Richard Pazdur, MD

Preface

On November 20, 2008, the US Food and Drug Administration (FDA) granted accelerated approval for eltrombopag (Promacta Tablets, GlaxoSmithKline) for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulin therapy, or splenectomy.

On August 22, 2008, the US Food and Drug Administration (FDA) granted marketing approval (licensure) to romiplostim (Nplate, Amgen Inc) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.

Liposomal doxorubicin received FDA approval for use in combination with bortezomib in patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

The fundamental principle behind this book, as stated by the publisher, The Oncology Group (also publisher of the journal ONCOLOGY and news magazine Oncology News International) was to provide a truly integrated, multidisciplinary approach to the management of cancer patients. For this updated 10th edition, the editors have enlisted 114 medical, surgical, and radiation oncologists, whose contributions provide an excellent overview of the important principles of cancer management.

This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis.

Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.

Drugs approved by the US Food and Drug Administration (FDA) must demonstrate substantial evidence of efficacy from adequate and well-controlled trials and be safe for their intended use. A 1962 amendment to that Act codifies the efficacy requirement. Guidance promulgated in the 1980s indicated that efficacy should represent a "clinical benefit" demonstrated by prolongation of life, better life, or effect on an established surrogate for at least one of these. Direct clinical benefit assessments have included improvements in survival, physical functioning, or tumor-related symptoms.

In the United States, cancer of the large bowel is the second most common cause of cancer deaths after cancer of the lung [1]. 1995 estimates place large bowel cancer as the third most common malignancy, behind lung and prostate carcinomas in men and behind lung and breast cancers in women.

Fluorouracil (5-FU) has remained the standard therapy for the treatment of advanced colorectal cancer for over 40 years. Unfortunately, only a minority of patients experience objective clinical response.

Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly

The use of combined modality regimens has been well established in the treatment of stages II and III rectal cancer. The most common chemotherapy regimens used include continuous-infusion 5-FU delivered with the help of a central venous catheter and the use of portable pumps.

Heidelberger and associates[1] synthesized fluorouracil (5-FU) in 1957 after observing that rat hepatomas utilized radiolabeled uracil more avidly than malignant tissues. For the past 40 years, 5-FU has been extensively investigated in various schedules, in combination with biochemical modulators, and for a variety of malignancies.[2]

Fluorouracil (5-FU) is one of the most extensively investigated chemotherapy agents in medical oncology. Generations of medical oncologists have equated this agent with the optimal treatment of colorectal cancer, both in the advanced and

Oxaliplatin is a unique platinum compound with single-agent activity in both chemotherapy-naïve colorectal cancer patients and patients who progressed on 5-fluorouracil (5-FU). The combination of oxaliplatin and 5-FU

Protracted infusions of 5-fluorouracil (5-FU) combined with pelvic radiotherapy have been associated with improved survival and decreased local and distant metastases in the adjuvant therapy of rectal cancer. However,

Discussed herein are selected oral fluorinated pyrimidines that are converted to 5-fluorouracil (5-FU) in vivo to exert antitumor activity. These agents include capecitabine (Xeloda), tegafur-uracil (UFT) plus leucovorin (Orzel), and S-1 (BMS247616). These agents offer the convenience of an orally administered therapy with potentially fewer toxic effects than conventional bolus regimens of 5-FU plus leucovorin. These oral agents provide prolonged 5-FU exposure at lower peak concentrations than observed with bolus intravenous administration of 5-FU and may confer pharmacoeconomic advantages by reducing administration costs and toxicity-related hospitalizations. These regimens also have the potential for improved therapeutic activity by achieving higher 5-FU concentrations in the tumor or by biochemically modulating 5-FU. Phase III trials in patients with advanced colorectal carcinomas are comparing the antitumor activity of these agents with that of intravenous 5-FU plus leucovorin. [ONCOLOGY 12(Suppl 7):48-51, 1998]

Nearly a decade ago, irinotecan (CPT-11 [Camptosar]) began clinical development in Japan. Early clinical trials in that country recognized its anti-tumor activity in a variety of advanced malignancies, including stomach, colon, cervical, and lung

The objective response rate is the initial method to assess the activity of a novel anticancer agent. Response rates may not characterize a new agent’s clinical benefit, however, especially if moderate to severe toxicity may be

Although the combination of uracil and tegafur (UFT) has been available commercially in Japan since 1984 and is one of the most extensively prescribed antineoplastic agents in that country, few physicians outside Japan have knowledge of and

The phase I development program of tegafur and uracil (UFT) in the United States has included evaluation of the drug as a single agent and subsequent studies of its biochemical modulation by oral leucovorin. Phase I trials of single-agent UFT examined both a 5-day schedule repeated every 21 days and a 28-day schedule repeated every 35 days. In all of the trials the total dose was divided by three and administered three times daily at 8-hour intervals. Like intravenous schedules of fluorouracil (5-FU), UFT has schedule-dependent toxicity, with granulocytopenia being the dose-limiting toxicity for the 5-day regimen and diarrhea being the dose-limiting toxicity for the 28-day regimen. The suggested phase II doses for UFT administered without leucovorin were 800 mg/m2/day for the 5-day schedule and 360 mg/m2/day for the 28-day schedule. Subsequent phase I studies combining UFT with oral leucovorin used a 28-day schedule repeated every 35 days. Diarrhea was the dose-limiting toxicity, and the recommended phase II dose was UFT, 300 mg/m2/day, plus leucovorin, 90 mg/day. Pharmacokinetic evaluation showed that single-dose UFT results in maximum plasma levels and an area under the concentration-time curve that increased with escalating UFT doses. In addition, 5-FU levels were detectable throughout the 28-day dosing period; however, there was no evidence of significant accumulation of uracil, tegafur, or 5-FU. The administration of leucovorin in this trial provided continuous exposure of d,l-leucovorin and 5-methyltetrahydrofolate with little variation between doses or days.[ONCOLOGY 11(Suppl 10):35-39, 1997]

Several trials performed in the United States and Europe have demonstrated the efficacy of UFT (uracil and tegafur in a 4:1 molar combination) with oral leucovorin in the treatment of several tumor types, but particularly

The article by Eckardt et al reviews numerous anticancer drugs presently undergoing clinical development in the United States. These drugs have an array of biochemical targets. Some agents, such as the camptothecin analogs, represent a novel class of antineoplastic drugs. Other drugs, such as docetaxel (Taxotere), are analogs of currently available drugs (paclitaxel [Taxol]) [1,2]. Still other agents, such as thymidylate synthase (TS) inhibitors (eg, ZD1694 [Tomudex], AG-331, and LY231514) and 5-ethynyluracil, a uracil reductase inhibitor, have been designed prospectively to inhibit specific enzymatic pathways [3-5]. Some agents discussed have preliminary activity in refractory diseases, such as that of irinotecan (CPT-11) in fluorouracil-refractory colon carcinoma and that of docetaxel in cisplatin (Platinol)-refractory non-small-cell lung carcinoma, or show activity in diseases for which standard therapies are less than optimal.