Cancer Chemotherapy by Infusion

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1 Cancer Chemotherapy by Infusion Second Edition Precept Press, Inc. Chicago

2 CONTENTS Preface xvii SECTION I RATIONALE AND TECHNICAL ASPECTS 1. Experimental Rationale for Continuous Infusion Chemotherapy 3 R. Brian Mitchell, M.D., Mark J. Ratain, M.D., and Nicholas J. Vogelzang, M.D. Introduction 3 Antimetabolites 6 Plant Alkaloids 11 Alkylating Agents 14 Antineoplastic Antibiotics 19 Miscellaneous Agents 23 Biological Agents 23 Conclusion Clinical Pharmacology of Infusional Chemotherapy 35 Gregory A. Curt, M.D., and Jerry M. Collins, Ph.D. Pharmacokinetics of Infusional Therapy 37 Regional Therapy Cellular Basis for Infusional Chemotherapy 42 Frederick A. Valeriote, Ph.D., and Mark Edelstein, M.D, Ph.D. Introduction 42 Generation Time and Its Variance 43 Progression Delay 46 Recruitment 47 Dose-Limiting Normal Tissues 49 Discrepancies between Theory and Experimental Data 50 Conclusion 50 VII

3 Viii CANCER CHEMOTHERAPY BY INFUSION 4. Stability and Compatibility of Admixtures of Antineoplastic Drugs 52 David A. Williams, Ph.D. Pharmaceutic Principles 56 Stability of Individual Antineoplastic Agents 61 Antibiotics 61 Alkylating Agents 64 Antimetabolites 66 Metal Complexes 67 Stability of Two- and Three-Agent Admixtures Principles of Phase 1 Studies for Infusion Schedules 74 Types of Infusional Chemotherapy 75 Preclinical Pharmaceutical Analysis 76 Experimental Design of Phase 1 Trials 76 Patterns of Dose-Limiting Toxicity 78 Protracted Infusion Dose Studies 78 Maximum Tolerated Dose and Dose Rates Relative to Duration of Infusion 79 Experimental Design for Admixture Infusions 80 Summary 80 SECTION II CHEMOTHERAPEUTIC AGENTS 6. The Pyrimidine Antagonists: 5-Fluorouracil and Floxuridine 85 Bach Ardalan, M.D, Stuart Waldman, M.D, and Lilliam Sklaver, Pharm.D. Introduction 85 Anabolic Enzymes 89 Target Enzymes 98 Catabolic Enzymology 99 Pharmacologic Modulations of 5-FU Activity 100 Clinical Pharmacology and Assay Methods 104 Clinical Studies Purine Antimetabolites 122 Solomon Zimm, M.D, F.A.C.P. Drug Chemistry and Pharmaceutical Information 122 Pharmacology 123 Clinical Pharmacology 124 Standard Bolus Regimens 125

4 Contents ix Spectrum of Activity 125 Mercaptopurine Administered by Intravenous Infusion 125 Thioguanine Administered by Intravenous Infusion Infusional Methotrexate 128 Carmen J. Allegra, M.D., and Gregory A. Curt, M.D. Introduction 128 Theoretical Considerations 129 Clinical Investigations Cytosine Arabinoside 137 Ross C. Donehower, M.D, F.A.C.P., and Eric K. Rowinsky, M.D. Clinical and Biochemical Pharmacology: Rationale for Infusion 138 Use of Ara-C in Bolus or Short Infusion Schedules 142 Use of Ara-C by Continuous Infusion 144 Comparison of Bolus and Continuous Ara-C Administration 148 Present Status of Continuous Infusion Ara-C; Future Areas to Explore The Periwinkle Alkaloids 155 Don V. Jackson Jr., M.D. Background 155 Clinical Trials 159 Conclusion Cisplatin, Carboplatin, and Gallium Nitrate 176 Everett E. Vokes, M.D, Stephen P. Ackland, M.D, and Nicholas J. Vogelzang, M.D. Cisplatin 176 Carboplatin 185 Gallium Nitrate The Anthracyclines and Mitoxantrone 197 Sewa S. Legha, M.D. Introduction 197 General Considerations 198 Pharmacologic Parameters 199 Methods of Doxorubicin Infusion 200 Therapeutic Implications of Doxorubicin Infusion 204 Anthracycline Analogues 206 Mitoxantrone (Novantrone) 212

5 CANCER CHEMOTHERAPY BY INFUSION 13. Bleomycin 218 Robert B. Catalano, Pharm.D, and Robert L. Comis, M.D. Mechanism of Action 218 Pharmacology 219 Bleomycin Toxicology 220 Animal Studies 220 Pharmaceutical Data 221 Clinical Trials in Humans 222 Summary Alkylating Agents 230 Introduction 230 Infusion and Comparative Trials 231 Bone Marrow Transplantation and Infusional Alkylating Agents 237 Summary The Epipodophyllotoxins 240 Robert L. Comis, M.D. Introduction 240 Mechanism of Action 241 Clinical Pharmacology 241 Schedule Dependency 245 Pharmaceutical Data 245 Clinical Trials 246 Discussion Biological Response Modifiers 253 Michael E. Osband, M.D. Introduction 253 Tumor Immunobiology 254 Problems with Biological Response Modifiers 254 Specific Agents 257 Continuous Infusion Therapy with Biological Response Modifiers 263 A Final Perspective Investigational Agents on Infusional Schedules 270 Drug Classification 271 Drugs Specifically Evaluated on an Infusion Schedule 272 Summary 275

6 Contents xi 18. Hematopoietic Growth Factors in Cancer Treatment 278 Clinical Applications of Growth Factors 279 Rationale for Schedule Dependency 279 GM-CSF in Solid Tumors 281 GM-CSF with Bone Marrow Transplantation 282 Growth Factors as Primary Treatment of Malignancy and Hematologic Disorders 283 Clinical Status of Growth Factors 284 SECTION III SYSTEMIC INFUSION BY TUMOR SITE 19. Head and Neck Cancer 289 Efstathios Tapazoglou, M.D, F.A.C.P., John F. Ensley, M.D, F.A.C.P., Julie A. Kish, M.D, F.A.C.P., and Muhyi Al-Sarraf, M.D, F.R.C.P.(C), F.A.C.P. Introduction 289 Single-Agent Chemotherapy 290 Combination Chemotherapy 292 Neoadjuvant Chemotherapy 292 Chemotherapy Combined with Radiotherapy 293 Rationale for Infusion Chemotherapy 294 Clinical Trials 296 Summary Esophageal and Anal Carcinoma 313 Paul F. Engstrom, M.D., Lawrence R. Coia, M.D., and Edward M. Soffen, M.D. Incidence and Etiology of Squamous Cell Carcinoma of the Esophagus and Anus 313 Staging and Patterns of Spread 314 Surgical Therapy 316 Radiation as a Primary Modality 317 Single-Agent Chemotherapy for Esophageal Cancer 317 Combination Chemotherapy and Radiotherapy for Anal Carcinoma 318 Chemotherapy and Radiotherapy for Esophageal Carcinoma 319 Future Prospects and Applications Colon and Rectal Cancer 323 Standard Bolus 5-Fluorouracil 324 Infusional 5-Fluorouracil 325 Combination Therapy with Infusional 5-Fluorouracil 329

7 Xii CANCER CHEMOTHERAPY BY INFUSION Biochemical Modulation of 5-Fluorouracil 330 Adjuvant Infusional Trials in Colorectal Cancer 333 Future Applications Gastric and Pancreatic Carcinomas 340 Richard M. Hansen, M.D. Cancer of the Stomach 340 Cancer of the Pancreas 346 Conclusion and Future Directions Breast Cancer 358 Craig J. Gordon, D.O., and Laurence H. Baker, DO. Protracted Infusion of Anthracycline Derivatives 359 Continuous Infusion of Fluorinated Pyrimidines 362 Protracted Infusion of Vinca Alkaloids 365 Prolonged Infusion of Miscellaneous Agents Hematologic Malignancies 372 Murray M. Bern, M.D. Vinca Alkaloids 373 Epipodophyllotoxins 375 Antibiotics 375 Alkylating Agents 377 Antimetabolites 378 Metals 382 New Drugs 383 Combination Chemotherapy 386 Conclusion Lung Cancer 400 James D. Ahlgren, M.D. Nonsmall-Cell Lung Cancer (NSCLC) 400 Small-Cell Lung Cancer 412 Conclusions and Direction of Continuing Research Cancers of the Kidney, Bladder, and Prostate 421 Jon T. Holmlund, M.D, and Richard Schulof, M.D, Ph.D., F.A.C.P. Renal Cell Cancer 421 Bladder Cancer 438 Prostate Cancer 445

8 Contents xiii 27. Gynecologic Malignancies 463 Rolland J. Barrett, M.D, and Hyman B. Muss, M.D. Introduction 463 Cancer of the Cervix 465 Ovarian Cancer 474 Other Sites 477 Conclusion Soft-Tissue and Osteogenic Sarcomas 484 C. Julian Rosenthal, M.D. Intravenous Bolus Chemotherapy 487 Systemic Infusional Chemotherapy 491 Regional Infusion Chemotherapy 493 Combined Modality Therapy 495 Conclusion Testicular Cancer 501 Norwood R. Anderson, M.D. Clinical Staging for Testicular Cancers 501 Chemotherapy: Early Trials 503 Cisplatin-Based Combination Chemotherapy Regimens 505 Review of Recent Literature and Chemotherapy Protocols 509 Theoretical Role for Infusional Therapy in Advanced Testis Cancer 512 Conclusion 514 SECTION IV SPECIAL CATEGORIES OF INFUSION CHEMOTHERAPY 30. Combined Modality Infusional Chemotherapy with Radiation 521 John E. Byfield, M.D., Ph.D. Introduction 521 Preclinical Studies 522 Development of Clinical 5-FU RS Programs 533 Current Clinical Status of Infused 5-FU and X Rays 536 Conclusion Intraperitoneal 'Belly Bath' Chemotherapy 552 Maurie Markman, M.D. Principles of Intraperitoneal Chemotherapy 552 Toxicities Associated with Intraperitoneal Chemotherapy 557

9 XiV CANCER CHEMOTHERAPY BY INFUSION Single-Agent Intraperitoneal Trials 558 Combination Intraperitoneal Trials 563 Intraperitoneal Administration of Biological Agents 564 Innovative Programs Employing the Intraperitoneal Route 564 Conclusion Combination Chemotherapy and Infusional Schedules 575 Introduction 575 Tactics of Infusional Combination Chemotherapy 576 Combination Chemotherapy with Single-Agent Infusions and Added Bolus 577 Combination Chemotherapy Using Drug Admixtures 580 Summary and Outlook 584 ' 33. Hepatic Regional Infusion Chemotherapy 587 JohnM. Daly, M.D, NoelN. Williams, F.R.C.S.(I), and Michael H. Torosian, M.D. Introduction 587 Rationale for Regional Infusion Chemotherapy 588 Intrahepatic versus Systemic Infusion 590 Hepatic Artery versus Portal Vein 592 Tumor Blood Supply and Drug Uptake 594 Summary Regional Perfusion for Extremity Lesions 599 Harold J. Wanebo, M.D, Virginia R. Litle, M.D, and James H. Muchmore, M.D. Background 599 Preclinical Experimental Observations 600 Effects of Hyperthermia 602 Clinical Studies: Melanoma 603 Complications of Perfusion 611 Clinical Studies of Soft-Tissue Sarcoma Chronobiology of Cancer Therapy: Prototype Use of Fluoropyrimidine Infusions 619 Reinhard W. von Roemeling, M.D., and William J. M. Hrushesky, M.D. Introduction 619 Preclinical Circadian Studies of Fluoropyrimidine Toxicity 622 Discussion 640 Conclusion 643

10 Contents xv 36. Monitoring Plasma Concentrations of Clinically Useful Antineoplastics During Continuous Infusion Chemotherapy 647 Mark J. Ratain, M.D. Therapeutic Drug Monitoring 648 Summary 651 Index 653

Cancer Chemotherapy by Infusion

Cancer Chemotherapy by Infusion Cancer Chemotherapy by Infusion Jacob J. Lokich, M.D. ~ MTP PRESS LIMITED... ~ a member of the KLUWER ACADEMIC PUBLISHERS GROUP _.' LANCASTER / BOSTON / THE HAGUE / DORDRECHT