bluuebunny/crossref_metadata_2025 huggingface dataset:
Progress and Promise in the Treatment of Indolent Lymphomas
Authors: McLaughlin Peter
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe subsets of patients with indolent lymphoma for whom cure may be a realistic goal. Describe the ways by which the polymerase chain reaction for bcl-2 can be utilized to monitor patients with follicular lymphoma. Identify immunotherapy approaches that have shown promising results for patients with indolent lymphoma.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

In the era of conventional alkylating agent-based chemotherapy, advanced stage indolent lymphoma has been considered incurable. The failure of our traditional therapies to cure these patients, coupled with the indolent course of the disease and the elderly population affected, has fostered a nihilistic attitude about the treatment of these diseases. Twenty years ago, in the absence of interesting alternatives to alkylating agents, judicious use and reuse of alkylators was perhaps the best we could do. There are now many reasons for optimism and excitement in the treatment of these diseases, including the availability of promising agents such as interferon-α, the nucleoside analogues, and rituximab. Radioimmunotherapy will also likely play a role in future therapy programs. Allogeneic stem cell transplantation is a high-risk approach that is not an option for all patients, but it has the potential to cure patients, even in the setting of relapse. Mini-allogeneic transplantation may permit an approach to allogeneic transplantation that is better tolerated than standard transplant strategies. In addition to these therapy options, biological insights have provided new options for monitoring patients. Molecular monitoring (polymerase chain reaction for bcl-2) is a stringent measure of short-term treatment efficacy, and one that correlates with durability of remission, i.e., it is a surrogate marker by which to judge treatment efficacy. There used to be a limited number of conventional treatment approaches, which consistently failed. The pendulum has swung. There are now many promising new options. It is time to plan and conduct trials that are geared for success.
Is There a Preferred Combination Chemotherapy Regimen for Metastastic Non-Small Cell Lung Cancer?
Authors: Ettinger David S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Choose the appropriate chemotherapeutic regimen to treat a patient with metastatic non-small cell lung cancer. Identify the advantages and disadvantages of the various regimens to treat stage IV non-small cell cancer. Understand the toxicities associated with each of the various chemotherapeutic regimens.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Since over 70% of patients with non-small cell lung cancer (NSCLC) have advanced (locally advanced or metastatic) disease, the majority of NSCLC patients might benefit from chemotherapy. During the past decade, a number of new agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan) have been found to be effective against lung cancer. These agents have been combined with cisplatin, carboplatin, and nonplatinum drugs to treat NSCLC. They, in general, produce median survival times of 8-10 months and 1- and 2-year survival rates of 35%-40% and 10%-15%, respectively. Based on this review, there is not a preferred combination chemotherapy regimen to treat advanced NSCLC patients. However, there are a number of different regimens from which to choose.
Small Cell Lung Cancer: Current Therapy and Promising New Regimens
Authors: Okuno Scott H. , Jett James R.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Understand the treatment options for limited versus extensive small cell lung cancer. Understand the role of prophylactic cranial irradiation for small cell lung cancer. Understand second-line chemotherapy regiments for small cell lung cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

In this review, we cover current therapy and promising new regimens and highlight areas where improvement is needed in the management of small cell lung cancer.
The Molecular Perspective: Bcl-2 and Apoptosis
Authors: Goodsell David S.
Published: August 2004

Learning Objective

After completing this course, the reader will be able to:

Gain a basic understanding of the structure and function of the bcl-2 family of proteins, and their place in apoptosis and cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Staging of Regional Nodes in AJCC Stage I and II Melanoma: 18FDG PET Imaging versus Sentinel Node Detection
Authors: Belhocine Tarik , Pierard Gérald , de Labrassinne Michel , Lahaye Thierry , Rigo Pierre
Published: August 2004

Primary Purpose. The staging of regional nodes by means of sentinel node detection has been shown to accurately detect subclinical nodal metastases from cutaneous melanoma. On the other hand, the oncological applications of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) are, nowadays, firmly established. However, the sensitivity of such metabolic imaging for staging the regional nodes in primary melanoma remains debatable. We prospectively assessed the actual value of PET for detecting sentinel node metastases in 21 consecutive patients presenting with early-stage melanoma.

Materials and Methods. Twenty-one melanoma patients scheduled for lymphatic mapping and sentinel lymphadenectomy underwent fully corrected whole-body PET using 18FDG. In all cases, the disease was initially classified as either stage I or II, from the latest version of the American Joint Committee on Cancer staging system. The sentinel node detection was systematically performed within the week following the PET scan. Serial sections of the sentinel nodes were analyzed by both conventional pathology and immunohistochemical staining. Metastatic sentinel nodes were also assessed for the size of tumor deposits and the degree of nodal involvement (focal, partial, or massive). The median follow-up time was 12 months.

Results. Six of the 21 patients (28.5%) had an involved sentinel node. PET was positive in only one case with a sentinel node >1 cm. In the five other cases, the sentinel nodes missed by PET were <1 cm with focal and/or partial involvements. One patient, free of regional nodal metastases in both sentinel node detection and PET imaging, had, however, a same-basin recurrence 3 months later. In another case, PET had one false positive result. Overall, the sentinel detection of subclinical nodal metastases had a sensitivity of 86%. PET detected only 14% of sentinel node metastases.

Conclusions. Sentinel node detection remains the procedure of choice for detecting subclinical lymph node involvement from primary cutaneous melanoma. Owing to its limited spatial resolution, PET appears insufficiently sensitive to identify microscopic nodal metastases. As a practical consequence, metabolic imaging is not recommended as a first-line imaging strategy for staging regional lymph nodes in patients with stage I or II melanoma.
Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review
Authors: Malet-Martino M. , Martino R.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Define the main oral prodrugs of fluorouracil. Know the indications of the new oral prodrugs of fluorouracil. Review the main toxicities and drug interactions of oral prodrugs of fluorouracil. Evaluate the benefit(s) of using an oral prodrug of fluorouracil compared with classical treatments.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro- and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines.

In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation.

The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented.

The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.
Managing Anemia in the Cancer Patient: Old Problems, Future Solutions
Authors: Gordon Michael S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Identify potential benefits for EPO therapy beyond those of transfusions. Recognize the impact of EPO therapy on aspects of health-related quality of life. Appreciate recent advances in the field of hematopoietic growth factor support as it relates to anemia management.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Anemia and associated symptoms commonly manifest in cancer patients and may have a considerable impact on outcomes. Preliminary studies suggest that overall survival and locoregional control following radiation therapy may be compromised by anemia, and recent preliminary data also suggest that anemia may be related to poorer outcomes following chemotherapy. Health-related quality of life of cancer patients is also significantly reduced by anemia. Treatment of anemia with recombinant human erythropoietin can improve these health-related quality-of-life outcomes. However, despite this knowledge, anemia remains under-recognized and under-treated in the cancer patient population. A number of issues may be determinants of this suboptimal management of anemia. These include limitations of current therapies for anemia, varying practice strategies, and the lack of guidelines on how to treat anemia. Additionally, clinicians may underestimate the importance of health-related quality of life for their patients. It is vital that these issues are addressed, which, together with the development of novel erythropoietic agents, a review of the guidelines for anemia management, and consideration of further outcomes such as survival and cognitive function, may help to ensure that the cancer patient receives the best possible course of supportive care.
Faith, Identity, and Leukemia: When Blood Products are Not an Option
Authors: Knuti Kristine A. , Amrein Philip C. , Chabner Bruce A. , Lynch Thomas J. , Penson Richard T.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Acknowledge the emotions (guilt, frustration, and anger)of caregivers treating patients with different world/religious viewsUnderstand the legal requirement to respect patient autonomy in medical decisions.Explore the influence of religious views on quality of life.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital, founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers and gain insight and support from fellow staff members.

When a competent adult patient refuses lifesaving treatment for religious or personal reasons, caregivers have a legal obligation to respect this decision. A patient's refusal of treatment adds particular challenges to the delivery of compassionate care. The case of a 50-year-old Jehovah's Witness with acute myelocytic leukemia who declined blood product support is presented. Respecting her religious beliefs during chemotherapy required balancing risk and benefit, watching her suffer while unable to intervene with what the staff saw as simple treatment, and eventually undertaking a complicated grief process. Jehovah's Witness beliefs regarding blood products are reviewed. Caregiver roles and responsibilities are discussed in the context of psychosocial, legal, familial, and ethical issues.
The Molecular Perspective: DNA Topoisomerases
Authors: Goodsell David S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Gain a basic understanding of the structure and function of the DNA topoisomerases and their place as targets for chemotherapy.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Gleevec™ for the Treatment of Chronic Myelogenous Leukemia: U.S. Food and Drug Administration Regulatory Mechanisms, Accelerated Approval, and Orphan Drug Status
Authors: Cohen Martin H. , Moses Marie L. , Pazdur Richard
Published: August 2004

Gleevec™ (imatinib mesylate), a highly promising new drug for the treatment of chronic myelogenous leukemia in blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance, received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001. The purpose of this report is to summarize FDA regulatory mechanisms, i.e., accelerated approval and orphan drug regulations, that have permitted patients to receive this drug as rapidly as possible.
U.S. Food and Drug Administration Drug Approval Summaries: Imatinib Mesylate, Mesna Tablets, and Zoledronic Acid
Authors: Cohen Martin H. , Dagher Ramzi , Griebel Donna J. , Ibrahim Amna , Martin Alison , Scher Nancy S. , Sokol Gerald H. , Williams Grant A. , Pazdur Richard
Published: August 2004

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec™ (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex® (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa® (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.
Clinical Trial Design for Target-Based Therapy
Authors: Fox Elizabeth , Curt Gregory A. , Balis Frank M.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Differentiate between cytotoxic and molecularly-targeted drug development in terms of drug discovery, mechanism of action, pharmacological effect, and specificity.Define the primary objectives of phase I, II, and III clinical trials of cytotoxic and molecularly targeted anticancer agents.Compare the end points used in clinical trials for cytotoxic agents to the proposed end points for target-based (cytostatic) agents.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target-based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target-based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target-based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.
Phase II Trial of Weekly Vinorelbine and Trastuzumab as First-Line Therapy in Patients with HER2+ Metastatic Breast Cancer
Authors: Jahanzeb Mohammad , Mortimer Joanne E. , Yunus Furhan , Irwin David H. , Speyer James , Koletsky Alan J. , Klein Paula , Sabir Tariq , Kronish Lori
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Summarize the epidemiology and natural history of HER2+ breast cancer.Differentiate the two primary methods for measuring HER2 in breast cancer patients.Appreciate the rationale for investigating vinorelbine in combination with trastuzumab.Discuss the relative efficacy and safety of trastuzumab and vinorelbine in HER2+ breast cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Purpose. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with a more aggressive form of breast cancer that responds well to trastuzumab therapy. Trastuzumab-based combination regimens have shown greater antitumor activity than chemotherapy alone. These findings, coupled with the favorable antitumor activity and tolerability profile of vinorelbine in breast cancer, provided the rationale for investigating the novel combination of vinorelbine and trastuzumab.

Patients and Methods. A phase II, open-label trial of intravenous vinorelbine (30 mg/m2 on day 1, then weekly) and trastuzumab (4 mg/kg on day 0, then 2 mg/kg weekly) was conducted in previously untreated HER2+ metastatic breast cancer patients. Vinorelbine dose was adjusted for grade 3/4 neutropenia; patients remained on combination therapy until disease progression or patient withdrawal due to adverse events.

Results. Of 40 enrolled patients (median age 51 years, range 30-82), 37 were evaluable for response. Overall response rate was 78% (29/37, 95% confidence interval [CI] 62%-90%), including four (11%, 95% CI 3%-25%) complete and 25 (68%) partial responses. Objective tumor response correlated with degree of HER2 positivity: immunohistochemistry (IHC) 3+ = 82% (18/22) response and IHC 2+ = 58% (7/12) response. Median time to progression was 72 weeks (95% CI 37-138 weeks); median survival has not been reached. Grade 3/4 neutropenia was the most frequent serious toxicity and cause of dose reductions (9% of courses) and omissions (10% of courses). No patient experienced serious cardiac toxicity.

Conclusions. Weekly vinorelbine/trastuzumab offers a high therapeutic index as initial therapy in patients with HER2+ metastatic breast cancer. Further investigation of this novel regimen is planned.
Efficacy of a Primary Chemotherapy Regimen Combining Vinorelbine, Epirubicin, and Methotrexate (VEM) as Neoadjuvant Treatment in 89 Patients with Operable Breast Cancer
Authors: Van Praagh Isabelle , Cure Hervé , Leduc Bernard , Charrier Sabine , Le Bouedec Guillaume , Achard Jean-Louis , Ferriere Jean-Pierre , Feillel Viviane , Latour Monique , Dauplat Jacques , Chollet Philippe
Published: August 2004

Purpose. In order to improve the breast conservation rate for noninflammatory operable breast cancer stage II and IIIa, neoadjuvant chemotherapy containing vinorelbine, 25 mg/m2, epirubicin, 35 mg/m2, and methotrexate, 20 mg/m2, VEM, was administered days 1 and 8 every 28 days for six cycles.

Methods. From October, 1991 to April, 1996, 89 patients (median age 52 years, range 31-72; 68 stage II and 19 stage IIIa) received 519 cycles (median six) of VEM chemotherapy.

Results. Hematotoxicity was mild (World Health Organization grade 3-4 neutropenia in 28% of cycles for 22 patients, and anemia or thrombocytopenia >grade 2) when it occurred, and there were no toxic deaths. The clinical objective response was 90% (28% complete response and 62% partial response). All patients underwent surgery: 77 (87%) had conservative and 12 (13%) had modified radical mastectomy, and 12 (14%) reached pathological complete response. At December, 2000, with a median follow-up of 86 months (39-100), 13 patients had relapsed, and five had died of metastatic disease. Median disease-free survival was 100 months (8.4 years) and median survival had not yet been reached.
5-HT3-Receptor Antagonists for the Treatment of Nausea and Vomiting: A Reappraisal of Their Side-Effect Profile
Authors: Goodin Susan , Cunningham Regina
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: List the differences in side-effect profiles of the 5-HT3-receptor antagonists.Explain the potential issues of each 5-HT3-receptor antagonist in patients with cardiovascular disease.Understand the potential issues of each 5-HT3-receptor antagonist in patients with hepatic or renal impairment.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents exist to combat these side effects, though the 5-HT3-receptor antagonists have become the first-line treatment choice for many cancer patients and are considered the “gold standard” in antiemetic therapy. Compared with the older generation antiemetic drugs, 5-HT3-receptor antagonists are effective, well tolerated, and associated with few side effects. However, emerging differences among these agents suggest that the incidence and/or intensity of adverse events should not be regarded as a class effect.

The side-effect profile of any supportive care therapy is particularly important in certain subgroups of patients, including pediatric patients and the elderly, as well as those suffering comorbid conditions, such as cardiovascular disease and renal or hepatic impairment. Indeed, dolasetron is associated with cardiovascular effects, and thus, should be used with extreme caution in patients who suffer from or may develop prolongation of cardiac conduction intervals. Ondansetron, on the other hand, is associated with a greater incidence of central nervous system side effects than either dolasetron or ondansetron, and pharmacokinetic parameters are affected in patients with hepatic impairment, thereby requiring dose adjustments.

Clinicians are encouraged to evaluate patients on an individual basis when choosing which 5-HT3-receptor antagonist to prescribe.
CA125 Response: Can it Replace the Traditional Response Criteria in Ovarian Cancer?
Authors: Guppy A.E. , Rustin G.J.S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Determine in what situations measuring CA125 levels could alter patient management.Discuss with patients the pros and cons of measuring CA125 during follow-up of ovarian cancer.Define response or progression of ovarian cancer.Incorporate CA125 use into clinical trial design.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

CA125 is well established as an accurate and reliable means of monitoring response to treatment and confirming relapse in ovarian cancer patients. Its role in follow-up after initial treatment is less certain and the subject of a current clinical trial. Measuring response with computerized tomography scans is futile in the majority of patients, as disease is often nonmeasurable at presentation, e.g., ascites or peritoneal deposits, or all measurable disease has been removed at the time of surgery. Serial changes in CA125 can be used as a reliable indicator of disease response or progression so that patients can be classified as responding or progressing according to either standard or CA125 criteria. These precise definitions are currently being prospectively validated in conjunction with the new response evaluation criteria in solid tumor response guidelines and are being incorporated into all future clinical trials.
A Phase I Trial of Weekly Paclitaxel Plus Prolonged Oral Eniluracil/5-Fluorouracil in Patients with Refractory Malignancies
Authors: Jones Suzanne F. , Greco F. Anthony , Hainsworth John D. , Patton Jeffrey W. , Barton John H. , Willcutt Noel T. , Baker Margaret N. , McGuirt Paul V. , Levin Jeremey , Burris Howard A.
Published: August 2004

Purpose. This phase I study was conducted to determine the dose-limiting toxicity (DLT), maximum-tolerated doses, and recommended phase II doses of the combination of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU).

Patients and Methods. Patients received paclitaxel i.v. over 1 hour weekly for four consecutive weeks of each cycle. Oral eniluracil/5-FU was administered orally twice daily for 28 consecutive days starting on day 1 of each cycle. Cycles were repeated every 35 days. Patients were accrued at six different dosing combinations. Weekly paclitaxel doses ranged from 60 mg/m2 to 80 mg/m2, and oral eniluracil/5-FU doses ranged from 8.0/0.8 mg/m2 to 11.5/1.15 mg/m2 twice daily.

Results. Thirty-seven patients received 126 cycles of therapy. Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or thrombocytopenia reported. DLT was reported in three out of six patients enrolled at the highest dose level and consisted of grade 3 diarrhea (two patients) and grade 3 mucositis (one patient). No DLTs were reported in patients enrolled at lower dose levels. One complete response and three partial responses were reported in patients with taxane-resistant metastatic breast cancer.

Conclusion. The combination of paclitaxel and eniluracil/5-FU was generally well tolerated. The recommended doses for further phase II testing are paclitaxel 80 mg/m2 i.v. weekly for 4 weeks plus eniluracil/ 5-FU 10.0/1.0 mg/m2 orally twice daily on days 1-28 with cycles repeated every 35 days.
Aberrant DNA Methylation in Lung Cancer: Biological and Clinical Implications
Authors: Zöchbauer-Müller Sabine , Minna John D. , Gazdar Adi F.
Published: August 2004

Genetic abnormalities of proto-oncogenes and tumor suppressor genes are well-known changes that are frequently involved in lung cancer pathogenesis. However, another mechanism for inactivation of tumor suppressor genes is coming more and more into focus. Epigenetic inactivation of certain tumor suppressor genes by aberrant promoter methylation is frequently observed in lung carcinomas and seems to play an important role in the pathogenesis of this tumor type. While genetic abnormalities are associated with changes in DNA sequence, epigenetic events may lead to changes in gene expression that occur without changes in DNA sequence. Recent findings demonstrate that aberrant methylation can also be detected in the smoking-damaged bronchial epithelium from cancer-free heavy smokers, suggesting that aberrant methylation might be an ideal candidate biomarker for lung cancer risk assessment and monitoring of chemoprevention trials. Moreover, in vitro studies demonstrate that methylation can be reversed by demethylating agents resulting in gene re-expression. This concept is currently under investigation in clinical trials. In summary, recent studies demonstrate that aberrant methylation may be the most common mechanism of inactivating cancer-related genes in lung cancer, occurs already in smoking-damaged bronchial epithelium from cancer-free individuals, can be reversed in vitro by demethylating agents, and may be a useful biomarker for lung cancer risk assessment.
Combining Radiotherapy with Gene Therapy (From the Bench to the Bedside): A Novel Treatment Strategy for Prostate Cancer
Authors: Teh Bin S. , Aguilar-Cordova Estuardo , Vlachaki Maria T. , Aguilar Laura , Mai Wei-Yuan , Caillouet James , Davis Maria , Miles Brian , Kadmon Dov , Ayala Gustavo , Lu Hsin H. , Chiu J. Kam , Carpenter L. Steven , Woo Shiao Y. , Grant Walter H. , Wheeler Thomas , Thompson Timothy C. , Butler E. Brian
Published: August 2004

Combined radiotherapy and gene therapy is a novel therapeutic approach for prostate cancer. There are various potential benefits in combining ionizing radiation with gene therapy to achieve enhanced antitumor effects: A) ionizing radiation improves transfection/ transduction efficiency, transgene integration, and possibly, the “bystander effect” of gene therapy; B) gene therapy, on the other hand, may interfere with repair of radiation-induced DNA damage and increase DNA susceptibility to radiation damage in cancer cells, and C) radiotherapy and gene therapy target at different parts of the cell cycle. Preclinical data have demonstrated the enhanced antitumor effects of this combined approach in local tumor control, prolongation of survival, as well as systemic control. This combined radio-gene therapy is under study in an ongoing clinical trial in prostate cancer. Our study adds gene therapy to the standard of care therapy (radiotherapy). These treatment modalities have different toxicity profiles. The goal of this combined approach is to enhance cancer cure without an increase in treatment-related toxicity. This approach also offers a new paradigm in spatial cooperation, whereby two local therapies are combined to elicit both local and systemic effects. Early clinical results showed the safety of this approach.
The Molecular Perspective: Cadherin
Authors: Goodsell David S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Gain a basic understanding of the structure and function of cadherins and their role in cancer metastasis.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
FDA Drug Approval Summaries: Fulvestrant
Authors: Bross Peter F. , Cohen Martin H. , Williams Grant A. , Pazdur Richard
Published: August 2004

Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex®, ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.
The Use of Zoledronic Acid, a Novel, Highly Potent Bisphosphonate, for the Treatment of Hypercalcemia of Malignancy
Authors: Major Pierre
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Recognize the natural history and clinical presentation of hypercalcemia of malignancy (HCM).Compare the relative efficacy of available bisphosphonates in the treatment of HCM.Examine the efficacy and safety of zoledronic acid, a new-generation bisphosphonate.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Background. Hypercalcemia of malignancy is a serious complication of cancer that affects patients with and without bone metastases. A single infusion of pamidronate disodium, a nitrogen-containing bisphosphonate, effectively normalizes serum calcium in the majority of patients treated for up to 1 month. Zoledronic acid is a new-generation, heterocyclic nitrogen-containing bisphosphonate and the most potent inhibitor of bone resorption identified to date.

Methods. The natural history, clinical presentation, and treatment of hypercalcemia of malignancy are reviewed, with a focus on the mechanisms of action and relative efficacy and safety of bisphosphonate therapies.

Results. The improved efficacy of zoledronic acid compared with pamidronate disodium has been demonstrated in a pooled analysis of two randomized clinical trials in patients with hypercalcemia of malignancy. In these trials, both zoledronic acid and pamidronate disodium were safe and well tolerated; however, zoledronic acid treatment resulted in a significantly higher number of complete responses, more rapid calcium normalization, and more durable responses compared with pamidronate disodium.

Conclusions. Given the superior efficacy and comparable safety profile of zoledronic acid compared with pamidronate disodium, zoledronic acid is likely to become the treatment of choice for hypercalcemia of malignancy.
A Dose-Escalation Study of Weekly Topotecan, Cisplatin, and Gemcitabine Front-Line Therapy in Patients with Inoperable Non-Small Cell Lung Cancer
Authors: Guarino Michael J. , Schneider Charles J. , Grubbs Stephen S. , Biggs David D. , Himelstein Andrew L. , Hogaboom Kurt , Tilak Samir
Published: August 2004

Purpose. To determine the optimal dose of combination topotecan, cisplatin, and gemcitabine in advanced non-small cell lung cancer patients.

Materials and Methods. This single-center, single-practice, phase I trial enrolled chemotherapy-naïve patients with inoperable stage IIIB/IV disease. Initial treatment was topotecan (0.5-2.0 mg/m2), cisplatin (20 mg/m2), and gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle. Dose-limiting thrombocytopenia at week 3 necessitated less frequent gemcitabine dosing (days 1 and 15 of each cycle). Thereafter, topotecan dose escalation proceeded to the target dose of 2 mg/m2.

Results. Thirty patients were enrolled and evaluable for toxicity assessment. Treatment was extremely well tolerated: only one grade 4 adverse event (leukopenia); no hospitalizations for treatment-related toxicities; no fever/neutropenia. Although no dose-limiting toxicities developed, 1.75 mg/m2 topotecan is considered optimal and recommended for further study because it was well tolerated, active, and did not require dose adjustments or delays in therapy. Eleven of 29 (38%) evaluable patients achieved a partial response. Median survival was 38 weeks (range 4-110 weeks), median progression-free survival was 17 weeks, and the 1-year survival rate was 33%. Two patients remain alive after 108-122 weeks of follow-up.

Conclusion. A 28-day cycle of topotecan (1.75 mg/m2 days 1, 8, 15), cisplatin (20 mg/m2 days 1, 8, 15), and gemcitabine (1,000 mg/m2 days 1, 15) was a safe and well-tolerated outpatient treatment for advanced non-small cell lung cancer. The favorable preliminary efficacy and safety of this regimen suggest that further study in phase II trials, including quality-of-life end points, is warranted.
Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview
Authors: Kruijtzer C.M.F. , Beijnen J.H. , Schellens J.H.M.
Published: August 2004

The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs.
A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors
Authors: Ryan David P. , Puchalski Thomas , Supko Jeffrey G. , Harmon David , Maki Robert , Garcia-Carbonero Rocio , Kuhlman Caroline , Winkelman Jennifer , Merriam Priscilla , Quigley Travis , Jimeno Jose , Manola Judith , Demetri George D.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the mechanism of action, administration, and pharmacokinetics of ecteinascidin 743. Recognize the classification and pathophysiology of gastrointestinal stromal tumors. Appreciate that conventional cytotoxic chemotherapy has no efficacy in patients with gastrointestinal stromal tumors and that STI571 has dramatic efficacy.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Purpose. To assess the efficacy, tolerability, and pharmacokinetics of ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal tumors (GISTs).

Patients and Methods. The study was confined to adult patients with radiographically measurable GISTs. ET-743 was administered as a 24-hour continuous i.v. infusion at a dose of 1.5 mg/m2 repeated every 3 weeks. Pharmacokinetic blood sampling was performed during the first cycle of therapy. Tumors were restaged after every second cycle of therapy.

Results. A total of 20 patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET-743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3 transaminitis in 10 patients and grade 3 fatigue in one patient. There were no objective responses, and disease stabilization occurred in two patients lasting for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean ± standard deviation values of the maximum plasma concentration and total plasma clearance were 1.1 ± 0.4 ng/ml and 44 ± 16 l/h/m2, respectively, for 19 of the 20 patients.

Conclusion. This study is the first report of a prospective phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study underscores the primary resistance of GISTS to chemotherapy and stands in stark contrast to the encouraging results recently achieved with STI571. The lack of response may be associated with a therapeutically ineffective exposure to the drug based upon the lower incidence of severe toxicities and greater clearance than described in phase I and II trials of ET-743.
Controversies Regarding the Use of Radiation After Mastectomy in Breast Cancer
Authors: Buchholz Thomas A. , Strom Eric A. , Perkins George H. , McNeese Marsha D.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Explain the potential benefits of delivering radiation after mastectomy for patients with breast cancer.Provide a list of appropriate indications for selecting which patients would benefit from radiation after mastectomy and chemotherapy.Appreciate how radiation can potentially cause cardiovascular injuries and understand the importance of radiation technique in minimizing the risk for such injuries.Appreciate how immediate breast reconstruction can affect the delivery of postmastectomy radiation.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Despite years of clinical study, there are still many unanswered questions regarding postmastectomy radiation. It is clear that radiation therapy plays a critical role in the multidisciplinary management of patients with locally advanced or inflammatory breast cancer. It is also accepted that postmastectomy radiation is not required for most women with noninvasive disease or stage I disease. Randomized clinical trials studying radiation treatments for women with stage II or III breast cancer have shown that the addition of radiation after mastectomy can reduce local-regional recurrence rates, which then improves survival. However, other data have indicated that the risk of local-regional recurrence after mastectomy and chemotherapy is low for patients with small tumors and one to three positive lymph nodes, leading some to question whether postmastectomy radiation is useful for this group. A second controversy regards the sequencing of postmastectomy radiation and breast reconstruction. In this article we discuss these controversies, review the data that are relevant, and provide our institutional approaches to these issues.
Breast Cancer in the Very Young Patient: A Multidisciplinary Case Presentation
Authors: Mintzer David , Glassburn John , Mason Bernard A. , Sataloff Dahlia
Published: August 2004

A case is presented that exemplifies many issues and controversies in the diagnosis and treatment of breast cancer in the very young. This woman was 22 years of age at diagnosis; she initially underwent breast-conservation therapy and adjuvant chemotherapy, retained fertility, had a subsequent uncomplicated pregnancy and delivery, and 7 years later developed a local recurrence in the breast. The discussion addresses risk factors, diagnosis, and treatment of breast cancer in the young; the impact of treatment on fertility; implications regarding pregnancy, and the management of local recurrence after breast conservation.
The Molecular Perspective: VEGF and Angiogenesis
Authors: Goodsell David S.
Published: August 2004

Learning Objective

After completing this course, the reader will be able to:

Gain a basic understanding of VEGF and its role in angiogenesis.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Living as a Cancer Surpriser: A Doctor Tells His Story
Authors: Knuti Kristine A. , Wharton Robert H. , Wharton Karen Levine , Chabner Bruce A. , Lynch Thomas J. , Penson Richard T.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Identify the unique issues confronted by caregivers who become patients.Appreciate how addressing issues of life and death affects patients, families, and caregivers.Recognize the advantages and limitations of prognostication.Better care for and communicate with patients and families who face life-threatening illnesses.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to the caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers and gain insight and support from fellow staff members.

We tell the story of one physician with incurable non-small cell lung cancer (NSCLC) who had an unexpectedly favorable response to an experimental treatment while receiving it as a part of his palliative care. His unique insight provides an opportunity to elucidate some of the issues that arise from living both as a patient-caregiver and as a cancer “surpriser.” When caregivers face their own cancer, their reflections as patient-caregivers offer an internal perspective on the illness experience and help us as fellow caregivers to better understand and support all patients who face serious illnesses, both those who are colleagues and those who are not. Just like any patient with cancer, patient-caregivers experience the dramatic changes in health, daily life, and perspective that come with serious illness. Within the context of a life-threatening illness, caregiver-patients and their families search for new meaning as they face an uncertain future and address the issues of life and death. In addition to such processes, patient-caregivers with cancer also find that their own medical knowledge and their colleagues’ reactions shape their experiences and to an extent separate them from those of other patients.