ONCOLOGY Vol 24 No 7

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are>90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.

As a psychiatrist who has cancer, I have developed a deep understanding of how clinicians can help patients who are facing the complicated emotional aspects of dealing with a potentially life-threatening illness. When it comes to cancer, I have been through a lot and have learned a lot.

Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), given alone or in combination with vaccine,w increased overall survival (OS) in patients with unresectable stage III/IV melanoma for whom previous treatment had failed, according to phase III trial results presented at the 44th annual meeting of ASCO (abstract 4). The double-blind randomized study evaluated ipilimumab and vaccine therapy with gp100 alone and in combination. Patients were assigned to receive ipilimumab (n = 137), ipilimumab and gp100 (n = 403), or gp100 alone (n = 136). Ipilimumab at a dosage of 3 mg/kg was given once every 3 weeks for four cycles, and gp100 was given at 1 mg every 3 weeks for four cycles. The primary endpoint was overall survival (OS). After 12 months, 46% of patients receiving ipilimumab alone, 44% receiving ipilimumab plus gp100, and 25% receiving gp100 were still alive. The hazard ratio (HR) for OS demonstrated a 32%–34% reduction in the risk for death in the two ipilimumab arms vs the gp100 arm alone (P = .0026 for ipilimumab alone vs gp100; P = .0004 for the combination vs gp100).

Postmenopausal women at average risk of ovarian cancer may benefit from ROCA (Risk of Ovarian Cancer Algorithm), a new ovarian cancer screening strategy that combines information about trends in CA-125 blood test results and age, followed by transvaginal ultrasound (TVU) as needed and referral to a gynecologic oncologist. Results of a prospective multicenter trial of ROCA were reported at the 44th annual meeting of ASCO (abstract 5003). Results of ROCA testing were used to categorize women as low risk (requiring a repeat CA-125 test in 1 year); intermediate risk (repeat CA-125 test in 3 months); or high risk (TVU and referral to a gynecologic oncologist, who decides, based on clinical findings and the TVU result, whether the patient needs to undergo surgery).

T umor human papillomavirus (HPV) status is confirmed as a strong and independent prognostic factor for survival of patients with oropharyngeal cancer, report investigators for a large phase III trial established by the Radiation Therapy Oncology Group. Results were presented at the 44th annual meeting of the American Society of Clinical Oncology (ASCO abstract 5510) and published in the New England Journal of Medicine on June 7. Investigators performed a retrospective analysis of the association between tumor HPV status and survival among 323 patients with stage III or IV oropharyngeal squamous cell carcinoma who were enrolled in a randomized trial comparing cisplatin therapy combined with either accelerated- or standard-fractionation radiotherapy. Risk of death among patients with HPV-positive vs HPV-negative cancer was compared using a proportional-hazards model.

Querfeld et al have written a comprehensive evaluation of primary cutaneous and systemic anaplastic large cell lymphoma (ALCL). The important similarities between them are outlined in the article, for example tumor cells expressing the CD30 antigen for both subtypes. In addition, important differences such as the wide spectrum of CD30+ lymphoproliferative disorders of the skin and the large differences in outcomes of the primary cutaneous vs systemic types of ALCL are discussed. Other important differences include expression of the anaplastic lymphoma kinase (ALK) protein. The ALK protein is activated most frequently through the nonrandom t(2;5) chromosome translocation, resulting in fusion of the nucleophosim (NPM) gene located at 5q35 to 2p23 and encoding the receptor tyrosine kinase, ALK. Most patients with primary cutaneous ALCL are ALK-negative, yet their 5-year disease-free survival rate is > 90%. Systemic ALCL is divided into ALK-positive and ALK-negative cases. Patients with systemic ALCL that is ALK-positive have a much higher 5-year survival rate of 70%, compared with a rate of 49% for those with systemic ALCL that is ALK-negative.[1]

Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous non-Hodgkin lymphomas that have been separated by clinical presentation, histology, immunohistochemistry markers, infectious agents, and genetic abnormalities. They may have extranodal dissemination and are often aggressive, especially when they express cytotoxic markers. The international T-cell Non-Hodgkin Lymphoma Study Group collaboration has highlighted differences in the frequency of these entities in different geographic areas.[1,2] For example, HTLV-1+ adult T-cell lymphomas are found in Japan and nasal NK/T-cell lymphoma occurs predominantly in Asian countries. The most common PTCLs are unique and not able to be classified by a specific marker or tumor antigen, and are known as peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS).

As genome-wide association studies (GWAS) have opened the door to systematic discovery of genetic factors for complex diseases, including cancers, the clinical utility of the findings remains to be determined. This is elegantly discussed in the article in this issue of ONCOLOGY by Stadler et al. The authors rightfully caution against the use of “personal genomic tests” based on cancer GWAS results for personal cancer risk prediction.

Genome-wide association studies (GWAS) have emerged as a new approach for investigating the genetic basis of complex diseases. In oncology, genome-wide studies of nearly all common malignancies have been performed and more than 100 genetic variants associated with increased risks have been identified. GWAS approaches are powerful research tools that are revealing novel pathways important in carcinogenesis and promise to further enhance our understanding of the basis of inherited cancer susceptibility. However, “personal genomic tests” based on cancer GWAS results that are currently being offered by for-profit commercial companies for cancer risk prediction have unproven clinical utility and may risk false conveyance of reassurance or alarm.

Breast cancer is predominantly a disease of older women. Many of these older patients with breast cancer have low-risk disease owing to low proliferation indices, positive hormone receptors, node-negativity, or p53-negative and HER-2 (human epidermal growth factor 2)-negative tumors.[1,2] They do well without chemotherapy and will receive adjuvant hormonal therapy with tamoxifen or an aromatase inhibitor. Yet there are older women who do not have these favorable tumor characteristics and so are potential candidates for chemotherapy. The review by Muss points out this issue, highlighting benefits of chemotherapy and describing appropriate treatment regimens for these patients.

Although increasing age is the major risk factor for breast cancer incidence and mortality, when adjusted for disease stage, breast cancer mortality is similar among younger vs older patients. Importantly, about 90% of older women with breast cancer present with early-stage disease. The biologic characteristics of breast tumors in older patients suggest they would derive benefit from adjuvant therapy, particularly endocrine therapy, but older women are still frequently undertreated, resulting in poorer survival. Studies suggest that focusing on comorbidity rather than “chronologic age” as a surrogate for life-expectancy is a key aspect of adjuvant decision-making for older patients. Morbidity and mortality from cancer in vulnerable patients with poorer health can be accurately predicted by the Comprehensive Geriatric Assessment (CGA), which evaluates comorbidities, functional status, cognition, social support, psychological state, nutritional status, and polypharmacy. Use of the CGA and newer versions of this tool can lead to interventions that maintain function and improve quality of life in older patients with breast cancer.

Vitamin E is a fat-soluble vitamin found in green leafy vegetables, whole grains, nuts and seeds, wheat germ, eggs, and in oils derived from soybeans, almonds, safflower, and sunflower. It is also an antioxidant and is said to confer protection against Alzheimer’s, Parkinson’s, cardiovascular disease, arthritis, and cancer. Although observational data suggest a correlation between high intake of foods rich in vitamin E and lowered risk of cancer, randomized trials using vitamin E supplements failed to validate those findings; some studies suggest that vitamin E supplementation can actually increase all-cause mortality.

Conventional wisdom would have one believe that melanoma is a highly radioresistant tumor, perhaps even “radiation proof.” This reputation developed as a result of a combination of factors. First, early in vitro studies of melanoma radio-biology suggested that melanoma cells displayed enhanced postradiation survival vs comparison cells.[1] Second, clinical use of radiation therapy for melanoma did not seem to work very well.[2] This combination, a clinical observation supported by laboratory work, seems to have led radiation therapy to be avoided for melanoma treatment.

The case report by Magnuson and Halligan presents the palliative treatment of a patient with stage IV melanoma, distantly metastatic to several sites, including the lung, pulmonary vein, left atrium, and CNS. The article focuses on the external beam radiotherapy employed to treat the cardiac metastasis and includes a discussion of the role of radiotherapy in treating metastatic melanoma.

Officials at the International Agency for Research on Cancer in Lyon, France, part of the World Health Organization, have announced findings from GLOBOCAN 2008, an online resource that provides worldwide estimates of numbers of new cases, and deaths from, cancer for 2008.

he National Institutes of Health has announced the awarding of 10 new Centers for Population Health and Health Disparities. The centers are designed to advance understanding of and address inequities associated with cancer and heart disease, the two leading causes of death in the US.

The European Commission (EC) has granted marketing authorization for the RANK ligand inhibitor denosumab (Prolia) for treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. The European approval of Prolia marks its first approval worldwide. Amgen, the manufacturer of Prolia, announced the EC authorization on May 28, 2010.

Dr. Hy Muss is a well recognized expert in the treatment of elderly women with breast cancer, and his article “Adjuvant Chemotherapy of Breast Cancer in the Older Woman” is an extremely important addition to the limited existing literature on this topic. As he points out, nearly half of all breast cancer diagnoses occur in women over 65 years of age. As the total number of women in that demographic increases with the aging of our population, medical oncologists will be faced with a growing number of elderly breast cancer patients, for whom evidence-based recommendations on treatment are needed. As any medical oncologist who sits face-to-face with these older women knows, it is not acceptable to simply tell the patient that there are inadequate data to guide recommendations for adjuvant chemotherapy in her age group, though this is what the EBCTCG (Early Breast Cancer Trialists Collaborative Group) overview has concluded.

The successful treatment of a patient with primary nasal melanoma metastatic to the lung, pulmonary vein, and left atrium using radiation therapy is described. The patient was effectively treated with a conventional external beam radiation fractionation scheme (rather than a more commonly used hypofractioned regimen) that was utilized to minimize risk of arterial embolus of the tumor or rupture of a vessel wall. A post-treatment CT demonstrated a significant decrease in the caliber of the right pulmonary vein and tumor thrombus. The patient never developed cardiac valvular dysfunction or acute life-threatening massive embolism of tumor from the atrium. Unfortunately, the patient experienced clinical decline secondary to the massive progression of intra-abdominal disease and subsequently died from multiple liver metastases and liver failure. Numerous studies and this case report demonstrate that radiation therapy can be very effective in the treatment of malignant melanoma, especially when only small volumes of disease need to be treated and adequate total doses are used. Therefore, radiation therapy appears to play an important yet underutilized role in the treatment of metastatic melanomas.