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primeLINES CLINICAL OPINION POLL

August 2011 Issue

The Jury Is Still Out on Whether Ovarian Suppression Prevents Chemotherapy-Induced Menopause

The risk of premature chemotherapy-induced menopause and subsequent infertility is a major concern for younger women receiving adjuvant therapy for early breast cancer. Depending on a variety of factors, including the patient's age and the chemotherapy regimen used, approximately 40% of premenopausal women will not recover normal ovarian function and fertility. It has been postulated that temporary ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist may protect against chemotherapy-induced ovarian failure perhaps by placing the ovaries in a quiescent state, but this effect remains controversial. In July 20 issue of JAMA, Lucia Del Mastro (Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy) and colleagues reported the results of a phase III randomized PROMISE-GIM6 study (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) that investigated whether the GnRH analogue triptorelin could prevent early menopause in young women receiving adjuvant chemotherapy. In this study, 281 women were randomized to chemotherapy alone or chemotherapy plus triptorelin and the results showed that the incidence of menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol) 1 year after the last cycle of chemotherapy was significantly reduced from 26% with chemotherapy alone to 9% with the addition of triptorelin (odds ratio = 0.28). Protection with triptorelin from early menopause was greater in women with hormone receptor–negative disease than in those with hormone receptor (HR)–positive disease and recovery of menses was less common in women receiving tamoxifen. Based on these results, the authors concluded that triptorelin could be offered to premenopausal patients with breast cancer who wish to decrease the risk of chemotherapy-induced permanent ovarian failure. In an accompanying editorial, Hope Rugo (University of California, San Francisco, United States) commented that the PROMISE-GIM6 study is "intriguing and represents an important and encouraging addition to the study of ovarian preservation," but unfortunately does not provide a definitive answer. Dr Rugo points out that PROMISE-GIM6 study is the largest of 5 randomized studies to address this question but these studies varied widely in terms of ovarian failure rate, the use of tamoxifen, and the definition for recovery of menses. Based on the available evidence, she concluded that the use of GnRH agonists concomitant with chemotherapy can potentially expand fertility possibilities for women with HR-negative disease, but cannot be recommended as a standard therapy and should be used with caution in HR-positive disease. The results of 2 additional studies (Southwestern Oncology Group 0230 and the OPTION study) are eagerly awaited and may further clarify this important issue.

JAMA. 2011;306(3):269-276.

JAMA. 2011;306(3):312-314. (Editorial)

Biology Challenges Anatomy in Breast Cancer

Two retrospective studies recently published in the Journal of Clinical Oncology are challenging our notion of how human breast cancers progress and metastasize.

In the first article, Jennifer Wo and colleagues from the Dana-Farber Cancer Institute (Boston, Massachusetts, United States) used Surveillance, Epidemiology and End Results (SEER) registry data on more than 50,000 women who were diagnosed with nonmetastatic T1 or T2 invasive breast cancer between 1990 and 2002 and treated with surgery and axillary lymph node dissection. Their data showed that among women with at least 4 positive lymph nodes (N2), patients with a T1a primary tumor (≤0.5 cm) had a significantly higher risk of breast cancer–specific mortality (BCSM) compared to patients with T1b primary tumors (>5 to ≤1.0 cm). This is surprising because it challenges the concept that larger primary tumors are more likely to metastasize to distant sites. In the second article, Leonel Hernandez-Aya and colleagues from The University of Texas, M. D. Anderson Cancer Center (Houston, Texas, United States) and the University of Miami (Florida, United States) analyzed the association of tumor size and nodal status with relapse-free survival (RFS) and overall survival (OS) in 1711 patients with (triple-negative breast cancer) TNBC diagnosed between 1980 and 2009. Surprisingly, they found no significant difference in OS between patients with N1 disease (1-3 positive nodes) and those with N2 (4-9 positive nodes) or N3 (≥10 positive nodes) disease, regardless of primary tumor size. This suggests that once lymph nodes are involved, RFS and OS are not greatly affected by the absolute number of positive lymph nodes. Together, these provocative articles highlight the imperfect connection between tumor size and potential to colonize lymph nodes and distant organs.

In an accompanying editorial, Elizabeth Comen and Larry Norton (Memorial Sloan-Kettering Cancer Center, New York, United States) discussed the implications of these two studies, which challenge the idea that malignant progression and metastases are an orderly sequential process (ie, tumors grow and gradually acquire the ability to migrate and metastasize first to lymph nodes and then to distant sites). On the contrary, the results of these two studies support the concept that tumor metastasis can be both predictable and unpredictable at the same time, and the results are consistent with the hypotheses of cancer self-seeding and site-specific genetic programs for establishing distant metastases. In a nut shell, these evolving concepts of the dynamic nature of tumor metastasis suggest that every tumor has a unique ability to self-seed or to seed regional lymph nodes and/or distant sites depending on the genetic signature that it expresses. Thus, some primary breast tumors may be good at seeding axillary lymph nodes but not distant sites, resulting in an imperfect connection between the extent of axillary involvement and involvement of distant organs. Whereas a tumor that expresses a different genetic signature may be proficient at seeding axillary nodes and distant sites but not at self-seeding, which could result in a small primary tumor with extensive lymph node involvement and a high risk of distant metastasis. The authors of the editorial concluded that, for better prognostication, we must elucidate the molecular mechanisms that underlie the biology of individual cancers.

J Clin Oncol. 2011;29(19):2619-2627.

J Clin Oncol. 2011;29(19):2628-2634.

J Clin Oncol. 2011;29(19):2610-2612 (Editorial).

Predictive Genetic Biomarkers for Response to Pazopanib in Patients with Renal Cell Carcinoma

Pazopanib is one of several small molecule angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). However, similar to other conventional and molecular-targeted therapies, response to pazopanib and its toxicity varies between patients and no validated biomarkers have been identified to predict which patients might derive the most clinical benefit and least toxicity. Inherited genetic variability may be one of several contributing tumor-related and host-related factors that underlie individual treatment response.

Therefore, Chun-Fang Xu and colleagues set out to test the hypothesis that the variations in genes that affect the exposure and mode of action of pazopanib may affect treatment response. The authors evaluated 27 functional polymorphisms within 13 genes in 397 patients with advanced RCC who were treated with pazopanib in three clinical trials, and they looked for associations with progression-free survival (PFS) and objective response rate (ORR). They found 3 polymorphisms in IL-8 and HIF1A genes that were significantly associated with worse PFS and 5 polymorphisms in HIF1A, NR1/2, and VEGFA genes that were significantly associated with a lower ORR compared with the wildtype genotype. These data suggest that patients with genotypes associated with increased angiogenesis and/or increased pazopanib clearance may receive less clinical benefit from treatment with pazopanib. In particular, upregulation of the IL-8 pathway of angiogenesis may represent an important mechanism of resistance to inhibition of VEGF-driven angiogenesis by pazopanib. The authors concluded that these biomarkers, if validated, could be used to select patients with RCC for alternative therapeutic strategies. A confirmation study will be conducted when data from the ongoing COMPARZ study (NCT00720941) become available. Genes that affect angiogenesis pathways, such as IL-8, HIF1A, and VEGFA, would be expected to affect response to other angiogenesis inhibitors as well. However, this remains to be seen.

J Clin Oncol. 2011;29(18):2557-2564.

Rituximab Plus Bortezomib: Chemotherapy-Free Option for Relapsed Follicular Lymphoma

First-line chemoimmunotherapy with rituximab followed by rituximab maintenance therapy has substantially improved clinical outcomes for patients with follicular lymphoma (FL), and median PFS is now nearly 4 years. To date, however, no standard treatment for relapsed FL exists, and most patients are retreated with rituximab with or without chemotherapy. In this context, the LYM 3001 study, a large, randomized, phase III trial involving 676 patients, compared rituximab alone versus rituximab plus weekly bortezomib in patients with relapsed FL. This combination has demonstrated additive antitumor activity in preclinical models and appears promising. The final results of the LYM 3001 study reported by Bertrand Coiffier (Hospices Civils de Lyon, Lyon, France) and colleagues demonstrated a statistically significant improvement in PFS (median 12.8 months versus 11.0 months) for patients treated with rituximab plus bortezomib compared with rituximab alone (hazard ratio = 0.82; P = .039). The combination regimen also improved response rate, durability of response, and time to next treatment, but was associated with an increase in grade ≥3 adverse events, particularly neutropenia and infections, as well as peripheral neuropathy. The authors concluded that this regimen is feasible, but the PFS benefit was less than expected. However, they suggested that it might represent a treatment option, particularly for patient subgroups, such as those with high FLIPI score and/or high tumor burden.

In an accompanying editorial, José Tomás (M. D. Anderson Cancer Center Madrid, Madrid, Spain) seemed to be a bit more bullish with regard to the potential utility and tolerability of this regimen and suggested that it might benefit from the addition of rituximab maintenance. He commented that this regimen is attractive because it avoids the use of chemotherapy in the relapsed setting. In particular, he was impressed by the fact that 71% of patients in the combination arm completed planned treatment (5 cycles) and that neither previous use of rituximab nor the presence of high-risk disease reduced the response rate. Based on these results, Dr Tomás concluded that the combination of bortezomib plus rituximab should be considered an alternative treatment for relapsed FL.

Lancet Oncol. 2011;12(8):773-784.

Lancet Oncol. 2011;12(8):714-716. (Editorial).

Eculizumab Improves Survival in Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic disorder characterized by complement-mediated intravascular hemolysis, which leads to cardiovascular complications (eg, anemia, thromboembolism, pulmonary hypertension, and renal dysfunction) and requires frequent blood transfusions to maintain hemostasis. Eculizumab, a monoclonal antibody against complement protein 5, has been shown to stop intravascular hemolysis in PNH and to dramatically alter the natural course of the disease by reducing symptoms and disease complications and improving quality of life. The analysis of efficacy and clinical outcomes reported by Richard Kelly (Leeds Teaching Hospitals, Leeds, United Kingdom) et al was based on 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. In this cohort, treatment with eculizumab significantly reduced the rate of thrombosis events and transfusion requirements. However, most importantly, eculizumab therapy improved survival to a level similar in the general population (P = .46 for eculizumab-treated PNH patients compared to age-matched and sex-matched normal controls). These data support the use of eculizumab for the treatment of PNH.

Blood. 2011;117(25):6786-6792.

Lung Cancer Screening with Low-Dose Computed Tomography: Ready for Prime Time?

The long-awaited results of National Lung Screening Trial (NLST), which enrolled 53,454 persons at high risk for lung cancer between August 2002 and April 2004, were reported in the New England Journal of Medicine. Participants (with a history of heavy smoking and aged between 55-74 years) were randomized to three annual screenings with either low-dose helical computed tomography (CT) or single-view posteroanterior chest radiography and followed for a median of 6.5 years. The results showed that screening with low-dose CT significantly reduced lung cancer—specific mortality by 20% (P = .004). In an accompanying editorial, Harold Sox (Dartmouth Medical School, West Lebanon, New Hampshire, United States) said that the findings of the NLST represent "the beginning of the end of one era of research" because they provide solid evidence of the benefit of lung-cancer screening, but these results are just the beginning of another era of research to determine the public health policy implications. Although these findings are important, Dr Sox suggests that policymakers should wait for a cost-effectiveness analysis of the NLST data, further follow-up data to determine the amount of over diagnosis that occurred in the NLST, and perhaps identification of biologic markers of cancers that do not progress. In addition, biomarkers may help to define subgroups of smokers who are at higher or lower risk for lung cancer, which would allow the screening strategy to be tailored accordingly. Implementing annual screening with low-dose CT for the 7 million US adults who meet the entry criteria for the NLST would be very expensive. So, while this trial is a victory for those who have been searching for years for solid evidence to support lung cancer screening, it may be years before we know precisely how this landmark study will reshape public health policy.

N Engl J Med. 2011;365(5):395-409.

N Engl J Med. 2011;365(5):455-457.

Cancer of Unknown Primary (CUP): Progress in the Search for Improved Diagnosis and Clinical Outcomes. The authors of this review article explore the enigma of CUP, the difficulties of classifying this widely heterogeneous disease, and evolving diagnostic and pathologic techniques, focusing on rapidly improving molecular approaches including molecular profiling and their implementation in CUP patient care. Ann Oncol. 2011 Aug 4. [Epub ahead of print].
St Gallen 2011 Consensus Recommendations Is Based on Intrinsic Subtypes of Breast Cancer This special article summarizes the recommendations of the St Gallen expert panel on treatment of early breast cancer based on 4 intrinsic biologic subtypes (luminal A, luminal B, HER2-positive, basal-like triple-negative). Additionally, it provides recommendation for the use of better tolerated local therapies in selected patients. It also highlights that individualized treatment decisions should also consider extent of disease, host factors, patient preferences, and social and economic constraints. Ann Oncol. 2011;22(8):1736-1747.
International Myeloma Working Group Consensus on Treatment of Transplant-Eligible Patients With Multiple Myeloma (MM). This review article provides important perspectives and guidance on the optimal management of younger, transplantation-eligible patients with MM using modern regimens. Newer induction regimens incorporating thalidomide or lenalidomide and bortezomib with chemotherapy have substantially improved rates of complete response and outcomes following autologous stem cell transplantation, and these agents are now being used for consolidation and maintenance therapy. Blood. 2011;117(23):6063-6073.