Showing papers in "Current Treatment Options in Oncology in 2006"

Follicular Lymphoma International Prognostic Index.

Abstract: Although numerous treatment approaches are proposed for patients with follicular lymphoma, criteria to help in choosing a treatment for a given patient and for comparing trial results are lacking. Several retrospective studies have analyzed prognostic factors, but their conclusions rely on limited numbers of patients treated during long periods, and their results are discordant. The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide. Five factors are used (age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level) to build a three-category index. This index, together with new biologic markers such as gene profiling and proteomics, could help provide an optimal treatment option for patients with follicular lymphoma.

Managing the cognitive effects of brain tumor radiation therapy.

Abstract: Postoperative radiation therapy (RT), either alone or in combination with chemotherapy, is the mainstay of treatment for primary and/or metastatic brain tumors. The majority of patients with brain tumors will have significant symptoms of their disease and of RT that will have a negative impact on their quality of life and neurocognitive function. The symptoms of brain tumors depend on tumor location. Radiation-induced brain injury is a complex and dynamic process involving all cells in the brain, including endothelial and oligodendroglial cells, astrocytes, microglia, neurons, and neuronal stem cells. The symptoms of radiation-induced brain injury may be acute, subacute, or chronic, occurring hours, days, weeks, months, and even years after exposure to radiation, the pathogenesis of which is oxidative stress and inflammation. At present, there are no effective preventive approaches for radiation-induced brain injury. Rather, the management of radiation-induced fatigue, changes in mood, and cognitive dysfunction involves a multidisciplinary approach using pharmacologic, behavioral, and rehabilitative therapies. Given the prevalence of brain neoplasms and the high incidence of the radiation-induced symptom cluster and brain injury, clinical research to address these important clinical problems is critical.

Imaging in head and neck cancer.

Abstract: The goals of imaging in head and neck cancer are to establish tumor extent and size, to assess nodal disease, to evaluate for perineural tumor spread, and to distinguish recurrent tumor from post-treatment changes. MRI is the preferred modality for assessment of nasopharyngeal, sinonasal, and parotid tumors, because of better contrast resolution, high frequency of perineural spread, and less prominent motion artifacts. MRI is the best modality to delineate the extent of intraorbital and intracranial extension of malignant tumors. Tumors of the oropharynx, larynx, and hypopharynx are frequently primarily imaged with CT, which is less affected by breathing and swallowing artifacts. MRI is also the initial study of choice for tumors confined to the oral tongue, and possibly also for other oral cavity locations because MRI is superior in detection of tumor spread into the bone marrow. There is no clear advantage of CT or MRI for evaluation of nodal disease. Positron emission tomography (PET) is very sensitive for metastatic lymph nodes that are at least 8 mm in size and is the technique of choice in dubious cases. Imaging-guided biopsies are performed whenever needed. For imaging of treated head and neck cancer, PET scans have been found to generally offer higher sensitivity than MRI or CT. Combined PET/CT may be the modality of choice because it almost completely eliminates the false-positive and false-negative PET findings. Patients with head and neck cancer who are referred to tertiary care centers commonly arrive with cross-sectional images obtained at other institutions. Reinterpretation of these studies by dedicated radiologists frequently leads to changes in findings, which alter treatment and affect prognosis.

Management of pineal region tumors.

Abstract: Tumors of the pineal region represent a diverse collection of tumors with a variety of natural histories. This diversity necessitates accurate histologic diagnosis to allow rational therapeutic planning. Evaluation of a pineal lesion should begin with craniospinal MRI and analysis of the cerebrospinal fluid (CSF). Whereas certainty of the histologic diagnosis is now a requirement for treatment in Western nations, some Asian centers continue to recommend a test dose of radiation therapy based on the high incidence of germinoma in those countries. If there is high clinical suspicion of a germinoma or tectal glioma, stereotactic or endoscopic biopsy may be pursued. All other lesions should be referred for open biopsy with microsurgical techniques. This approach provides adequate tissue for diagnosis, may be curative in low-grade tumors, and may substantially improve survival in patients with malignant tumors. If open surgery is not desired by the patient or practitioner, stereotactic or endoscopic biopsy may be followed by radiosurgery for localized, well-demarcated tumors. Radiation therapy is the first-line therapy for germinomas. Although the optimal radiation dosage and volume have not been decided, the current Children's Oncology Group trial may offer definitive evidence to address this dilemma in germ cell tumors. Evidence of CSF seeding requires craniospinal radiation and adjuvant chemotherapy regardless of tumor type. Diagnosis of any of the malignant tumors (non-germ cell tumors, pineoblastomas, and parenchymal tumors of intermediate determination) also requires craniospinal radiation (with local tumor doses of at least 50 Gy) and adjuvant chemotherapy (generally platinum based). Patients with tectal gliomas may undergo excision with or without postoperative radiation; however, they also may be observed with vigilant follow-up alone.

Current therapeutic approaches in patients with brain metastases

Abstract: The development of brain metastases is often viewed as the end stage of a disease course and engenders skepticism about the efficacy of treatment. Aggressive management of brain metastases is effective in both symptom palliation and the prolongation of life. The majority of patients with controlled intracranial metastases will expire from systemic disease rather than from recurrence of these metastases. Single brain metastases should be treated with surgical resection or stereotactic radiosurgery, though it is unclear at this time if one modality is more effective than the other. Surgical resection is preferred when a pathologic diagnosis is needed, for tumors larger than 3.5 cm, or when immediate tumor mass decompression is required. Stereotactic radiosurgery (SRS) should be applied for single tumors less than 3.5 cm in surgically inaccessible areas and for patients who are not surgical candidates. Small tumors (ie, < 3.5 cm) that cause minimal edema and are surgically accessible may be treated with either surgery or SRS. There is controversy over whether whole brain radiation therapy (WBRT) can be omitted following surgical resection or SRS. Omission of WBRT increases intracranial tumor recurrence; however, this has not been correlated with decreased survival. Clinicians who choose to omit upfront WBRT are obligated to monitor the patient closely for intracranial recurrence, at which time further salvage therapy in the form of surgery, SRS, or WBRT may be considered. Histology is of particular importance when considering WBRT for patients with radioresistant tumors such as melanoma, renal cell carcinoma, or sarcoma. WBRT may be of less clinical benefit in this setting. Chemotherapy has been demonstrated to improve response rates when used as an adjunct to radiation therapy. These improvements in response rates have not been correlated with an improvement in median survival. Noncytotoxic radiosensitizing agents such as motexafin and efaproxiral show promise. Phase III trials to assess the benefit of motexafin in patients with metastatic lung cancer and efaproxiral in patients with metastatic breast cancer are ongoing. Targeted therapies offer promise in achieving therapeutic efficacy while minimizing side effects. Surgical adjuncts such as BCNU (carmustine) wafers and the GliaSite Radiation System (Cytyc Corporation, Marlborough, MA) may be useful in the future in achieving optimal local tumor control.

Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies.

Abstract: The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.

Active surveillance versus radical treatment for favorable-risk localized prostate cancer.

Abstract: Widespread prostate-specific antigen (PSA) screening in North America has resulted in a profound stage migration and a marked increase in incidence. One in six men is now diagnosed, many with small-volume, low-grade cancer. This incidence is dramatically higher than the 3% lifetime risk of prostate cancer death that characterized the prescreening era. This article summarizes the case for active surveillance for “favorable-risk” prostate cancer with selective delayed intervention for rapid biochemical progression, assessed by increasing PSA levels, or grade progression. The results of a large phase II trial using this approach are reviewed. To date, this study has shown that virtually all men with favorable-risk prostate cancer managed in this fashion will die of unrelated causes. Based on the Swedish randomized trial of radical prostatectomy versus watchful waiting, the Connecticut observation series, and the Toronto active surveillance experience, a number needed to treat analysis of the benefit of radical treatment of all newly diagnosed favorable-risk prostate cancer patients, compared with a strategy of active surveillance with selective delayed intervention, is presented. This suggests that approximately 73 patients will require radical treatment for each prostate cancer death averted. This translates into a 3- to 4-week survival benefit, unadjusted for quality of life. This figure is confirmed based on an analysis of the 2004 D'Amico et al. PSA velocity data in favorable-risk disease. The approach of active surveillance with selective delayed intervention based on PSA doubling time and repeat biopsy represents a practical compromise between radical therapy for all patients (which results in overtreatment for patients with indolent disease) and watchful waiting with palliative therapy only (which results in undertreatment for those with aggressive disease).

Management of osteosarcoma.

Abstract: Improving cure rates for osteosarcoma continues to be a major challenge. The clinical management of individual patients is exacting and requires a skilled, experienced team including a surgeon, pathologist, oncologist, and radiologist, with support from specialist nurses and rehabilitation teams. Outcomes from treatment have improved little in 20 years and remain disappointing. Chemotherapy for osteosarcoma is among the most grueling of any given for solid tumors, and treatment of the primary tumor is associated with permanent disability of some degree in a significant proportion of patients. New systemic treatments remain beyond the horizon. In recognition of these difficulties, an international cooperation has begun with the opening of a randomized trial, European and American Osteosarcoma (EURAMOS) 1, in Europe and the United States. This study heralds a new era of clinical investigation into osteosarcoma, with the promise of valuable biologic insights and rapid evaluation of investigational strategies. Osteosarcoma should always be treated under the guidance of a specialist team, and we recommend that whenever possible, patients be offered entry into EURAMOS 1 or other well-designed clinical trials.

The enigma of desmoid tumors.

Abstract: Desmoid tumors (aggressive fibromatosis) are rare neoplastic tumors that may occur sporadically or in association with familial adenomatous polyposis (FAP). The etiology of these tumors is unknown, but hormonal, genetic, and physical factors play a role in their development and growth. A distinction is often made between desmoids in patients with FAP and those in patients without FAP, but clinically these tumors are treated the same; the only difference is the preferential intra-abdominal location of FAP desmoids. The goal of desmoid treatment is local control. Choosing the appropriate method for achieving local control may be complex as the functional and cosmetic outcomes of each method must be considered. In addition, because desmoids spontaneously regress, any claim of successful intervention must be viewed skeptically. Local control is mainly achieved by surgical intervention and may be improved with the addition of radiation therapy (RT). For patients who cannot undergo surgery, the options for local control include RT and systemic therapies such as hormones, nonsteroidal anti-inflammatory drugs (NSAIDs), interferon, and chemotherapy. Patients with symptomatic, progressive disease who can tolerate chemotherapy should be presented with the option of low-dose or standard antisarcoma chemotherapy. Although it is unclear which regimen is better, patients appear to have quicker responses to the standard antisarcoma therapy. Hormone therapy, NSAIDs, and interferon are used often, with varying success, and should be reserved for minimally symptomatic patients or for patients who do not want or are not candidates for chemotherapy. The treatment of desmoid tumors remains an enigma. As more options become available, selecting the correct therapy becomes more nuanced. Further clinical trials are needed to help the clinician navigate his or her way through the morass of desmoid tumor therapies.

Papillary thyroid cancer.

Abstract: Papillary thyroid cancer (PTC), the most common thyroid malignancy, is associated with an excellent prognosis. Overall survival is more than 90%. The first-line treatment is surgical excision, and although the debate continues as to whether a total thyroidectomy or thyroid lobectomy should be recommended, most patients at the University of California, San Francisco are treated with a total thyroidectomy. Not only has this been shown to be superior for overall survival in select patient populations, but local recurrence is also significantly lower with this approach. Total thyroidectomy also optimizes the adjuvant treatment options that are unique to “differentiated” thyroid cancer because these malignant cells retain many of the features of the native thyroid follicular cell. These cellular features are used for specialized investigations and treatment options in patients with PTC. For example, PTC cells retain the ability to produce thyroglobulin, to be stimulated by thyroidstimulating hormone (TSH), and to take up iodine. These features are vital and separate differentiated thyroid cancer from other epithelial malignancies because such features can be used in clinical follow-up (monitoring serum thyroglobulin levels, whole body radioactive iodine scans) and in the treatment of patients with PTC (TSH suppression, radioactive iodine ablation of thyroid remnant, local recurrences, and regional or distant metastases). In summary, the wide array of treatment options for patients with PTC includes surgery, radioactive iodine, thyroid hormone suppression of TSH, external beam radiation (less commonly), and rarely, chemotherapy. This continues to be an area of exciting research for emerging therapy, much of which concentrates on enhancing or re-establishing the differentiated features of the thyroid cancer cell, in an effort to optimize the adjuvant treatment options. The treatment options that are chosen depend on patient factors, disease factors, and the decisions of the patient and treatment team.

The benefits and limitations of sentinel lymph node biopsy

Abstract: The status of the axilla is the single most important prognostic indicator of overall survival in patients with breast cancer. Staging is based on tumor size and on the presence of lymph node metastases. The number of lymph nodes, although prognostic, no longer impacts treatment options. Sentinel lymph node (SLN) mapping and dissection is a more sensitive and accurate technique for nodal evaluation and has been applied to staging of axillary lymph nodes in patients with breast cancer, providing prognostic information, with less surgical morbidity than with axillary lymph node dissection (ALND). When analyzed by an experienced pathologist with serial sectioning and immunohistochemical evaluation, SLN is the most accurate detection tool used in staging of breast cancer. In many centers that use these staging principles, ALND is no longer performed for histologically negative axillary SLNs. In addition, this technique may also be therapeutic because in most patients, the SLN is the only positive axillary node. SLN biopsy is justified in women with ductal carcinoma in situ who have a high risk of invasive carcinoma, such as those with large tumors, a mass, or high-grade lesions. SLN biopsy is performed in the setting of neoadjuvant chemotherapy and demonstrates accurate evaluation of the axilla in 90% of the cases. Women with locally advanced breast cancer may derive great benefit from a minimally invasive approach to the axilla because the extent of nodal involvement is unlikely to change further treatment. For clinically palpable nodes, ALND should be performed for therapeutic and local control. The use of sentinel node mapping in pregnancy is controversial. Vital blue dye is contraindicated in pregnant patients, although some have used radioactive colloid alone to map this subgroup of patients.

Prostate-specific antigen and detection of prostate cancer: What have we learned and what should we recommend for screening?

Abstract: Prostate-specific antigen (PSA) has become one of the most commonly used cancer clinical tests, and routine PSA-based screening has led to a dramatic increase in prostate cancer detection. A significant downward stage migration has resulted, and a decrease in prostate cancer mortality has also been observed. However, PSA screening remains controversial because there is no definitive proof that it decreases prostate cancer death rates, and there is concern that it may detect a significant number of clinically insignificant cancers. Screening age and interval have been recently questioned, and the best threshold to recommend biopsy has been complicated by new data showing that prostate cancer exists at all PSA levels, even those thought to be “normal” in the past. It is hoped that ongoing prospective screening trials will determine the value of PSA screening. However, until these results are available the controversy will continue, and men will continue to be screened.

Ex vivo programmed cell death and the prediction of response to chemotherapy.

Abstract: Since the earliest introduction of cytotoxic chemotherapy, investigators have pursued laboratory techniques designed to match patients to available drugs. Most of the work, published through the 1980s, reflected the prevailing view of cancer as a disease of dysregulated cell proliferation. Noteworthy, the description of apoptosis and programmed cell death, fundamental to our modern understanding of human tumor biology, did not occur until well after the heyday of in vitro chemosensitivity testing. By incorporating the modern tenets of carcinogenesis associated with perturbations in cell survival we can now re-examine laboratory assays of drug response in the context of drug-induced programmed cell death. Although there is interest in the use of genomic analyses for the prediction of chemotherapy response, the painful recognition that genotype does not equal phenotype will continue to limit broad application of these platforms. Biosystematics instructs that biological pathways rarely follow predicted routes. Efforts to force human biology to behave according to preconceived scientific dictates have proven costly and unsuccessful. Whole-cell experimental models with the capacity to evaluate all the operative mechanisms of cellular response to injury, acting in concert, provide valid tools for the study of human cancer. Educated by cellular behavior, we can expeditiously examine molecular processes of interest. This article briefly reviews the history of whole-cell experimental models of in vitro chemosensitivity testing then focuses on cell-death measures as the most robust predictors of clinical outcome in human cancer.

Epidemiology and prevention of cutaneous melanoma

Abstract: Melanoma incidence has continued to increase in all white populations, and mortality from melanoma remains high in older men worldwide. In Australia, Europe, and the United States, a substantial number of thick melanomas in older men are of the nodular subtype, a subtype lacking asymmetry or color change. Educating the public and pro-fessionals about the significance of evolving pigmented lesions as emphasized in the revised ABCDE of pigmented lesions is relevant. Targeting screening efforts toward older men will be necessary to decrease worldwide melanoma mortality. Among preven-tion strategies, emphasizing multiple methods of sun protection in early childhood, adolescence, and adulthood is needed to decrease sunburn rates. Chemoprevention research in melanoma should become a research priority to complement ongoing prevention strategies.

Predictive and prognostic markers in human glioblastomas.

Abstract: Glioblastomas (GBMs) are among the most aggressive of all known human tumors. The median survival times remain in the 12- to 15-month range despite aggressive surgery, radiation, and chemotherapy. Through molecular and genetic profiling efforts, underlying mechanisms of resistance to these therapies are becoming better understood. The present standard of care has been shaped by the recently reported phase III study by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada, which found that the addition of temozolomide (TMZ) to radiation therapy significantly improved outcome compared with radiation alone. However, careful examination of these data reveals that not all GBM patients benefited from the addition of TMZ to radiation therapy. A companion correlative study found that GBM patients with tumors with MGMT promoter methylation appeared to derive the greatest benefit from the addition of TMZ to radiation therapy. Although this finding is provocative, it should be kept in mind that this study was performed retrospectively and that prospective validation is required before MGMT methylation can be used for clinical stratification purposes. However, this study does show promise for the tailoring of future treatments according to the molecular and genetic profiles of an individual's tumor rather than using the "one-glove-fits-all" approach that is currently being followed. As more effective "smart drugs" are developed, molecular and genetic profiling will assume even greater importance in this regard.

Advances in molecular diagnostics and therapeutics in head and neck cancer.

Abstract: Extensive treatment-related morbidities and stagnant survival rates over the past few decades for patients with squamous cell cancer of the head and neck (SCCHN) emphasize the need for novel diagnostics and therapeutics based on the molecular characteristics of the tumor. The development of an early detection test remains largely preliminary. Much attention has recently been given to saliva-based early detection assays that use accepted tumor markers such as p53 and DNA methylation. Most of these studies have focused on feasibility as opposed to prospective clinical trials. To date, early detection saliva assays have failed to yield a high enough sensitivity and specificity for broad population-based screening. The use of saliva as a noninvasive, inexpensive, and accessible diagnostic substrate remains desirable. Unlike SCCHN diagnostics, molecular-targeted therapies for SCCHN will soon be a reality, with many more compounds in the pipeline. The most promising of these drugs target the epidermal growth factor receptor (EGFR), which is known to be overexpressed in squamous cell carcinomas. Cetuximab, a monoclonal EGFR antibody, has shown efficacy in combination with radiotherapy in advanced SCCHN in a recent phase III trial and is currently being petitioned for US Food and Drug Administration approval. Likewise, erlotinib, an EGFR tyrosine kinase inhibitor, has shown favorable results in phase II trials as monotherapy and in combination with chemotherapy. Gefitinib, another EGFR tyrosine kinase inhibitor, has shown efficacy as monotherapy, in combination with chemotherapy, and with chemoradiotherapy. At least two phase III trials of gefitinib in patients with advanced SCCHN are ongoing. Such low-toxicity, tumor-specific targeting strategies will soon be available for patients with head and neck cancer. The challenge is to establish assays to determine which patients are most likely to benefit from these agents.

Blastic Phase of Chronic Myelogenous Leukemia

Abstract: Chronic myelogenous leukemia (CML), also known as chronic myelocytic or chronic myeloid leukemia, is a clonal disorder of hematopoiesis that arises in a hematopoietic stem cell or early progenitor cell. This is characterized by the dysregulated production of mature non-lymphoid cells with normal differentiation. Eventually, in spite of the term chronic, there is progression to acute leukemia, usually of the myeloid variety, which is highly resistant to current therapies. Despite recent improvements in the treatment of early-stage disease, CML blast crisis (CMLBC) remains a therapeutic challenge. CMLBC is highly refractory to standard induction chemotherapy, with a response rate in myeloid blast crisis of less than 30%. Conventional chemotherapy has been much less successful in this disease compared with de novo acute leukemia, with a mean survival after diagnosis of blast crisis of only 2 to 4 months for nonresponders. Many regimens of chemotherapies have been tried in CMLBC, with minor success. Although imatinib was evaluated in patients with CMLBC, most CMLBC cases today arise in patients already on imatinib-based therapy and developing blastic phase on that therapy; thus there is no standard therapy for patients with CMLBC. Further studies of the mechanisms of transformation of chronic-phase CMLBC at a molecu-lar level, and methods to target these molecular abnormalities, will determine the future direction of new treatment modalities. The prognosis of CML in blast crisis remains dis-appointing, despite great efforts. Currently, the most successful strategy for improving survival in CML is by prolonging the chronic phase and delaying the onset of blast crisis.

Bronchogenic carcinoma in solid organ transplant recipients.

Abstract: Malignancies are increased in some types of solid organ transplant patients receiving immunosuppressive therapy and are a significant contributor to patient morbidity and mortality. There may be a 100-fold increase in the incidence of de novo neoplasia in this population. The risk of lymphoproliferative malignancies is well appreciated. In contrast, the risk of solid tumors with their consequent morbidity and mortality is less well known, probably because of their common occurrence in the general population. Lung cancer is the most common cause of cancer death in the United States; therefore, lung cancer in patients undergoing organ transplantation would be expected to occur frequently on the basis of chance alone. However, the lung cancer risk is approximately 20 to 25 times that of the general population, with an incidence of 0.28% to 4.1% in patients after heart and lung transplant. Risk factors thought to contribute include cigarette smoking, advanced age at transplantation, and chronic immunosuppressive therapy. The role of transplantation (and consequent therapy) in the development of lung cancer in this high-risk population remains unclear. As in the nontransplant population, adequate screening techniques are lacking, making early diagnosis and treatment a challenge. Despite close follow-up and routine imaging with chest radiography and CT, lung cancers continue to be discovered incidentally and at advanced stages. Treatment is similar to that of patients who are nontransplanted with similar stage, histology, and performance status.

Management of marginal zone lymphomas.

Abstract: Marginal-zone lymphoma (MZL) includes three subtypes depending on the site of lymphoma involvement: extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma); splenic MZL; and nodal MZL. Although there is a common cell of origin and similarities concerning a possible chronic antigenic stimulation by microbial pathogens and/or auto-antigens, the clinical presentation is very different with symptoms related to lymphoma location. MALT and splenic MZL present with an indolent disease with good performance status, no B symptoms, and no adverse prognostic factors and are associated with long survival. Patients with nodal MZL present with a shorter progression-free survival. Clinical and biological prognostic factors identified in reported series are heterogeneous. The optimal treatment has yet to be defined for the three subtypes, and current strategies are described in this review.

Gastrointestinal stromal tumors: imatinib and beyond.

Abstract: Opinion statementGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Clinicians previously classified GISTs as “benign≓ or “malignant,≓ but now place resected tumors in risk categories that are based on size and mitotic rate. Historically, GIST patients were managed with surgery alone, as chemotherapy and radiotherapy have minimal activity in this disease. In the pre-imatinib era, patients with recurrent or metastatic disease generally did very poorly. GIST therapy was revolutionized following the discovery of oncogenic mutations in the c-kit gene, as well as in the platelet-derived growth factor receptor. Subsequently, it has been confirmed that the KIT receptor tyrosine kinase is both a diagnostic marker and a useful therapeutic target in GIST. Imatinib, a potent inhibitor of KIT activity, is now standard frontline therapy for advanced GIST. With the introduction of imatinib, there have been dramatic improvements in response rates, time to progression, and survival. Imatinib is now being investigated and shows promise in the neoadjuvant and adjuvant settings. Unfortunately, many patients eventually recur or progress during imatinib therapy. For these patients, imatinib dose escalation and/or surgical evaluation are appropriate. Additionally, a novel tyrosine kinase inhibitor such as SU11248 (sunitinib) is a reasonable option for progressive, imatinib-resistant disease. With the identification of other downstream pathways, several other promising therapies are under current investigation either alone or in combination with imatinib and surgery.

Gene expression in breast cancer.

Abstract: We now recognize that all breast cancers are not the same. Different characteristics in gene expression profiles result in differential clinical behavior. With the use of gene microarrays, different subtypes of breast cancer have been characterized. The basal subtype is characterized by high expression of keratins 5 and 17, laminin, and fatty acid-binding protein 7. The ERBB2+ subtype is characterized by high expression of genes in the ERBB2 amplicon. The luminal A subtype is characterized by the highest expression of the ER α gene. The luminal B and C subtypes have a lower expression of the ER cluster. The importance of these different subtypes lies in the fact that they differ in clinical outcome, with the basal and ERBB2+ subtypes having the worse prognosis and the luminal A group having the best prognosis. Different strategies for evaluating tumors in a clinical setting have been developed. Two such strategies are the 21-gene assay (Oncotype DX; Genomic Health, Redwood City, CA), which is currently in commercial use in the United States, and the 70-gene assay, which has been developed by a group in the Netherlands. These assays have been shown to predict clinical outcome and response to therapy. However, to date these gene assays have not been studied in a prospective manner. Over the next year, prospective clinical trials will be initiated using these predictive tools in the treatment of breast cancer. In the near future, clinical decisions will most likely be dictated by the genetic characteristics of the tumor, with the clinical characteristics becoming less important. Tailoring our treatment based on individual tumor characteristics will help us develop better therapeutic strategies and save many patients from receiving unnecessary toxic therapy.

Decompressive percutaneous gastrostomy tube use in gynecologic malignancies.

Abstract: Percutaneous gastrostomy tube placement is a technically feasible and safe procedure for palliation in patients with small bowel obstruction (SBO) caused by advanced gynecologic malignancies. It is used commonly in patients who are poor surgical candidates, those who elect to not undergo surgery, and in patients with a limited lifespan because of end-stage cancer. Percutaneous gastrostomy tube placement is even technically possible in patients with tumor encasing the stomach, diffuse carcinomatosis, and ascites. Percutaneous endoscopic gastrostomy (PEG) tubes provide symptomatic relief of nausea and vomiting in most patients with advanced gynecologic cancer and SBO. PEG tube placement allows most patients to have end- of-life care at home or in an inpatient hospice. It is a cost effective procedure and is associated with low morbidity and mortality. Placement of PEG tubes should be highly considered in patients who present with recurrent bowel obstruction and who have undergone a prior operation for SBO in the setting of advanced gynecologic malignancy.

Testosterone therapy for men at risk for or with history of prostate cancer

Abstract: Since the early 1940s when Huggins showed that severe reductions in serum testosterone by castration or estrogen therapy caused regression of prostate cancer (PCa), it has been assumed that higher testosterone levels cause enhanced growth of PCa. For this reason, it has been considered taboo to offer testosterone replacement therapy (TRT) to any man with a prior history of PCa, even if all objective evidence suggests he has been cured. The fear has been that higher testosterone levels would "awaken" dormant cells and cause a recurrence. Thus, US Food and Drug Administration-mandated language in all testosterone package inserts states that testosterone is contraindicated in men with a history of, or suspected of having, PCa. Although there is little modern experience with administration of testosterone in men with known history of PCa, there is a varied and extensive literature indicating that TRT does not pose any increased risk of PCa growth in men with or without prior treatment. For instance, the cancer rate in TRT trials is only approximately 1%, similar to detection rates in screening programs, yet biopsy-detectable PCa is found in one of seven hypogonadal men. Moreover, PCa is almost never seen in the peak testosterone years of the early 20s, despite autopsy evidence that men in this age group already harbor microfoci of PCa in substantial numbers. The growing number of PCa survivors who happen to be hypogonadal and request treatment has spurred a change in attitude toward this topic, with increasing numbers of physicians now offering TRT to men who appear cured of their disease. Publications have now reported no prostate-specific antigen (PSA) recurrence with TRT in small numbers of men who had undetectable PSA values after radical prostatectomy. Although still controversial, there appears to be little reason to withhold TRT from men with favorable outcomes after definitive treatment for PCa. Monitoring with PSA and digital rectal examination at regular intervals is recommended.

Pediatric rhabdomyosarcoma of the head and neck

Abstract: Pediatric rhabdomyosarcoma is not exclusive to the head and neck. However, the unique anatomy of the head and neck requires special consideration and treatment modifications. The low incidence of these tumors has prevented the development of rigorous treatment protocols. Treatment strategies must be individualized on the basis of histopathologic subtype, prognostic indicators, tumor location, tumor extent, available clinical trial data, and hospital resources. The primary treatment of these tumors typically involves a combination of surgery, radiation, and chemotherapy. Advancements in surgical and radiotherapy techniques have reduced patient morbidity, whereas new chemotherapeutic protocols have improved local disease control and overall survival. Because of the infrequency and complexity of these tumors, patients may benefit from referral to centers with a comprehensive multidisciplinary team that has experience treating these tumors in the pediatric population. If possible, patients should be enrolled and treated on the current Children's Oncology Group protocol.

Management of small cell lung cancer

Abstract: Small cell lung cancer (SCLC) is an aggressive type of lung cancer characterized by rapid growth and early metastasis. It is chemosensitive and radiosensitive, yet decades of research investigating multimodality treatments have failed to control or cure this disease in most patients. First-line treatment of limited-stage disease consists of chemotherapy (often etoposide/cisplatin or etoposide/carboplatin) combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation to decrease brain metastases as a site of disease progression for those who experience complete remission or a very good partial response to multimodality treatment. In a Japanese trial, the combination of irinotecan and cisplatin had initially shown promise in treating patients with extensive-stage SCLC, but a confirmatory trial in the United States did not find a difference in overall survival with irinotecan/cisplatin versus etoposide/cisplatin. Adding a third drug to the etoposide/cisplatin combination, as well as other triplet therapies, has mostly been ineffective in improving outcomes. Variables in chemotherapy administration, including maintenance therapy, alternating non-cross-resistance regimens, and dose intensification, have not been shown to increase survival at large. In terms of radiation therapy, early administration of TRT concurrent with chemotherapy, and hyperfractionation, have been beneficial in treatment of limited-stage disease. In patients who relapse, second-line therapy options consist of reinduction of previous chemotherapy or administration of a single agent. Targeted biological therapies for SCLC are now being investigated, and although a great deal of research remains to be done, these agents and their derivatives may provide the most hope for future treatment of SCLC.

Chemotherapeutic options for primary brain tumors.

Abstract: Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, treatment for most primary brain tumors remains inadequate. Most are associated with a high rate of recurrence after primary therapy and a dismal outcome following recurrence. Surgery and radiation remain the primary modalities of therapy for malignant brain tumors. The role of chemotherapy in malignant gliomas, especially glioblastoma multiforme, has been inconclusive. However, a recent trial by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada combining radiation therapy with temozolomide for newly diagnosed glioblastoma patients showed a significantly improved survival benefit over radiation therapy alone. In addition to this encouraging progress, recent experience has shown that selected malignant brain tumors--for example, anaplastic oligodendrogliomas, primary central nervous system lymphomas, medulloblastomas, and intracranial germ cell tumors--are often highly responsive to chemotherapy. Molecular genetic studies are becoming indispensable aids in the diagnosis and treatment of the malignant gliomas. For example, we have learned that allelic loss of chromosome 1p is a significant predictor of chemosensitivity, whereas combined loss of chromosomes 1p and 19q is a strong predictor of chemosensitivity, progression-free survival, and overall survival in patients with anaplastic oligodendroglioma. Similarly, MGMT promoter methylation is associated with more frequent responses and longer survival in patients with glioblastoma multiforme receiving temozolomide-based therapy. These and other recent advances have led to the development and testing of several novel chemotherapeutic and molecular-targeted agents. Several different approaches and modalities to improve the efficacy of chemotherapy (eg, MGMT promoter methylation) are currently under way. Clinical trials implementing angiogenesis inhibitors, biologic modifiers, or molecular-targeted therapies are also actively being investigated.

Liver-directed therapies for patients with primary liver cancer and hepatic metastases.

Abstract: Liver cancer, whether primary or metastatic, is a major cause of death throughout the world. The surgical management of these diseases varies according to the extent of disease and the overall health of the patient. Surgical resection of hepatic disease remains the only chance for cure. However, a large proportion of patients with liver cancer are unable to undergo a complete surgical resection. These patients are often treated with liver-directed therapies. Although not as effective as surgical resection, these approaches can help to improve the survival of patients. In patients with primary liver cancer, underlying liver disease often prohibits surgical intervention. However, survival advantages have been gained with the application of percutaneous alcohol injection and radiofrequency ablation (RFA). In patients with hepatic metastases, the number of metastases is often what prevents surgical resection. In these patients, RFA, cryoablation, and hepatic artery infusional therapy have all aided in prolonging survival. As chemotherapeutic agents improve and targeted therapies are developed, more patients will be able to undergo surgical management of their liver cancer, primary or metastatic.

Sentinel node dissection in vulvar cancer.

Abstract: Vulvar cancer is an uncommon but devastating disease. In addition to radical vulvectomy, most patients require inguinofemoral lymphadenectomy, which often results in wound infection, wound breakdown, and chronic lymphedema. In the past, the gold standard for early lesions was radical vulvectomy with complete bilateral inguinal-femoral lymphadenectomy. This resulted in a low rate of recurrence but devastating disfigurement and high complication rates. Because only approximately 20% of patients with vulvar cancer have positive lymph nodes upon presentation, the traditional approach of inguinal-femoral lymphadenectomy for all patients resulted in many patients undergoing a morbid procedure without any real benefit. Sentinel node dissection, by removing only the nodes with the highest risk of containing metastases, offers a much less morbid alternative. In addition, because only one or two lymph nodes are removed, these can be subjected to a more thorough histopathologic analysis than conventional complete lymphadenectomy. This involves serial sectioning and immunohistochemical staining for cytokeratin antigen. Very small metastases, termed micrometastases, can be detected in this fashion. Therefore, sentinel node dissection with serial sectioning and immunohistochemical staining potentially offers a more accurate assessment of the regional nodes with less morbidity. Patients with positive sentinel nodes may then undergo additional therapy. Patients with negative sentinel nodes are theoretically at very low risk for metastases and should not require any additional treatment.

Transperitoneal laparoscopic pelvic and paraaortic lymphadenectomy in gynecologic cancers.

Abstract: Laparoscopy, a minimally invasive surgery, may benefit select patients more than traditional abdominal approaches. The benefits of this procedure include low morbidity, shorter length of hospital stay, less blood loss, no significant increase in complications, and a shorter postoperative recovery period; this allows patients to begin adjuvant therapy more quickly. Laparoscopy has been used in gynecologic oncology since the early 1990s and has continued to grow and develop. Complex gynecologic oncology procedures can be performed with a low rate of complication and a low rate of conversion to laparotomy. The literature supports the fact that laparoscopy can be performed with short-term benefit with no increase in morbidity. Although the data are limited and emerging, the risk of cancer recurrence does not appear to increase because of this minimal access approach. Currently, advanced laparoscopic techniques are used to evaluate and treat cervical, endometrial, and ovarian malignancies. Specifically, transperitoneal laparoscopic lymphadenectomy including pelvic and paraaortic nodes is a feasible and efficacious procedure in the management of certain gynecologic malignancies.

Second- and third-line treatments in non-small cell lung cancer.

Abstract: Slow but steady progress has been made in the treatment of advanced non-small cell lung cancer. For first-line therapy, multiple chemotherapy combination therapies can extend survival and improve quality of life. And recently, for the first time ever, a noncytotoxic agent, the antivascular endothelial growth factor antibody bevacizumab, has been shown to improve survival when added to chemotherapy. Striking improvements have also been made in second-line treatment. In August 2004, only one agent was US Food and Drug Administration (FDA) approved in this setting, docetaxel, but by the beginning of 2005, two more were available, pemetrexed and erlotinib. All three of these drugs can significantly benefit patients, with 1-year survival in excess of 30%. Choosing between the three agents can be challenging, and this review focuses on the toxicity differences and predictors of response that can help guide this decision. Docetaxel and pemetrexed, both traditional intravenous cytotoxins, are excellent options for patients who have shown some response to first-line chemotherapy, but at this time, no other means exist to determine likelihood of response. When choosing between the two, pemetrexed causes significantly less neutropenia than does docetaxel, at least on the standard every-3-week regimen. With erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, there are factors that can predict for response, including little or no smoking history, and adenocarcinoma histology. Therefore, patients who fit these characteristics are good candidates for second-line erlotinib. However, the relationship between response to erlotinib and improved survival remains unclear, and several laboratory analyses that may help further, such as evaluation of EGFR gene copy number, are still under development. Although erlotinib is the only FDA-approved option currently available for third-line therapy, many patients with good performance status may benefit from third-line therapy and beyond. In addition to the approved second-line options, other single-agent chemotherapies to consider for treatment beyond second-line are gemcitabine, irinotecan, and oral topotecan. Many new drugs, including bevacizumab, ZD6474 (AstraZeneca, Wilmington, DE), sorafenib, cetuximab, paclitaxel poliglumex, epothilones, and others, alone or in combination with traditional agents, are currently undergoing investigation and hold great promise.