one partial response [39] which lasted four months. The dose limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m2 for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.
- Published
- 1997
43. All-trans retinoic acid and interferon-?-2a in patients with metastatic or recurrent carcinoma of the uterine cervix
- Author
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Scott Wadler, Gary L. Goldberg, H. Haynes, Abbie Fields, Robert E. Gallagher, Robert C. Wallach, Steven J. Hallam, Ronalde Rameau, Carolyn D. Runowicz, Scott Jennings, John Mandeli, Astrid Quish, Edward L. Schwartz, and Frances McGill
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Alpha interferon ,Gastroenterology ,Metastatic carcinoma ,Clinical trial ,Regimen ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Pharmacokinetics ,Epidermoid carcinoma ,Internal medicine ,medicine ,business ,Cervix ,Interferon alfa ,medicine.drug - Abstract
BACKGROUND Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.
- Published
- 1997
44. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer
- Author
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Enrique Velez-Garcia, Richard A. Gams, Darcy V. Spicer, Ajit Desai, Sandra M. Swain, Joseph R. Bianchine, James L. Speyer, Steven Weisberg, Abraham Mittelman, Fredrick S. Whaley, Martin York, Stephen E. Jones, Scott Wadler, Kelly Pendergrass, Sandeep K. Reddy, Miriam C. Gerber, Charles L. Vogel, and Michael S. Ewer
- Subjects
Cancer Research ,medicine.medical_specialty ,Combination therapy ,Cyclophosphamide ,medicine.medical_treatment ,Urology ,Breast Neoplasms ,Disease-Free Survival ,Double-Blind Method ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Doxorubicin ,Prospective Studies ,Aged ,Heart Failure ,Chemotherapy ,Antibiotics, Antineoplastic ,Ejection fraction ,business.industry ,Cardiovascular Agents ,medicine.disease ,Survival Analysis ,Surgery ,Treatment Outcome ,Oncology ,Fluorouracil ,Heart failure ,Female ,Dexrazoxane ,Razoxane ,business ,medicine.drug - Abstract
PURPOSE To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.
- Published
- 1997
45. Chemo-embolization in the treatment of liver metastases from colorectal cancer
- Author
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Scott Wadler and Stefano Cascinu
- Subjects
medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Rectum ,Antineoplastic Agents ,Malignancy ,Gastroenterology ,Cachexia ,Metastasis ,Internal medicine ,Ascites ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Embolization ,Chemoembolization, Therapeutic ,Clinical Trials as Topic ,Chemotherapy ,business.industry ,Liver Neoplasms ,General Medicine ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Injections, Intra-Arterial ,Oncology ,medicine.symptom ,Colorectal Neoplasms ,business - Abstract
Colorectal cancer is the third most common malignancy in the U.S.A., with approximately 147,000 newly-diagnosed cases yearly and 66,000 deaths (1). Liver metastases are present at diagnosis in 1520% of patients and occur in 60% of patients who subsequently develop advanced disease, making the liver the most common site of metastatic disease (2). The presence of hepatic metastases has a major influence on survival, even when metastatic disease is present at other sites. Survival of untreated patients with liver metastases generally ranges from a few months up to 2 years, depending on the tumour volume and biological characteristics of the tumour, and they often die as a consequence of ascites, cachexia or hepatic failure (3). Surgical re-section offers the only potential for cure for patients with liver metastases, but it is feasible in only the minority of cases (4). The remaining patients have extrahepatic disease, bulky metastases, bilateral metastases or metastases which cannot technically be re-sected. Thus, only about 5000 patients each year in the U.S.A. are suitable candidates for surgical exploration and possible re-section of hepatic metastases. They represent only 34% (IOOO-1,500 of 40,000) of patients with liver metastases (4). The use of conventional intravenous chemotherapy for patients with liver metastases from colorectal cancer has generally produced responses in only lo-20% of patients, is marginally effective in palliation, gives no survival prolongation, and requires prolonged treatment with inevitable systemic toxicities (2). Thus, strategies to deliver locoregional treatment are logical to explore. In the early 196Os, the concept of administering chemotherapy into the
- Published
- 1996
46. Phase I/II study of PIXY321 in combination with cyclophosphamide and carboplatin in the treatment of ovarian cancer
- Author
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James F. Holland, Howard S. Hochster, Scott Wadler, John Mandeli, Carolyn D. Runowicz, James L. Speyer, and Leslie Garrison
- Subjects
Adult ,medicine.medical_specialty ,Neutropenia ,Cyclophosphamide ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Ovary ,Gastroenterology ,Carboplatin ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Dosing ,Aged ,Ovarian Neoplasms ,Chemotherapy ,business.industry ,Granulocyte-Macrophage Colony-Stimulating Factor ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Surgery ,medicine.anatomical_structure ,chemistry ,Toxicity ,Female ,Interleukin-3 ,Ovarian cancer ,business ,medicine.drug - Abstract
OBJECTIVE: Our purpose was to evaluate the safety and biologic effects of PIXY321 after chemotherapy in patients with ovarian carcinoma. STUDY DESIGN: A multicenter, nonrandomized, phase I/II study of subcutaneously administered PIXY321 after the second cycle of chemotherapy in cohorts of three or more patients at 50, 125, 250, 500, 750, or 1000 μg/m 2 per day. RESULTS: Cyclophosphamide (600 mg/m 2 ) and carboplatin (400 mg/m 2 ) were administered every 28 days to 34 patients. At doses ≥ 500 mg/m 2 per day, the median nadir platelet and median nadir absolute neutrophil counts in cycle 2 (with PIXY321) compared with cycle 1 (control) were both higher in 13 of 26 (50%) patients. Twenty-one patients were withdrawn from the study. A total of 17 of 21 (81%) were removed for myelosuppression ( n = 15) or PIXY321 toxicity ( n = 2). A total of 28 of 34 (82%) patients had injection site reactions. Thirty-seven nonhematologic grade 3 events occurred. CONCLUSIONS: At these doses and schedules PIXY321 can be safely administered. Aggressive dosing of cyclophosphamide and carboplatin could not be maintained for six cycles in the majority (62%) of patients. (AM J OBSTET GYNECOL 1996;174:1151-60.)
- Published
- 1996
47. Audiological findings in a Phase I protocol investigating the effect of WR 2721, high-dose cisplatin and radiation therapy in patients with locally advanced cervical carcinoma
- Author
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Alla Rozenblet, Hilda Haynes, Scott Wadler, Carolyn D. Runowicz, Gary L. Goldberg, John Rubin, Jonathan J. Baitler, and Frances McGill
- Subjects
Oncology ,Radiation-Sensitizing Agents ,medicine.medical_specialty ,Hearing Loss, Sensorineural ,medicine.medical_treatment ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,Radiation-Protective Agents ,Amifostine ,Audiometry ,Ototoxicity ,Internal medicine ,Carcinoma ,Humans ,Medicine ,Cisplatin ,Chemotherapy ,Epithelioma ,business.industry ,Drug Tolerance ,General Medicine ,medicine.disease ,Combined Modality Therapy ,Surgery ,Radiation therapy ,Otorhinolaryngology ,Toxicity ,Female ,business ,medicine.drug - Abstract
WR 2721 (ethiofos) protects against the toxic effects of the heavy metal compound cisplatin. which is used in the treatment of solid tumours. In a Phase I protocol designed to determine the maximum dose of WR 2721 which could be tolerated when administered in combination with cisplatin and radiation therapy to patients with cervical carcinoma. 11 patients were evaluated by audiologic testing before and after cisplatin WR 2721 administration in an attempt to identify the degree of ototoxicity. Forty-five per cent were noted to have significant hearing threshold changes. predominantly in the high frequencies. There were no significant changes in the speech frequencies in this series. This contrasts with the greater degrees of ototoxicity observed in controls treated in the same way who received cisplatin without WR 2721 protection.
- Published
- 1995
48. Thymidine Phosphorylase Mediates the Sensitivity of Human Colon Carcinoma Cells to 5-Fluorouracil
- Author
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Della F. Makower, Nicole Baptiste, Scott Wadler, and Edward L. Schwartz
- Subjects
chemistry.chemical_classification ,Thymidine Phosphorylase ,Expression vector ,Interferon-alpha ,Cell Biology ,Transfection ,Biology ,Biochemistry ,Molecular biology ,In vitro ,Enzyme ,chemistry ,In vivo ,Colonic Neoplasms ,Tumor Cells, Cultured ,Humans ,Fluorouracil ,Thymidine phosphorylase ,Cytotoxicity ,Molecular Biology ,IC50 - Abstract
Interferon-alpha (IFN alpha) potentiates the antitumor activity of 5-fluorouracil (FUra) in colon cancer in vitro, in vivo, and clinically. A likely mechanism for this action is the induction by IFN alpha of thymidine phosphorylase (TP), the first enzyme in one pathway for the metabolic activation of FUra to fluorodeoxyribonucleotides. To test this hypothesis, an expression vector containing the TP cDNA was transfected into HT-29 human colon carcinoma cells. Five stable transfectants were selected and analyzed. All showed increased sensitivity to FUra cytotoxicity, ranging from a 2-fold to a 19-fold decrease in the IC50 for FUra, compared to wild-type cells. Levels of TP mRNA, protein, and enzyme activity were elevated in the transfectants, and there was a significant correlation between the relative increase in sensitivity to FUra and both the increase in both TP mRNA levels and TP activity. Transfected cells exhibited increased formation of FdUMP, but not the ribonucleotides FUDP and FUTP, from FUra when compared to wild-type cells. The changes in TP activity, FdUMP formation, and FUra sensitivity in the transfected cells were comparable with those seen after treatment of wild-type cells with IFN alpha. These studies provide direct evidence for the role of TP in mediating the sensitivity of colon carcinoma cells to FUra, and further support the importance of the induction of TP in the biomodulating action of IFN alpha on FUra chemosensitivity.
- Published
- 1995
49. Phase II trial of chemotherapy, external and intraluminal radiation plus surgery for oesophageal cancer
- Author
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H. Haynes, Scott Wadler, Barry A. Levine, Stanley C. Fell, Jonathan J. Beitler, Ellen L. Wolf, and Alla M. Rozenblit
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,medicine.medical_treatment ,Brachytherapy ,Alpha interferon ,Pilot Projects ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Chemotherapy ,business.industry ,Esophageal disease ,Granulocyte-Macrophage Colony-Stimulating Factor ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Recombinant Proteins ,High-Dose Rate Brachytherapy ,Surgery ,Regimen ,Oncology ,Fluorouracil ,Interferon Type I ,Feasibility Studies ,Female ,Nuclear medicine ,business ,Hyperfractionation ,medicine.drug - Abstract
A pilot study was performed to assess the feasibility of combining 5-fluorouracil, recombinant alpha-2b-interferon, external radiation therapy and intraluminal high dose rate brachytherapy with surgery in patients with locally advanced esophageal carcinoma. 5-fluorouracil, 750 mg m-2, was administered via continuous 5-day infusion beginning day 1 and weekly thereafter; interferon, 10 mu subcutaneously, was administered three times per week beginning day 1 and sargramostin, 5 micrograms kg-1, was administered on days without 5-fluorouracil. External radiation began on day one using 1.5 daily fractions to 55.5 Gy. Intraluminal brachytherapy was delivered concomitantly once each week for 5 fractions of 4 Gy. None of the first eight patients went to surgery. The external radiation was changed to 1.5 Gy BID to 45 Gy followed by BID intraluminal radiation to 15 Gy. Of the last four patients, there was one case of radiation myelitis. It was found that successful surgery was not possible and excessive toxicities, including radiation myelitis, occurred with this aggressive regimen.
- Published
- 1995
50. Modulation of 5-fluorouracil by interferon: a review of potential cellular targets
- Author
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Edward L. Schwartz, Robert W. Horowitz, and Scott Wadler
- Subjects
Cancer Research ,medicine.medical_treatment ,Antineoplastic Agents ,Interferon ,Neoplasms ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Thymidine Phosphorylase ,Neovascularization, Pathologic ,Chemistry ,Cell Cycle ,Thymidylate Synthase ,Hematology ,General Medicine ,Drug interaction ,Combined Modality Therapy ,Cytokine ,Oncology ,Mechanism of action ,Fluorouracil ,Immunology ,Cancer research ,Interferons ,medicine.symptom ,Thymidine ,medicine.drug - Published
- 1995
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