FROM THE LITERATURE

Duration of Chemotherapy for Metastatic Breast Cancer: How Long Is Long Enough?

That is the question posed by Andrew Seidman from Memorial Sloan-Kettering Cancer Center, United States, in his editorial discussing the implications of a meta-analysis that looked at the optimal duration of chemotherapy for the first-line treatment of MBC. This question highlights the uncomfortable uncertainty that oncologists often face when attempting to determine the best course of treatment for any given patient. Unfortunately, the evidence available to determine the optimal duration of chemotherapy remains inadequate. The challenge is finding the right balance between maximum therapeutic benefit and the toxic effects of chemotherapy that can diminish the patient's quality of life.

The meta-analysis reported by Gennari and colleagues identified 11 randomized clinical trials including 2269 patients that compared different durations of chemotherapy and reported progression-free survival (PFS) and OS outcomes. Some regimens were given for a defined number of cycles, and some were administered to progression. The results of this analysis showed that longer duration of first-line chemotherapy was associated with marginally longer OS and substantially longer PFS. Thus, the conclusions from the meta-analysis, despite its limitations, seem to lend support to the current approach used in clinical practice, which is to treat to maximum response and extend treatment with well tolerated maintenance therapy (eg, trastuzumab in patients with HER2-positive disease). However, Seidman suggests that the dialogue should continue between patient and oncologist, and among oncologists, regarding the risks and benefits of longer first-line chemotherapy duration or a treat-to-progression approach for MBC.

J Clin Oncol. 2011 Apr 4. [Epub ahead of print].

J Clin Oncol. 2011 Apr 4. [Epub ahead of print]. (Editorial)

Neoadjuvant Androgen Deprivation Therapy (NADT) for Locally Advanced Prostate Cancer: Yes, But for How Long?

The long-awaited 10-year results of the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial are in, and they clearly show the benefits associated with 6 months of NADT plus conventional fractionated radiotherapy (RT) to a dose of 66 Gy in patients with high-risk, locally advanced, prostate cancer. In this landmark study, over 800 men were randomized to either RT alone, RT plus 3 months of NADT, or RT plus 6 months of NADT. At a median follow-up of 10.6 years, patients who received 3 months of NADT had significantly improved event-free survival (EFS), but no improvement in prostate cancer–specific or all-cause mortality was observed. In contrast, 6 months of NADT significantly improved EFS as well as prostate cancer–specific mortality (hazard ratio [HR] = 0.49; P = .0008) and all-cause mortality (HR = 0.63; P = .0008) compared with RT alone.

In his commentary, Chris Parker from Royal Marsden Hospital, United Kingdom, summarized the important implications of this trial, which has two clear messages for current clinical practice. First, it confirms that addition of NADT to conventional RT significantly improves survival in patients with locally advanced prostate cancer and, therefore, it should be a standard of care. Indeed, the magnitude of the benefit compared with RT alone is truly remarkable; at 10 years, the risk of death from prostate cancer was reduced from 22% to 11%. Second, it helps to resolve the uncertainty regarding the optimal duration of NADT, and strongly suggests that 6 months is better than 3 months, provided the patient does not have pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation therapy. However, there remain a number of unanswered questions, including the benefit of NADT in conjunction with modern escalated-dose RT or whether NADT plus conventional-dose RT might be better than NADT plus escalated-dose RT. These questions are currently being addressed in ongoing studies.

Lancet Oncol. 2011;12(5):451-459.

Lancet Oncol. 2011;12(5):411-412. (Commentary)

Subcutaneous Bortezomib Reduces Peripheral Neuropathy with No Loss of Efficacy

Bortezomib has become well established as a standard agent for the treatment of multiple myeloma (MM) both in the first-line and relapsed settings. However, bortezomib is associated with substantial toxicity, most notably peripheral neuropathy, and the twice-weekly intravenous (IV) dosing schedule is cumbersome and inconvenient for patients. This has spurred efforts to optimize the dosing schedule and to find ways to reduce the incidence of peripheral neuropathy. To that end, studies have shown that once-weekly IV dosing is equally effective and reduces the incidence of peripheral neuropathy compared with twice-weekly IV dosing.

The study reported by Moreau et al was a randomized, open-label study designed to test whether subcutaneous (SC) administration of bortezomib is noninferior to standard IV dosing in patients with relapsed MM. Both arms received bortezomib at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle. By every measure of efficacy (overall response rate, time to progression and 1-year OS), SC administration was noninferior to IV dosing. In addition, patients receiving SC bortezomib had significantly less peripheral neuropathy (38% versus 53%), and the incidence of grade 3 or greater neuropathy was reduced from 16% in the IV arm to 6% in the SC arm (P = .026). Based on these results, it is widely expected that SC dosing will be quickly approved for clinical use.

In an accompanying commentary, María-Victoria Mateos from University Hospital of Salamanca, Spain, hailed these results, saying that SC bortezomib offers a more convenient route of administration, fewer side effects, and similar or even improved efficacy. However, she cautioned that SC administration should not be implemented in routine practice until it has been fully approved and clinical practice guidelines are in place. Subcutaneous dosing will require close monitoring programs in conjunction with strict dose-modification guidelines to reduce the potential for serious side effects. Although many important questions remain to be answered, this study represents a step in the right direction.

Lancet Oncol. 2011;12(5):431-440.

Lancet Oncol. 2011;12(5):410-411. (Commentary)

BRIEF REPORTS

Fulvestrant Appears Effective in Male Breast Cancer

Male breast cancer is rare, and when it occurs, it is usually hormone receptor (HR)-positive. In contrast to breast cancer in women, aromatase inhibitors have no clear role in the treatment of HR-positive breast cancer in men because testicular production of estrogens, which accounts for approximately 20% of circulating estrogens in men, is independent of aromatase. Consequently, tamoxifen is the standard of care for the treatment of male breast cancer both in the adjuvant and metastatic setting, and response rates in metastatic disease range from 25% to 80%. Given the rarity of male breast cancer, only case reports have been reported, and the effectiveness of fulvestrant, an estrogen receptor antagonist, in this patient population has not been widely studied. This letter to the editor reports on a series of 5 men with HR-positive, progressive, visceral, metastatic breast cancer who were treated with fulvestrant (500 mg on day 1 followed by monthly intramuscular injections of 250 mg). Three patients had a partial response or stable disease lasting 6 months to 22 months, and no adverse events were reported. The authors of this report suggest that fulvestrant may be another endocrine treatment option for HR-positive, metastatic, breast cancer in men.

Ann Oncol. 2011;22(4):985-993

Meta-Analysis Confirms Value of Sentinel Lymph Node Biopsy in Melanoma

Sentinel lymph node (SLN) biopsy is a widely accepted minimally invasive technique for nodal staging that has been in use for the surgical management of melanoma since the early 1990s. However, there is considerable heterogeneity in the reported feasibility and performance of SLN biopsy with respect to mapping success rates, false negative rates, or recurrence rates in the same nodal basin. The comprehensive meta-analysis conducted by Valsecchi and colleagues, which analyzed data from 71 studies involving over 25,000 patients, confirmed and validated the feasibility, accuracy, and utility of SLN biopsy in patients with cutaneous melanoma. On average, 98% of SLNs were successfully mapped, the average false negative rate was 12.5%, and <5% of patients with a negative SLN biopsy had a recurrence in the same nodal basin. These results undoubtedly represent important information for the American Society of Clinical Oncology (ASCO) Melanoma Sentinel Node Guideline Panel and will likely stimulate further research into the optimal use and limitations of SLN biopsy in clinical practice.

J Clin Oncol. 2011;29(11):1479-1487.

Which Thromboprophylactic Agents for Patients with Multiple Myeloma Receiving Thalidomide-Containing Regimens?

Thalidomide has become an important part of the armamentarium against MM, but it increases the risk of thromboembolic events. Consequently, patients with MM receiving thalidomide-containing regimens are often given thromboprophylactic agents to reduce that risk. The ASCO Guidelines currently recommend prophylaxis with either low molecular weight heparin (LMWH) or adjusted-dose warfarin in patients receiving thalidomide, but available data on the comparative efficacy of these agents are limited. Therefore, a randomized, open-label, multicenter trial was conducted in 667 patients to compare aspirin (100 mg/day), fixed low-dose warfarin (1.25 mg/day), and LMWH (enoxaparin, 40 mg/day) for preventing thromboembolism in MM patients treated with thalidomide-based regimens. The primary composite endpoint was the incidence of any serious thromboembolic event, acute cardiovascular event, or sudden death during the first 6 months of treatment. The results of this study showed no significant difference in the incidence of these events between treatment groups (6.4% in the aspirin group, 8.2% in the warfarin group, and 5.0% in the LMWH group), except in elderly patients where warfarin was less effective than LMWH. These results led the authors to conclude that in the majority of patients with MM who are treated with thalidomide-containing regimens, aspirin and warfarin are just as effective as LMWH for reducing the risk of serious thromboembolic events, acute cardiovascular events, and sudden death.

J Clin Oncol. 2011;29(8):986-993.

Overall Survival Benefit Confirmed for Cetuximab Plus FOLFIRI in KRAS Wildtype Tumors

When the results of the CRYSTAL trial, which investigated the benefit of adding cetuximab to standard irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC), were retrospectively re-analyzed according to tumor KRAS mutational status, KRAS mutational status was successfully determined in only 45% of patients. It was shown that PFS and response rate were significantly improved in patients with wildtype KRAS (64% of those tested), but no benefit was observed in patients with KRAS mutations. At that time, the analysis of OS among patients with KRAS wildtype tumors showed only a trend toward improvement in the cetuximab arm (HR = 0.84). Now with further follow-up and improved analysis of KRAS mutational status that was successful in 89% of patients in this study, the benefit of cetuximab has come into sharper focus. The addition of cetuximab to FOLFIRI in patients with KRAS wildtype disease resulted in a statistically significant improvement in OS (median, 23.5 months versus 20.0 months; HR = 0.796; P = .009). These results further establish the clinical benefit of cetuximab plus FOLFIRI in this subset of patients with mCRC. In addition, mutational analysis of BRAF in this study demonstrated that BRAF mutations are associated with a poor prognosis in mCRC.

J Clin Oncol. 2011;29(15):2011-2019.

ADDITIONAL PUBLICATIONS WORTH READING

• Understanding Bendamustine and Its Expanding Role in the Treatment of Lymphoid Malignancies. The authors of this supplement explore the many facets of a newly discovered old drug, the alkylating agent bendamustine. After a review of clinical development and pharmacology, the authors of the supplement focus on the antitumor activity of bendamustine in non-Hodgkin lymphomas, including chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. Substantial efficacy was shown in rituximab-refractory and chemotherapy-refractory patients, as well as in previously untreated patients. Additionally, the evolving role of this agent in diffuse large B-cell lymphoma and ongoing trials of bendamustine in combination with other targeted agents in B-cell malignancies are discussed. Semin Hematol. 2011;48(2 suppl 1):S1-S38.
• Managing the Side Effects of Everolimus in Patients with Renal Cell Carcinoma (RCC). This paper summarizes the recommendations of an expert panel for the management of adverse effects associated with the use of everolimus in patients with RCC. The adverse events associated with mTOR inhibitors particularly discussed in this article are noninfectious pneumonitis, infections, stomatitis, and metabolic abnormalities. Patient education and proactive management of these possible side effects are important to optimize patient benefit. Eur J Cancer. 2011 Apr 8. [Epub ahead of print].
• ASCO Provisional Opinion on Testing for EGFR Mutations in Patients with Newly Diagnosed Advanced Non-Small Cell Lung Cancer (NSCLC). Based on the currently available data from 5 phase III randomized trials, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion endorsing testing for mutations in the epidermal growth factor receptor (EGFR) gene. The opinion states that patients with NSCLC who are being considered for first-line therapy with an EGFR tyrosine kinase inhibitor (TKI), should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. J Clin Oncol. 2011;29(15):2121-2127.

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