bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological Concepts of Prolonged Neoadjuvant Treatment plus GM-CSF in Locally Advanced Tumors
Authors: Pinedo H.M. , de Gruijl T.D. , van der Wall E. , Buter J.
Published: August 2004

Local treatment with surgery and radiotherapy gives unsatisfactory results in patients with locally advanced cancer. In many cases distant metastases appear shortly after the removal of the primary tumor. Selecting breast cancer as a model for locally advanced disease, we are extrapolating our findings to other solid tumors. Neoadjuvant chemotherapy has improved survival of these patients by downstaging the primary tumors allowing local treatment and early elimination of distant micrometastases.

We recently reported in this journal on a study of 42 patients with locally advanced breast cancer (LABC) who received prolonged neoadjuvant chemotherapy of doxorubicin, cyclophosphamide, and GM-CSF prior to surgery and postoperative radiotherapy. These results were promising and prompted us to initiate an international randomized phase III study in which either six neoadjuvant cycles or three neoadjuvant cycles plus three adjuvant cycles are being compared. In LABC patients treated with six neoadjuvant chemoimmunotherapy cycles, we observed a significant rise in the dendritic cell content of the axillary tumor-draining lymph nodes after therapy, associated with an encouraging disease free survival and overall survival. We hypothesize that the prolonged presence of draining lymph nodes in combination with the repeated tumor antigen release, dendritic cell recruitment, and activation may account for the observed increased survival of LABC patients. Based on our findings and the results of preclinical studies, we hypothesize that it is more effective to administer chemotherapy in an extended neoadjuvant regimen, taking advantage of the concurrent biological and immunological processes in the primary tumor and its draining lymph nodes.
Radiofrequency Ablation of Malignant Liver Tumors
Authors: Curley Steven A.
Published: August 2004

The majority of patients with primary or metastatic hepatic tumors are not candidates for resection because of tumor size, location near major intrahepatic blood vessels precluding a margin-negative resection, multifocality, or inadequate hepatic function related to coexistent cirrhosis. Radiofrequency ablation (RFA) is an evolving technology being used to treat patients with unresectable primary and metastatic hepatic cancers. RFA produces coagulative necrosis of tumor through local tissue heating. Liver tumors are treated percutaneously, laparoscopically, or during laparotomy using ultrasonography to identify tumors and guide placement of the RFA needle electrode. For tumors smaller than 2.0 cm in diameter, one or two deployments of the monopolar multiple array needle electrode are sufficient to produce complete coagulative necrosis of the tumor. However, with increasing size of the tumor, there is a concomitant increase in the number of deployments of the needle electrode and the overall time necessary to produce complete coagulative necrosis of the tumor. In general, RFA is a safe, well-tolerated, effective treatment for unresectable hepatic malignancies less than 6.0 cm in diameter. Effective treatment of larger tumors awaits the development of more powerful, larger array monopolar and bipolar RFA technologies.
Radiofrequency Ablation of Unresectable Hepatic Malignancies: Lessons Learned
Authors: Bilchik Anton J. , Wood Thomas F. , Allegra David P.
Published: August 2004

Radiofrequency ablation (RFA) is increasingly used for the local destruction of unresectable hepatic malignancies. Relative contraindications include tumors in proximity to vital structures that may be injured by RFA and lesions whose size exceeds the ablation capabilities of the probe system employed. Given current technology, we believe that RFA should be cautiously utilized for lesions greater than 5 cm in diameter. Open (celiotomy) and laparoscopic approaches to RFA allow intraoperative ultrasonography, which may demonstrate occult hepatic disease. In addition, RFA performed via celiotomy can be accompanied by resection or cryosurgical ablation, and isolation of the liver from adjacent organs. Percutaneous RFA should be reserved for patients who cannot undergo general anesthesia, those with recurrent or progressive lesions, and those with smaller lesions sufficiently isolated from adjacent organs. Complications may be minimized when these approaches are selectively applied.
Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities
Authors: Jonasch Eric , Haluska Frank G.
Published: August 2004

For the past 40 years, various forms of interferon (IFN) have been evaluated as therapy in a number of malignant and non-malignant diseases. With the advent of gene cloning, large quantities of pure IFN became available for clinical study. This paper reviews the biology, pharmacology, and clinical applications of IFN formulations most commonly used in oncology. It then reviews the most common side effects seen in patients treated with IFN, and makes recommendations for the management of IFN-induced toxicity.

The major oncological indications for IFN include melanoma, renal cell carcinoma, AIDS-related Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, and chronic myelogenous leukemia. Unfortunately, IFN therapy is associated with significant toxicity, which can be divided into constitutional, neuropsychiatric, hematologic, and hepatic effects. These toxicities have a major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient. Careful attention to all aspects of patient care can result in improved tolerability of this difficult but promising therapy. Conclusion: a better understanding of IFN biology, indications, side effect profiles, and toxicity management will aid in optimizing its use in the treatment of patients with cancer.
Drug Approval Summaries: Arsenic Trioxide, Tamoxifen Citrate, Anastrazole, Paclitaxel, Bexarotene
Authors: Cohen Martin H. , Hirschfeld Steven , Honig Susan Flamm , Ibrahim Amna , Johnson John R. , O'Leary James J. , White Robert M. , Williams Grant A. , Pazdur Richard
Published: August 2004

This report summarizes information on drugs recently approved by the Food and Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug Products. Five applications supporting new claims will be discussed: Trisenox™ (arsenic trioxide) for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; Nolvadex® (tamoxifen citrate) in women with ductal carcinoma in situ, following breast surgery and radiation, to reduce the risk of invasive breast cancer; Arimidex® (anastrazole) for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; Taxol® (paclitaxel), 175 mg/m2 by 3 h infusion in combination with cisplatin for first-line treatment of advanced ovarian cancer; and Targretin® gel (bexarotene) for the topical treatment of cutaneous lesions in patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated other therapies or who have refractory or persistent disease.

Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.
Irinotecan (CPT-11): Recent Developments and Future Directions–Colorectal Cancer and Beyond
Authors: Rothenberg Mace L.
Published: August 2004

Since its approval in the United States in 1996, irinotecan (CPT-11, Camptosar®, Pharmacia Corp.; Peapack, NJ) has undergone extensive clinical evaluation. In the past five years, the focus of development has evolved from evaluation of single-agent activity in refractory disease settings to evaluation of front-line irinotecan-based combination chemotherapy regimens and integration of irinotecan into combined modality regimens. Important studies have been performed clarifying the role of irinotecan in treating colorectal and other gastrointestinal cancers, small cell and non-small cell lung cancer, and a variety of other malignancies. Preclinical studies performed in conjunction with these clinical trials have also provided significant insights into the pharmacology, metabolism, mechanisms of resistance, and molecular determinants of response. This review summarizes that progress, focusing on the achievements of the past five years.
Irinotecan Plus Fluorouracil/Leucovorin for Metastatic Colorectal Cancer: A New Survival Standard
Authors: Saltz Leonard B. , Douillard Jean-Yves , Pirotta Nicoletta , Alakl May , Gruia Gabriela , Awad Lucile , Elfring Gary L. , Locker Paula K. , Miller Langdon L.
Published: August 2004

Background. Irinotecan is a topoisomerase I inhibitor that prolongs survival in patients with colorectal cancer refractory to fluorouracil (5-FU) and leucovorin (LV). This demonstrated activity of irinotecan as effective second-line therapy for colorectal cancer led to evaluation of combination irinotecan/5-FU/LV as first-line therapy for patients with metastatic disease. The results of two prospective phase III randomized, controlled, multicenter, multinational clinical trials in patients with previously untreated metastatic colorectal cancer served as the basis for U.S. and European approval of irinotecan/5-FU/LV for this indication. An overview of the findings of these two pivotal studies provides insights regarding the application of this new combination in clinical practice.

Methods. Patients were randomly assigned to receive 5-FU/LV, either alone, or with concurrent irinotecan. The study conducted primarily in North America (study 1), employed bolus 5-FU/LV schedules, while the study performed primarily in Europe (study 2), employed infusional 5-FU/LV regimens. Major endpoints included tumor response rate, time to tumor progression (TTP), overall survival, quality of life, and safety.

Results. In study 1, the respective confirmed response rates for irinotecan/5-FU/LV versus 5-FU/LV were 39% and 21% (p < .001); median TTPs were 7.0 months and 4.3 months, respectively (p = .004). In study 2, response rates for irinotecan/5-FU/LV versus 5-FU/LV alone were 35% and 22% (p = .005); median TTPs were 6.7 months and 4.4 months, respectively (p < .001). Survival time increased significantly with irinotecan/5-FU/LV versus 5-FU/LV alone in both studies (study 1: median 14.8 months versus 12.6 months, p = .042; study 2: median 17.4 months versus 14.1 months, p = .032). The combined analysis of the data from the two studies showed median survivals of 15.9 months versus 13.3 months, favoring the irinotecan-containing combinations (stratified-by-study p = .003). Patients in study 1 had a 36% lower risk of tumor progression and a 20% lower risk of death with the irinotecan combination than with 5-FU/LV alone; comparable risk reduction values in study 2 were 42% and 23%. While grade 3 diarrhea and vomiting were more common with irinotecan/5-FU/LV, grade 4 neutropenia, neutropenic fever, and mucositis were less common with irinotecan/5-FU/LV than with the Mayo Clinic 5-FU/LV regimen.

Conclusion. The combination of irinotecan/5-FU/LV is superior to 5-FU/LV alone as first-line therapy for patients with metastatic colorectal cancer, offering consistently improved tumor control and prolonged survival. Irinotecan-based combination therapy sets a new survival standard for the treatment of this life-threatening disease.
Medical Mistakes: A Workshop on Personal Perspectives
Authors: Penson Richard T. , Svendsen Sasha S. , Chabner Bruce A. , Lynch Thomas J. , Levinson Wendy
Published: August 2004

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center at MGH. 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.

Medical errors are difficult to discuss. Significant medical errors occur in approximately 3% of hospitalizations. Two-thirds are preventable. Despite an entrenched belief that doctors should be infallible, errors are inevitable. Dr. Wendy Levinson of the University of Chicago facilitated a discussion of the impact medical errors have on staff. Staff broke into small groups to share their personal experience and then discussed common themes: the sense of shame and guilt, the punitive culture, guidelines for disclosure to patients and colleagues, and changes in medical practice that can prevent future mistakes. Auditing and improving systems has led to considerable improvements in the field of aviation safety. However, in medicine people are more important than the process. While we should never cease to aim for the very best in delivered care, we must acknowledge how prone we all are to mistakes and that we can learn from and prevent errors. Openly sharing experiences in a confidential setting, such as the Schwartz Rounds, helps defuse feelings of guilt and challenges the culture of shame and isolation that often surrounds medical errors.
Update on the Treatment of Multiple Myeloma
Authors: Kyle Robert A.
Published: August 2004

The patient with multiple myeloma should be carefully evaluated from the standpoint of symptoms, physical findings, and laboratory data. If there are no symptoms or evidence of early or impending complications, the patient should not be treated. He or she should be followed and treatment delayed until progression of the disease occurs. If the patient is younger than 70 years, autologous peripheral blood stem cell transplantation should be considered. Hematopoietic stem cells should be collected before the patient is exposed to alkylating agents. If the patient is older than 70 years, chemotherapy is indicated. The two major shortcomings of autologous stem cell transplantation are: A) failure to eradicate myeloma, and B) contamination of autologous peripheral blood stem cells. Most physicians initially treat the patient with vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) for three to four months and then collect the peripheral blood stem cells. One can then proceed with transplant or treat the patient with alkylating agents and delay the transplant until the patient progresses. In a prospective trial comparing autologous bone marrow transplantation with conventional chemotherapy, five-year overall survival favored the transplant group (52% versus 12%). In a randomized trial of 400 patients from France, there was no difference in event-free or overall survival between double and single autologous stem cell transplant when evaluated at two years. In a subsequent evaluation, patients with a low β2-microglobulin value at diagnosis appeared to have better results with a double transplant. There is no evidence that combinations of chemotherapeutic agents are more effective than melphalan and prednisone. Allogeneic transplantation is associated with a high mortality. Depletion of T-cells or a mini-allogeneic transplant may be beneficial in an effort to reduce mortality. Thalidomide produces objective response in approximately 30% of refractory patients. The use of intravenous bisphosphonates is recommended for patients with skeletal lesions. Hypercalcemia and renal failure must be treated promptly.
Clinical Significance of Occult Metastatic Cells in Bone Marrow of Breast Cancer Patients
Authors: Braun Stephan , Pantel Klaus
Published: August 2004

The early and clinically occult spread of viable tumor cells to the organism is increasingly considered a hallmark in cancer progression, as emerging data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies to epithelial cytokeratins or tumor-associated cell membrane glycoproteins, individual carcinoma cells can be detected on cytologic bone marrow preparations at frequencies of 10–5 to 10–6. Prospective clinical studies have shown that the presence of these immunostained cells in bone marrow, as a frequent site of overt metastases, is prognostically relevant with regard to relapse-free and overall survival. This screening approach may be, therefore, used to improve tumor staging and guide the stratification of patients for adjuvant therapy in clinical trials. Another promising application is monitoring the response of micrometastatic cells to adjuvant therapies, which, at present, can only be assessed retrospectively after an extended period of clinical follow-up. The present review summarizes the current data on the clinical significance of occult metastatic breast cancer cells in bone marrow.
Chemotherapy of Metastatic Breast Cancer: What to Expect in 2001 and Beyond
Authors: Esteva Francisco J. , Valero Vicente , Pusztai Lajos , Boehnke-Michaud Laura , Buzdar Aman U. , Hortobagyi Gabriel N.
Published: August 2004

Chemotherapy plays an important role in the management of metastatic breast cancer. The anthracyclines (doxorubicin, epirubicin) and the taxanes (paclitaxel, docetaxel) are considered the most active agents for patients with advanced breast cancer. Traditionally, the anthracyclines have been used in combination with cyclophosphamide and 5-fluorouracil (FAC, FEC). The taxanes have single-agent activity similar to older combination chemotherapy treatments. There is great interest in developing anthracycline/taxane combinations. Capecitabine is indicated for patients who progress after anthracycline and taxane therapy. Vinorelbine and gemcitabine have activity in patients with metastatic breast cancer and are commonly used as third- and fourth-line palliative therapy. The role of high-dose chemotherapy is not well-defined and remains experimental. Novel cytotoxic therapy strategies include the development of anthracycline, taxane, and oral fluoropyrimidine analogues; antifolates; topoisomerase I inhibitors, and multidrug resistance inhibitors.

A better understanding of the biology of breast cancer is providing novel treatment approaches. Oncogenes and tumor-supressor genes are emerging as important targets for therapy. Trastuzumab, a monoclonal antibody directed against the Her-2/neu protein, has been shown to prolong survival in patients with metastatic breast cancer. Other novel biologic therapies interfere with signal transduction pathways and angiogenesis. The challenge for the next decade will be to integrate these promising agents in the management of metastatic and primary breast cancer.
Early Lung Cancer Action Project: A Summary of the Findings on Baseline Screening
Authors: Henschke Claudia I. , McCauley Dorothy I. , Yankelevitz David F. , Naidich David P. , McGuinness Georgeann , Miettinen Olli S. , Libby Daniel , Pasmantier Mark , Koizumi June , Altorki Nasser , Smith James P.
Published: August 2004

Purpose. The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low radiation dose computed tomography (low-dose CT) in persons at high-risk for lung cancer.

Methods. Since starting in 1993, the ELCAP has enrolled 1,000 asymptomatic persons, 60 years of age or older, with at least 10 pack-years (1 pack per day for 10 years, or 2 packs per day for 5 years) of cigarette smoking, no prior cancer, and medically fit to undergo thoracic surgery. After a structured interview and informed consent, baseline chest radiographs and low-dose CT were obtained on each subject. The diagnostic work-up of screen-detected noncalcified pulmonary nodules (NCN) was guided by ELCAP recommendations which included short-term high-resolution CT follow-up for the smallest nodules.

Baseline Results. On low-dose CT at baseline compared to chest radiography, NCN were detected three times as commonly (23% versus 7%), malignancies four times as commonly (2.7% versus 0.7%), and stage I malignancies six times as commonly (2.3% versus 0.4%). Of the 27 CT-detected cancers, 96% (26/27) were resectable; 85% (23/27) were stage I, and 83% (19 of the 23 stage I) were not seen on chest radiography. Following the ELCAP recommendations, biopsies were performed on 28 of the 233 subjects with NCN; 27 had a malignant and one a benign NCN. Another three individuals underwent biopsy outside of the ELCAP recommendations; all had benign NCNs. No one had thoracotomy for a benign nodule.

Conclusion. Baseline CT screening for lung cancer provides for detecting the disease at earlier and presumably more commonly curable stages in a cost-effective manner.
Hepatotoxicity of Chemotherapy
Authors: King Paul D. , Perry Michael C.
Published: August 2004

After assessment of tumor histology, the next important factor to consider in the selection of a chemotherapy regime is organ function. Patients who are to receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate, and which drug doses should be modified. Following therapy abnormalities of liver function tests may be due to the therapy rather than to progressive disease, and this distinction is of critical importance. Furthermore, not all abnormalities in liver function are due to the tumor or its treatment, and other processes, such as hepatitis, must be kept in mind. This article reviews the hepatic toxicity of chemotherapeutic agents, and suggests dose modifications based upon liver function abnormalities. Emphasis is placed on agents known to be hepatotoxic, and those agents with hepatic metabolism.
Treatment of Localized Prostate Cancer With Intermittent Triple Androgen Blockade: Preliminary Results in 110 Consecutive Patients
Authors: Leibowitz Robert L. , Tucker Steven J.
Published: August 2004

Objectives. To determine the effectiveness of triple androgen blockade as an alternative to watchful waiting, radical prostatectomy or radiation therapy in the management of patients with clinical stage T1 to T3 prostate cancer.

Methods. The records of 110 consecutive patients were retrospectively evaluated. Patients were treated with a three-drug androgen blockade regimen, consisting of a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) plus an antiandrogen (flutamide or bicalutamide) plus finasteride (a 5-alpha-reductase inhibitor), followed by finasteride maintenance therapy, as the sole intervention. All patients refused local therapy and had their prostates intact. Determinants of efficacy included serum prostate-specific antigen (PSA) levels and disease-specific survival.

Results. Patients were treated for a median of 13 months with triple androgen blockade. At baseline, mean PSA level was 13.2 ± 1.2 ng/ml (range, 0.39-100 ng/ml), and mean Gleason score was 6.6 ± 0.1 (range, 4-10). During treatment, PSA levels declined to ≤0.1 ng/ml in all patients, with a median time of 3 months. After a median follow-up of 36 months since initiation of treatment, PSA levels have remained stable in 105 of 110 patients (95.5%). At a median follow-up of 55 months (range, 38-125 months), the mean PSA level for the first 57 patients treated in this series is 1.88 ± 0.1 (range, 0-11.0 ng/ml). Only 9 of 110 (8.1%) patients have a PSA level ≥4.0 ng/ml. To date, no patient has received a second cycle of hormone blockade.

Conclusions. Although median follow-up is short, triple androgen blockade therapy followed by finasteride maintenance appears to be a promising alternative for the management of patients with clinically localized or locally advanced prostate cancer. Further study of this approach is warranted.
Progressing Prostate Carcinoma
Authors: Haut Michael J. , Harryhill Joseph F. , Rosenstock Jeffrey , Warhol Michael J. , Vitti Richard
Published: August 2004

In the Karnell Cancer Center Grand Rounds, we present a patient who underwent radical prostatectomy with bilateral pelvic lymphadenectomy, but had positive margins and subsequently developed local recurrence and then systemic disease. Pathologic and radiologic aspects of his disease are discussed. Therapeutic options at different stages of the disease are examined from the point of view of the urologist, radiation oncologist, and medical oncologist.

The surgical portion of the discussion focuses on the selection of initial therapy. Both the selection of surgical candidates and choice of pre- or post-operative therapy in patients can be aided by prognostic tools looking at several variables, including prostate-specific antigen (PSA) level, Gleason score of the tumor, seminal vesicle invasion, extracapsular invasion, and lymph node involvement. Low-risk patients can be treated with monotherapy, such as radical prostatectomy, external beam radiation therapy, prostate brachytherapy, or cryosurgical ablation of the prostate. Higher risk patients may require adjuvant and possibly neoadjuvant therapy in addition.

The radiation portion of the discussion focuses on the use of radiation therapy as salvage for relapsing disease. Of particular importance is the point that treating high-risk patients whose PSA levels have started to rise but are less than 1 ng/ml results in a long-term PSA control rate as high as 75%, but that limiting the use of salvage radiation therapy to patients with high PSA levels or biopsy confirmation of local recurrence in the face of a negative bone scan results in biochemical long-term control of less than 40%.

In the medical oncology part of the discussion, the major focus is on the use of chemotherapy to treat patients whose disease has become resistant to hormonal therapy. Mitoxantrone plus a corticosteroid has been found to offer significant palliation for such patients. Combination therapy with estramustine plus taxanes, other microtubule inhibitors, or other agents such as topoisomerase II inhibitors, has been found to cause shrinkage of measurable soft tissue disease and diminution of serum PSA levels. The development of effective hormonal and chemotherapeutic drugs for treatment of metastatic disease has led to new interest in adjuvant and neoadjuvant therapy of high-risk patients.
Caring for Colleagues
Authors: Penson Richard T. , Seiden Michael V. , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

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 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.

Caring for colleagues who develop cancer is a privilege woven with an extra dimension—caregiver-patient issues. As well as stretching the usual need for a supportive relationship, when one of the health care team develops cancer it particularly provokes concerns about our own mortality. The case is presented of a well-known physician who developed a second cancer and has been cared for at the MGH Cancer Center. Staff discuss her care as it has been effected by her status as a colleague. They perceived unique barriers to optimal care such as assumptions about the patient's level of medical knowledge, and technical, informational, emotional, and hierarchical issues that may obstruct the development of a trusting relationship between caregivers and the physician/patient. Emotional stress may prevent the sharing of an accurate prognosis. In the case under consideration, the patient had a frank and open attitude to her cancer yet her caregivers were concerned about continual breeches of patient confidentiality. Despite the many potential problems inherent when the caregiver becomes the patient, this case discussion was a poignant reminder of the unique challenges of every experience with cancer and the weighty privilege of being involved with patient care.
STI571: Targeting BCR-ABL as Therapy for CML
Authors: Mauro Michael J. , Druker Brian J.
Published: August 2004

Therapeutic agent STI571 (signal transduction inhibitor number 571) is a rationally developed, potent, and selective inhibitor for abl tyrosine kinases, including bcr-abl, as well c-kit and the platelet-derived growth factor receptor tyrosine kinases. Results of clinical trials to date have demonstrated the crucial role of the bcr-abl tyrosine kinase in chronic myelogenous leukemia (CML) pathogenesis and the potential of anticancer agents designed to target specific molecular abnormalities in human cancer.

An initial phase I study of STI571 included 83 Ph+ CML patients who had failed interferon-based therapy. Patients were required to be in chronic phase, defined liberally as less than 15% blasts in blood or bone marrow. Patients were treated with once-daily oral doses of STI571 in 14 successive dose cohorts ranging from 25-1,000 mg. In this phase I study, no dose-limiting toxicity was encountered and toxicity at all dose levels was minimal. The threshold for a maximally effective dose was found at 300 mg; for patients treated at or above this level, complete hematologic response was seen in 98% of patients, with complete cytogenetic responses in 13% and major cytogenetic responses in 31%. With a median duration of follow-up of 310 days, ongoing responses are evident in 96% of patients.

In the phase II study of the accelerated phase of CML, 233 patients were treated with either 400 or 600 mg of STI571. With similar follow-up to the chronic phase trial, 91% of patients showed a hematological response; 63% of patients achieved a complete hematological response but not all patients had recovery of peripheral blood counts.

In addition to the phase II clinical trials with STI571, a phase III trial randomizing newly diagnosed patients to either interferon with low-dose s.c. cytosine arabinoside versus STI571 is ongoing; this trial accrued rapidly and data collection is ongoing. Integration of STI571 into CML treatment algorithms will require long-term follow-up data from the ongoing phase II and III clinical studies.
Thymoma: Update for the New Millenium
Authors: Johnson Scott B. , Eng Tony Y. , Giaccone Giuseppe , Thomas Charles R.
Published: August 2004

Thymomas are relatively common tumors of the anterior superior mediastinum. They are usually relatively slowly growing tumors and their prognosis depends on the macroscopic and microscopic invasion of surrounding tissues. Surgery is the mainstay treatment of thymomas, and complete resection represents one of the most important prognostic factors in this disease. Other important prognostic indicators include the tumor stage and size and the presence of symptoms. Postoperative radiotherapy is indicated in tumors with invasion of surrounding tissues, even if resection was radical, since it improves local control and survival. Cytotoxic chemotherapy has been employed in several relatively small phase II studies and in advanced disease has been demonstrated to produce a 50%-80% objective response rate. Neoadjuvant cytotoxic chemotherapy and/or external beam radiotherapy has been used with some success in patients with tumors which are not readily resectable. Novel antiproliferative systemic agents, with both cytotoxic and cytostatic mechanisms of action, are being tested in ongoing prospective clinical trials.
High-Dose Therapy in Lymphomas: A Review of the Current Status of Allogeneic and Autologous Stem Cell Transplantation in Hodgkin's Disease and Non-Hodgkin's Lymphoma
Authors: Mink Scott A. , Armitage James O.
Published: August 2004

Autologous stem cell transplantation has proven to be beneficial in selected patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). In patients with HD, transplantation appears to increase event-free survival in patients who fail to enter complete remission with initial therapy. When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year. Transplantation as part of primary therapy for very high-risk patients may be beneficial, but is not standard therapy at this time. For patients with diffuse large-cell NHL, transplantation can be considered standard therapy for relapsed patients if they have chemotherapy-sensitive disease. The use of transplantation for high-risk patients in complete remission is promising, but definite recommendations cannot be made at this time. For follicular lymphomas, selected patients seem to benefit and studies are ongoing. Finally, the use of allogeneic stem cell transplantation can be useful in a select group of younger patients.
Review of Recent Advances in Fluorescence Bronchoscopy in Early Localization of Central Airway Lung Cancer
Authors: Kennedy Timothy C. , Lam Stephen , Hirsch Fred R.
Published: August 2004

Centrally located lung cancers are radiologically occult until so far advanced as to have a low cure rate or require extensive resection for cure, but at a cost of high morbidity. These cancers represent about one-fifth of new lung cancers.

Autofluorescence bronchoscopy appears to be an important tool in localizing premalignant and early malignant lesions in the large central airways, particularly when applied to high-risk patients. Applications include studies of molecular biology of premalignancy and early malignancy, chemoprevention studies, endobronchial therapy studies, localization of synchronous tumors, estimation of the extent of field cancerization, and better estimation of resection margins. Autofluorescence bronchoscopy appears to be significantly more sensitive than white light examination but has low specificity. This technology is likely to gain widespread use when evaluation of sputum for malignant changes is both more sensitive and specific, and when its application is demonstrated to reduce mortality in this important subgroup of non-small cell lung cancer patients.
Molecular Genetics of Neuroblastoma and the Implications for Clinical Management: A Review of the MSKCC Experience
Authors: Mora Jaume , Gerald William L. , Qin Jing , Cheung Nai-Kong V.
Published: August 2004

Neuroblastoma (NB) is a biological, genetic, and morphological heterogeneous neoplasm and demonstrates diverse clinical behavior. There exist at least three clinical patterns of NB: A) spontaneously regressing widespread disease; B) not metastatic local-regional disease, and C) metastatic disease (stage 4), frequently with lethal consequences. Patients with non-stage 4 NB are expected to survive even without medical treatment whereas stage 4 patients have an overall survival rate of 20% despite multimodality therapy protocols. The clinical management of patients with NB is therefore challenged by the objective identification of cases in which noncytotoxic approaches can be safely taken. Experience in the last decade at Memorial Sloan-Kettering Cancer Center supports the hypothesis that the natural history of disease defines relevant clinical groups of NB and has distinct molecular genetic profiles allowing therapeutic approaches tailored for each group. Here we review the natural history and clinicobiological features of 113 NB cases managed uniformly in our institution in an attempt to characterize useful genetic markers to support the decision making of noncytotoxic versus cytotoxic approaches for each category of NB.
Osteoporosis in Survivors of Acute Lymphoblastic Leukemia
Authors: Haddy Theresa B. , Mosher Revonda B. , Reaman Gregory H.
Published: August 2004

Osteoporosis is currently receiving increasing attention as an important late effect in survivors of childhood cancer and its treatment because of their quality of life and its negative effect on the survivors' ability to perform developmentally appropriate activities. Survivors of childhood cancer are especially vulnerable because they are affected during childhood and adolescence, a time when peak bone mass should be achieved. This paper reviews decreased bone density in acute lymphoblastic leukemia (ALL), which is the most common childhood cancer and has a cure rate approaching 80%. Osteopenia/osteoporosis has been observed in all phases of the disease: at diagnosis, during treatment, and throughout the post-treatment period for as long as 20 years. Among the findings that have been described are musculoskeletal pain, disturbed gait, fractures, kyphosis, lordosis, and growth failure. Risk factors not specifically related to ALL include smoking, ingestion of carbonated beverages, and family history of “brittle bone” or fractures. Patients should be counseled in regard to diet, exercise, smoking cessation, and avoidance of carbonated beverages. There are a number of options for specific drug therapy; however, the administration of bisphosponates to children and adolescents must be approached with caution. Research is needed to determine how extensive the problem is and how to best prevent and treat the osteopenia/osteoporosis associated with ALL.
Losing God
Authors: Penson Richard T. , Yusuf Rushdia Z. , Chabner Bruce A. , Lafrancesca Joanne P. , McElhinny Michael , Axelrad Albert S. , Lynch Thomas J.
Published: August 2004

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 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.

Nebulous language, distrust, and dogma confound spiritual aspects of cancer care. However, existential well being is an important determinant of quality of life: finding meaning and purpose make suffering more tolerable. The case presented is of a patient who experienced “losing God” as a Hodgkin's disease survivor with metastatic prostate cancer and severe coronary artery disease. His caregivers were able to provide the sense of community in which he could re-establish his faith. Health care providers do not have to be religious in order to help patients to deal with a spiritual crisis. The clinical skills of compassion need to be deployed to diagnose and respond to spiritual suffering. Acknowledging and addressing anger or guilt, common sources of suffering, are essential to adjustment. Simply being there for the patient and being open to their hurt can help resolve their spiritual crisis, a responsibility that is shared by the whole health care team.
Hematologic Malignancies
Authors: Petryk Magdalena , Grossbard Michael L.
Published: August 2004

This article reviews highlights in the field of hematologic malignancies presented at the 2001 annual meeting of the American Society of Clinical Oncology. Targeted therapies continue to proceed from the laboratory to the clinic. Monoclonal antibody-based therapies predominate, and further data on radioimmunoconjugates (RICs) (tositumomab and Iodine 131 tositumomab [Bexxar] and ibritumomab tiuxetan [Zevalin]) are presented. Both agents have high response rates in relapsed B-cell non-Hodgkin's lymphoma (NHL). Results from the first trial directly comparing an RIC (Zevalin) to an unconjugated antibody (rituximab) are presented. A novel application of RIC therapy as part of high-dose therapy for mantle cell NHL is described. A new fusion toxin, BL22, targets the CD22 antigen and shows marked activity in the treatment of hairy cell leukemia. Similarly, the Hu1D10 monoclonal antibody has activity in B-cell NHL and might have a relatively unique mechanism of action. Finally, advances in the treatment of mucositis are described. These abstracts all describe therapies derived from our enhanced understanding of tumor immunology and molecular biology.
Ovarian Cancer
Authors: Seiden Michael V.
Published: August 2004

Ovarian cancer remains the most lethal gynecologic malignancy in women in the United States. Studies from this year's American Society of Clinical Oncology more clearly defined the role of chemotherapy in women with early stage disease and now suggest that essentially all women with invasive disease should receive chemotherapy that contains carboplatin. Studies in women with advanced disease continue to support the use of carboplatin and paclitaxel in the treatment of women with newly diagnosed disease although early data suggest that carboplatin and docetaxel might be an acceptable alternative. Platinum-resistant disease remains a therapeutic challenge. Small molecules that inhibit the function of the epidermal growth factor receptor, such as OSI-774, and novel classes of chemotherapeutic agents, including the acylfulvene MGI-114 and epothilone B and its analogue, BMS247550, all warrant further study in this disease.
Sarcoma
Authors: Maki Robert
Published: August 2004

ASCO 2001 was a banner year for innovative systemic therapy for sarcomas. Imatinib mesylate (STI571, GleevecTM) shows clear activity not only in chronic myelogenous leukemia, for which the drug received Food and Drug Administration approval, but also in gastrointestinal stromal tumors as well, by virtue of imatinib mesylate binding to the abl, kit, and platelet-derived growthfactor receptor tyrosine kinases. Ecteinascidin-743 (ET-743) demonstrates activity against a fraction of other soft-tissue sarcomas. Gemcitabine-based regimens show at least some activity against a subset of soft-tissue sarcomas. Given the lack of new agents for sarcoma therapy since the development of ifosfamide, these studies give hope that the term “effective systemic therapy for sarcoma” might become a reality.
Breast Cancer
Authors: Kuter Irene
Published: August 2004

Several interesting aspects of breast cancer were covered at this year's American Society of Clinical Oncology meeting. Sentinel lymph node (SN) mapping is now in widespread use, in concert with the general trend toward trying to decrease the morbidity of breast cancer surgery. With every advance, however, comes new challenges, and there was a timely presentation from Giuliano's group addressing the controversial issue of how to interpret the presence of cells in the SN seen only with keratin stains but not by routine hematoxylin and eosin stains. Two abstracts addressed the issue of whether for certain women with invasive breast cancer radiation therapy could be omitted after lumpectomy. Another interesting topic related to hormonal issues in the adjuvant treatment of premenopausal women. An analysis from the ZIPP-TRIAL reported on bone marrow density studies in young women given two years of ovarian suppression in the adjuvant setting: it seems that the loss of bone density may be reversible and, more interestingly, may be prevented with concurrent tamoxifen. Two other presentations looked at the prognostic significance of drug-induced amenorrhea in young women treated with adjuvant chemotherapy and at the efficacy of ovarian suppression during chemotherapy in preserving fertility.

In an unpublicized presentation, Mary-Claire King presented very interesting results from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial suggesting that tamoxifen may be an effective chemopreventive drug for women with BRCA2, but not BRCA1, mutations. Two important presentations re-analyzed the outcome of the pivotal trials using Herceptin to treat metastatic breast cancer and nicely show that FISH analysis of HER-2 overexpression is a more accurate indicator of response to Herceptin than immunohistochemical staining. Finally, there were two interesting presentations related to tamoxifen resistance which may be relevant clinically, pertaining to subsequent raloxifene use and the interaction of the estrogen receptor and EGF receptor pathways, respectively.
Vinorelbine, Epirubicin, and Methotrexate (VEM) as Primary Treatment in Locally Advanced Breast Cancer
Authors: Abrahamova J. , Wagnerova M. , Kubala E. , Malec V. , Simova E. , Sirakova I. , Pavlikova E. , Machova D. , Kocak I. , Pavlikova I. , Tuma P. , Prausova J. , Kroslakova D. , Van Praagh I.
Published: August 2004

Purpose. This phase II trial of VEM (vinorelbine + epirubicine + methotrexate) in the treatment of locally advanced breast cancer was conducted to obtain downstaging to allow surgery and breast conservation.

Patients and Methods. This multicenter study recruited 58 patients with locally advanced breast cancer (two patients ineligible); 56 were evaluable for response and tolerance.

Results. Downstaging was obtained in 77% of the patients with a pathological complete response (pCR) rate of 9%. At 33 months of follow-up, median survival has not been reached. Neutropenia grade 3-4 was reported in 31% of cycles with 3% of cycles with infection grade 3. Alopecia grade 3 was noticed for 71% of patients.

Conclusion. VEM represents an effective regimen for patients with locally advanced breast cancer, allowing an important pCR. Moreover, this regimen appears to be particularly well tolerated.
Hormone Replacement in Women with a History of Breast Cancer
Authors: Pritchard Kathleen I.
Published: August 2004

Estrogen used alone (estrogen replacement therapy [ERT]) or with the addition of progesterone (hormone replacement therapy [HRT]) is known to be effective in reducing menopausal symptoms including hot flashes, vaginal dryness and urinary symptoms. It has been traditionally contraindicated, however, in women with a previous diagnosis of breast cancer because of fear that it may increase the risk of recurrence. There are considerable basic scientific data but little methodologically strong observational data and none from randomized studies concerning the use of ERT in women with a prior diagnosis of breast cancer. From our knowledge of the physiology of breast cancer, however, estrogen and/or progestational agents should be used with caution in women with a previous diagnosis of breast cancer. There are currently many alternatives to ERT/HRT in the prevention of menopausal symptoms such as vitamin E, clonidine and selective serotonin reuptake inhibitor antidepressants such as venlafaxine. There are also a variety of other approaches to the prevention of osteoporosis and cardiovascular disease including bisphosphonates, diet, and exercise; and diet, exercise, and statins, respectively. Other suggested beneficial effects of estrogen such as colon cancer prevention can be approached by the use of aspirin or the non-steroidals. Several trials of ERT/HRT used for 2 years versus no therapy in menopausal women with a previous diagnosis of breast cancer are ongoing in Europe and Britain, and should give us stronger data as to the role of HRT in this setting.