Cervical cancer is one of the most common causes of cancer in women worldwide. However, improvements in screening programs and treatment modalities have significantly reduced the morbidity and mortality of this disease. The discovery that infection with the human papillomavirus (HPV) is a crucial part of the causative pathway in cervical cancer pathogenesis has revolutionized screening, and prompted investigations into alternatives to traditional cytologic evaluation which may be useful in low-resource settings. Concomitant with improved screening has been a shift towards greater detection of both pre-invasive and early-stage neoplastic disease. Earlier detection not only allows for surgical management of disease, with the avoidance of chemotherapy and radiation, but also the possibility of fertility preservation. As surgical technologies advance to encompass minimally-invasive procedures, interventions for early-stage cervical cancer are becoming increasingly effective in disease eradication while permitting patients to maintain their quality of life.
Cervical Neoplasia; Cervical Screening; Cytology; Radical Hysterectomy; Trachelectomy; Minimally Invasive Surgery
The treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.
Alectinib; anaplastic lymphoma kinase (ALK); ceritinib; crizotinib; non–small cell lung cancer (NSCLC)
Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) commonly receive intensive chemotherapy to achieve disease remission. In the United States and many other countries, it is standard practice that these patients remain hospitalized “preemptively” until blood count recovery due to the risk for overwhelming infections and bleeding during pancytopenia. This care policy requires hospitalization for an average of 3–4 weeks after completion of chemotherapy. However, highly effective oral prophylactic antimicrobials are now available, and transfusion support of outpatients has become routine in recent years. As a result, the care of patients with hematologic malignancies treated with other intensive modalities is increasingly shifting from inpatient to outpatient settings. Benefits of this shift could include reduced need for medical resources such as transfusions or intravenous antimicrobial therapy, improved quality of life (QOL), decreased rates of nosocomial infections, and lower cost. Increasing evidence indicates that selected AML patients undergoing intensive remission induction or salvage chemotherapy can be discharged early after completion of chemotherapy and followed closely in a well-equipped and –staffed outpatient facility safely and less costly. Further demonstration that the current approach of “preemptive” hospitalization is medically unjustified, economically more burdensome, and adversely affects health-related QOL would very likely change the management of these patients throughout this country and elsewhere and establish a new standard practice that improves cancer care.
Acute myeloid leukemia (AML); early hospital discharge; health care cost; intensive chemotherapy; outpatient management; quality of life
Metastatic prostate cancer has a unique predilection for bone that can lead to significant clinical sequelae, such as fracture and cord compression. This tropism for bone yields not only clinical challenges, but also opportunities to understand the tumor biology in bone and to develop relevant therapeutic strategies. The process by which tumor cells migrate to bone, remain dormant, and then colonize and expand is based on complex interactions between prostate cancer tumor cells and the host microenvironment. This review will provide an overview of these interactions as well as therapies targeting osseous metastases in castration-resistant prostate cancer.
Osteoblast; osteoclast; RANKL; radiopharmaceutical; denosumab; radium-223
Breast cancer is a disease associated with aging, with almost one-half of all new breast cancer cases diagnosed annually in the United States occurring in women age 65 and older. Recent data suggest that although breast cancer outcomes in younger women have shown substantial improvement as a result of advances in treatment and screening, the benefits in older women have been less pronounced. Although older adults have been under-represented on cancer clinical trials there is an emerging body of literature to help guide treatment decisions. For early stage breast cancer, the discussion regarding treatment options involves balancing the reduction in risk of recurrence gained by specific therapies with the potential for increased treatment-related toxicity potentially exacerbated by physiological decline or comorbidities that often co-exist in the older population. A key component of care of the older adult is the recognition that chronologic age alone cannot guide the management of an older individual with breast cancer; rather, treatment decisions must also take into account an individual’s functional status, estimated life expectancy, the risks and benefits of the therapy, potential barriers to treatment, and patient preference. This article reviews the available evidence for therapeutic management of early-stage breast cancer in older adults, and highlights data from geriatric oncology literature that provides a basis on which to facilitate evidence-based treatment.
breast cancer; older patient; therapeutic management; geriatric oncology
In 2007, a group of experts charged by the American Society for Blood and Marrow Transplantation critically reviewed the available literature and summarized the indications for allogeneic hematopoietic cell transplantation versus chemotherapy in adults with acute myeloid leukemia. Much of the resulting position statement was based on studies conducted nearly 2 decades ago, and may not accurately represent current treatment. As a result of advances in both therapeutic regimens and supportive care, a number of recent studies have demonstrated clear and consistent improvements in the outcomes of patients receiving chemotherapy and allogeneic hematopoietic cell transplantation. In addition, prognostic accuracy has improved with the identification of mutations not detected by traditional cytogenetics. With these advancements in prognostic accuracy and treatment, it is now appropriate to revisit the indications for transplantation versus chemotherapy.
Acute myeloid leukemia; allogeneic hematopoietic cell transplantation; chemotherapy; American Society for Blood and Marrow Transplantation
This study investigated the impact of prognostic variables, including the distance a patient lives from a transplant center, on the outcome of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma.
This retrospective analysis included 77 myeloma patients who received an ASCT at Dartmouth Hitchcock Medical Center between 1996 and 2009, 70 of whom were treated between 2002 and 2009. Using linear regression and univariate analysis, we examined the impact of distance from the transplant center on survival. Kaplan-Meier curves identified overall and event-free survival. An association between distance from the transplant center and survival was examined using Cox regression analysis, while adjusting for patient-, disease-, and treatment-related variables.
Increasing distance from the transplant center correlated with improved overall survival (P=.004), but had no impact on disease-free survival (P=.26).
These results suggest that the distance from a transplant center should not be a barrier to ASCT for eligible patients with multiple myeloma.
Thrombotic; thrombocytopenia; purpura; ADAMTS13; microangiopathic; hemolytic
Even with hormone-targeted and human epidermal growth factor receptor 2 (HER2)–targeted anticancer agents, intrinsic resistance or acquired resistance are common occurrences in estrogen receptor–positive and HER2-positive breast cancers, respectively. Potential mechanisms for resistance to targeted agents include steric inhibition imposed by other cellular elements, molecular changes in the target receptor, alterations in the regulation of downstream signaling components, compensatory cross-talk with other signaling pathways, and pharmacogenetic alterations in the host. Evidence suggests that both hormone receptor–positive tumors and HER2-overexpressing tumors use the phosphoinositide 3-kinase/Akt/ mammalian target of rapamycin (mTOR) pathway to escape control of antihormone and anti-HER2 therapies. The combination of mTOR inhibitors with hormone-targeted or HER2-targeted therapies appears to be a promising strategy for overcoming resistant disease and preventing the development of resistance.
Breast neoplasms; mTOR inhibitors; everolimus; temsirolimus; ridaforolimus
Biliary tract cancers (BTC), though uncommon, are highly fatal malignancies, and current treatments fail to cure or control the majority of tumors. Given the complexity of the anatomy and often aggressive nature of the disease, multidisciplinary treatment, including palliation, is often required. However, systemic therapy with cytotoxics and/or targeted agents are routinely the mainstay of treatment for patients with advanced biliary tract cancers, and new targets and agents provide hope for this disease. This article focuses on recent advances in the management of biliary tract cancers, with a special focus on the molecular basis for current therapeutic investigation in this disease.
We present a unique case of a patient with deafness and blindness secondary to carcinomatous meningitis from colorectal adenocarcinoma with accompanying radiologic and pathologic images and a brief review of the relevant literature.
meningeal carcinomatosis; severe visual loss; severe hearing loss
Among men treated with prostatectomy or radiation therapy for localized prostate cancer, the state of an increasing prostate-specific antigen (PSA) level is known as biochemical recurrence (BCR). BCR can be predictive of the development of subsequent distant metastases and ultimately death, but BCR often predates other signs of clinical progression by several years. Although patients may be concerned about their rising PSA levels, physicians attempting to address patient anxiety must inform them that BCR is not typically associated with imminent death from disease, and that the natural history of biochemical progression may be prolonged. Misinterpretation of the significance of early changes in PSA may cause patients to receive androgen deprivation therapy (ADT) prematurely, especially in settings where the disease is unlikely to impact survival. In addition, knowledge of the morbidities associated with ADT (hot flashes, impotence, sarcopenia, metabolic syndrome, bone loss, and increased risk of vascular disease) has accelerated the search for alternative treatment options for these patients. Clinical trials investigating when and how to best use and supplement hormonal therapies in this patient population are under way, as are trials of novel nonhormonal targeted agents, immunotherapies, natural products, and other pharmaceuticals that have been approved by the US Food and Drug Administration (FDA) for other indications. This review will summarize the acceptable standards of care for the management of biochemically recurrent prostate cancer, and will also outline some novel experimental approaches for the treatment of this disease state.
Prostate cancer; biochemical recurrence; PSA recurrence
Waldenstrom’s macroglobulinemia (WM) is a B-cell disorder characterized by bone marrow infiltration with clonal lymphoplasmacytic cells (LPCs), along with an IgM monoclonal gammopathy. Recent studies have led to several insights into disease biology as well the development of an International Staging System. Patients with asymptomatic macroglobulinemia should be observed without therapy. Options for frontline therapy include alkylating agents, nucleoside analogs, and rituximab, either as monotherapy or in combination. Although objective responses are common, complete remissions are infrequent. Several novel agents including proteasome inhibitors, and thalidomide, as well as high-dose chemotherapy and stem cell transplantation are being incorporated into therapeutic armamentarium in WM and show promising activity. This report provides an update on recent advances in biology and treatment of this disease.
Until recently, development of chemotherapeutic agents that target mitosis has centered on inhibiting the mitotic spindle through interactions with microtubules. The taxanes, while significantly advancing the treatment of many types of cancer, suffer from problems of hematopoeitic and neurologic toxicities, development of resistance, and an inconvenient formulation. Novel microtubule inhibitors currently in clinical testing and in clinical use have the main advantage of overcoming resistance. Still, they have side effects related to the inhibition of microtubules in normal host cells. Novel anti-mitotics, which target the mitotic spindle through interactions with non-microtubule mitotic mediators like mitotic kinases and kinesins, have been identified and are now in clinical testing. They offer the prospect of surmounting more of the problems inherent with taxanes and the hope of improving upon their broad antitumor efficacy. This review will concentrate on novel agents in later clinical development that target both the spindle microtubule and non-microtubule constituents of mitosis.
Microtubule-inhibitor; Anti-mitotic; Epothilones; Mitotic Kinases; Mitotic Kinesins; Clinical Trials
Squamous cell carcinoma of the head and neck (HNSCC) while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated activity in this disease. Cetuximab, a monoclonal antibody, is FDA-approved in conjunction with radiation for locally advanced, potentially curable disease, and as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a 1st-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.