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PHARMA NEWS FROM THE LITERATURE BRIEF REPORTS PUBLICATIONS WORTH READING UPCOMING EVENTS AND OTHER ACTIVITIES
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March 2011 Issue


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PHARMA NEWS

FDA Approves Rituximab Maintenance for Follicular Lymphoma

On January 28, 2011, the US Food and Drug Administration (FDA) approved rituximab (Rituxan®) as maintenance therapy for patients with advanced follicular lymphoma who respond to induction therapy with rituximab plus chemotherapy. This indication was approved by the European Medicines Agency in October 2010. Regulatory approvals are based on the results of the phase III international Primary RItuximab and MAintenance (PRIMA) study, which showed that rituximab maintenance therapy every 2 months for 2 years nearly doubled progression-free survival (PFS; hazard ratio [HR] = 0.54). At a median follow-up of 25 months, only 18% of patients receiving rituximab maintenance had progressed compared with 34% of patients on the observation arm.

 

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FROM THE LITERATURE

To Dissect or Not to Dissect Axillary Lymph Nodes in Women With Breast Cancer and Positive Sentinel Node(s)?

The current standard of care for women with stage T1-T2 invasive breast cancer without palpable axillary lymph nodes (LNs) is sentinel lymph node dissection (SLND) followed by axillary lymph node dissection (ALND) for women with one or more positive sentinel nodes. However, it was not known whether further ALND improves survival in these patients. The American College of Surgeons Oncology Group set out to answer that question with Study Z0011. This study enrolled patients between 1999 and 2004; eligible patients were women with T1 and T2 invasive breast cancer with no palpable axillary LNs and 1 or 2 SLNs containing metastases identified using hematoxylin-eosin staining. All patients underwent
lumpectomy and received opposing tangential field whole-breast irradiation. Those with sentinel lymph node metastases by SLND were randomized to ALND (n = 445) or no further axillary treatment (n = 446). Use of systemic adjuvant therapy was at the discretion of the treating physician. Patients were then followed for overall survival (OS), and the results were reported at a median follow-up of 6.3 years. The data showed, definitively, that ALND did not improve OS. The 5-year OS rate was 91.8% in the ALND group and 92.5% with SLND alone. Moreover, there was no disease-free survival (DFS) advantage associated with ALND. The 5-year DFS rate was 82.2% in the ALND group and 83.9% with SLND alone. Locoregional recurrence-free survival at 5 years was 96.7% in the SLND-alone group and 95.7% in ALND group (P = .28). The results of this large, well-conducted trial clearly show that ALND does not confer any benefit in breast cancer patients with limited lymph node metastases. Authors concluded that these are practice-changing results, and their implementation in clinical practice could improve quality of life of thousands of patients with breast cancer by sparing them from complications associated with ALND.

In an accompanying editorial, Carlson and Wood commented that, despite increasing evidence that ALND is not beneficial, it remains included in widely recognized guidelines for breast cancer care. However, in the face of mounting evidence suggesting that ALND does not reduce recurrence rates, performance of ALND has been declining. The hope is that practice guidelines will finally change based on the strong evidence from Study Z0011 demonstrating that ALND does not improve survival in patients undergoing partial mastectomy, whole-breast irradiation, and systemic adjuvant therapy for early breast cancer with limited sentinel lymph node metastases. In the treatment of early breast cancer, less is clearly more when it comes to surgical resection.

JAMA. 2011;305(6):569-575.

JAMA. 2011;305(6):606-607. (Editorial)

 

Vinorelbine plus Trastuzumab: An Active and Well-Tolerated First-Line Option for HER2-Positive Metastatic Breast Cancer

The current standard of care for the treatment of human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) is trastuzumab plus taxane-based chemotherapy. Paclitaxel is the preferred chemotherapeutic agent and the only one that is FDA-approved for use in combination with trastuzumab; however, National Comprehensive Cancer Network (NCCN) guidelines also include docetaxel, vinorelbine, and capecitabine in the list of preferred first-line agents for use in combination with trastuzumab. The Herceptin Plus Navelbine or Taxotere (HERNATA) trial randomized 284 chemotherapy-naϊve patients to treatment with trastuzumab (8 mg/kg loading; 6 mg/kg maintenance) plus either docetaxel (100 mg/m2 on day 1) or vinorelbine (30 mg/m2 to 35 mg/m2 on day 1 and day 8) every 3 weeks. The results demonstrated no significant differences between these two regimens in terms of time to progression, objective response rate, or OS. More importantly, however, patients treated with docetaxel experienced significantly more treatment-related grade 3/4 febrile neutropenia (36% versus 10%), leukopenia (40% versus 21%), infections (25% versus 13%), and neuropathy (31% versus 4%) compared with the vinorelbine arm.

In an accompanying editorial, Lin and Winer from the Dana-Farber Cancer Institute commented that given the observed efficacy and more favorable toxicity profile of trastuzumab plus vinorelbine, and in light of similar results from the Trastuzumab Plus Vinorelbine or Taxane (TRAVIOTA) study, this regimen should be viewed as an acceptable, and perhaps even preferred, first-line treatment option for patients with HER2-positive MBC. They went on to express the opinion that studies comparing different chemotherapy regimens in combination with trastuzumab are not a good use of clinical research resources. These studies all suggest that the choice of chemotherapy matters little and perhaps we have reached a point of diminishing returns when it comes to optimizing chemotherapy in this setting. Therefore, ongoing research should focus on development of new molecularly targeted approaches and efforts to elucidate mechanisms of resistance to HER2-directed therapy.

J Clin Oncol. 2011:29(3):264-271.

J Clin Oncol. 2011:29(3):251-253. (Editorial)

 

Revisiting the Debate Over PSA Screening for Prostate Cancer

Debate over the value of PSA screening for prostate cancer continues, but new information—based on reanalysis of the two largest trials addressing this question—is shining more light on this debate and bringing the answers into sharper focus. The two trials that have fueled the controversy for years are known as the Prostate, Lung, Colorectal and Ovarian Cancer Screening study (PLCO), conducted in the United States, and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. The original reports from these trials reached opposite conclusions. The PLCO trial found that, at 7 to 10 years, the cumulative risk of death as a result of prostate cancer was low in both screened and unscreened men and did not differ significantly between them. However, this trial had several important limitations. In contrast, with longer follow-up, the ERSPC trial showed that PSA screening at 2-year or 4-year intervals was associated with a 20% relative risk reduction in prostate cancer–specific mortality. The authors estimated that the number needed to screen (NNS) was 1410 and the number needed to treat (NNT) was 48 to avoid one death as a result of prostate cancer.

Two studies reported in the February 1 issue of the Journal of Clinical Oncology have reanalyzed these important trials. Crawford et al reanalyzed the data from the PLCO trial, stratifying the analysis by comorbidity, and Loeb et al reanalyzed the data from the ERSPC trial. In the reanalysis of PLCO, Crawford et al demonstrated a significant decrease in the risk of prostate cancer–specific mortality among men with few or no comorbidities (HR = 0.56; P = .03). In the reanalysis of ERSPC, Loeb et al conducted an analysis of NNS and NNT, similar to the original report, and highlighted the time dependence of the results. Their model yielded a NNS of 1254 and a NNT of 43 at 9 years median follow-up, which is similar to the numbers cited in the original report. But with longer follow-up, the NNS and NNT estimates dropped to 837 and 29 at 10 years and 503 and 18 at 12 years, respectively. These results are supported by a third, less publicized trial known as the Göteborg randomized population-based screening trial. That trial showed a NNS of 293 and a NNT of 12 at a median follow-up of 14 years.

In their editorial, Carroll et al from the University of California at San Francisco summarized the implications of these contemporary analyses as follows. The weight of evidence suggests that PSA screening does reduce the risk of death as a result of prostate cancer among selected men, particularly those who are healthy and have a long life expectancy, because the benefits of screening accrue over time. The downside of screening is the potential for over detection, but the impact of over detection can be mitigated by selective treatment of patients at high risk of cancer-related morbidity and mortality and deferment of treatment for those at low-risk. In fact, they report that active surveillance in lieu of immediate treatment is gaining popularity, and favorable outcomes have been reported for well-selected and carefully observed patients. However, the benefits of screening should not be overstated as most men with prostate cancer die as result of other causes, and absolute risk reduction, rather than relative risk reduction, should be taken into consideration.

J Clin Oncol. 2011;29(4):355-361. (PLCO trial)

J Clin Oncol. 2011;29(4):464-467. (ERSPC trial)

Lancet Oncol. 2010;11(8):725-732. (Göteborg trial)

J Clin Oncol. 2011;29(4):345-347. (Editorial)

 
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BRIEF REPORTS

Defining the Role of Androgen Receptor in Breast Cancer

Treatment of breast cancer is guided by molecular subtypes, which are currently defined in clinical practice by expression of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type 2 (HER2). The role of estrogen and ER in the biology of breast cancer is well characterized, and ER-positive tumors have a more favorable prognosis and are generally responsive to endocrine therapy. However, the role of androgen receptor (AR) in breast cancer biology is not well understood. Androgen receptor is frequently co-expressed with ER and PgR, and recent studies suggest that AR may be an important prognostic factor in breast cancer. The study reported by Park et al suggests that AR expression is significantly associated with favorable clinicopathologic characteristics and better outcomes in patients with ER-positive breast cancer. Expression of AR was a significant independent prognostic factor for improved DFS and was associated with improved OS among patients with ER-positive breast cancer. The authors concluded that AR could be an additional biomarker for endocrine responsiveness in ER-positive breast cancer. In contrast, AR expression was associated with a trend toward worse survival outcomes in ER-negative, HER2-positive breast cancer. This has led to speculation that in addition to HER2, AR may be a rational therapeutic target in this subset of patients. Although in this retrospective analysis no impact of AR expression on survival was identified in the small number of patients with triple-negative breast cancer (TNBC), it was previously shown that AR expression in TNBC might be a potential target in these tumors, and a phase II feasibility study of the antiandrogen bicalutamide in patients with AR-positive, ER/PgR-negative MBC is currently ongoing in the US. (NCT00468715).

Ann Oncol. 2011 March 11 [Epub ahead of print].

 

Is Overall Survival Endpoint Holding Back Progress in the Treatment of Advanced Breast Cancer?

The authors of this systematic review of phase III breast cancer trials published between 1980 and 2009 highlight the challenges inherent in developing new drugs for the treatment of advanced MBC. Although the FDA considers improvement in OS to be the gold standard for new drugs approval, only 9 of 73 phase III trials (12%) evaluating chemotherapy or targeted agents for MBC over the past 30 years have succeeded in showing an improvement in OS, and only 8% of first-line trials have successfully achieved that goal. The authors explore some of the reasons for this and raise the question whether improvement in OS should remain the ultimate measure of clinical benefit, or is this slowing the progress of drug development for MBC? They point out that many effective therapies are available for the treatment of MBC. Consequently, the duration of post-progression survival (PPS) tends to be fairly long. Models have shown that the potential to demonstrate an OS benefit is vanishingly small when PPS is >12 months. There is also evidence to suggest that over the past 20 years OS has been improving overall for patients with MBC, which continues to raise the bar for new agents. Consequently, few randomized phase III trials are designed with OS as the primary endpoint, especially those in the first-line setting. These issues have important implications and underscore the need for consensus regarding how best to measure clinical benefit in MBC and the importance of collaboration between researchers, clinicians, patients, industry, and regulatory authorities. From the authors' perspective, what matters most is that safe and effective treatments that benefit patients be made available in a timely fashion.

Oncologist. 2011;16(1):25-35.

 

Intravenous Calcium and Magnesium Reduce the Sensory Neurotoxicity of Oxaliplatin

Adjuvant therapy with oxaliplatin plus infusional fluroruracil (FU)/leucovorin (FOLFOX) is the current standard of care for patients with resected stage III colon cancer, but the tolerability of oxaliplatin-based regimens is compromised by cumulative sensory neurotoxicity that can lead to early discontinuation. Chronic symptoms include numbness and tingling of the hands and feet that is correlated with the cumulative dose of oxaliplatin and may also include burning/shooting pain symptoms similar to those associated with cisplatin. In an effort to minimize the impact of this toxicity, a randomized, placebo-controlled trial (NCCTG N04C7) was conducted to investigate whether an intravenous regimen of calcium gluconate plus magnesium sulfate (1 gram each) pre-oxaliplatin and post-oxaliplatin would reduce neurotoxicity. Although the study was stopped early because preliminary results of another trial suggested that calcium and magnesium might reduce the efficacy of FOLFOX (later found to be incorrect), this study demonstrated that calcium and magnesium significantly decreased the incidence of chronic, cumulative, grade ≥2 sensory neuropathy, as measured by either NCI CTCAE (P = .038) or an oxaliplatin-specific neurotoxicity scale (P = .018). Therefore, this calcium/magnesium regimen appears to be an effective neuroprotectant against oxaliplatin-induced neurotoxicity, and there is no evidence that it reduces the efficacy of FOLFOX. But the authors acknowledge that this needs to be confirmed, and the NCCTG has recently initiated another randomized, double-blind trial to verify these results and determine the best dosing schedule.

J Clin Oncol. 2011;29(4):421-427.

 

Personalizing Neoadjuvant Fluorouracil-Based Chemoradiotherapy for Rectal Cancer

Biomarkers are increasingly being used to select the most appropriate treatment for patients with advanced cancer. To date, the only example in patients with advanced colorectal cancer is KRAS mutation status. Tumors that contain a mutation in the KRAS oncogene do not benefit from the use of antibody therapy directed against epidermal growth factor receptor (EGFR). Neoadjuvant FU-based chemoradiotherapy (CRT) is highly effective for pathologic downstaging of rectal tumors. However, patients with certain polymorphisms in the thymidylate synthase gene (TYMS) express higher levels of thymidylate synthase, and their tumors are thus more resistant to FU. Consequently, these patients have a low rate of downstaging and pathologic complete response (pCR) when treated with conventional FU-based CRT. The authors of this paper evaluated the germline TYMS genotype of 135 patients with rectal cancer, and those with a poor-risk genotype (27%) were treated with FU-CRT plus weekly irinotecan (50 mg/m2) while those with good-risk genotype received standard FU-CRT. This approach yielded similar rates of downstaging and pCR in both the good-risk and poor-risk subgroups, suggesting that the selection of patients based on TYMS genotype was effective. The authors acknowledge that while the results of this phase II study are intriguing, a prospectively randomized trial is needed to validate the use of TYMS genotyping to direct treatment selection in the clinical setting.

J Clin Oncol. 2011;29(7):875-883.

 
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ADDITIONAL PUBLICATIONS WORTH READING

  • Everolimus Significantly Improves Progression-Free Survival in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET). This paper reports the results of a phase III randomized trial (RADIANT-3) of everolimus in patients with advanced pNET. The median progression-free survival was 11.0 months with everolimus and 4.6 months with placebo (HR = 0.35; P<.001). N Engl J Med. 2011;364:514-523.
  • Biosimilars in Hematology/Oncology: From Approval to Practice. This review discusses regulation issues regarding biosimilars and highlights specific issues pertaining to their use in clinical practice in oncology. Information on marketing approval, extrapolation, labeling, substitution, immunogenicity, and traceability of specific products is provided. Eur J Haematol. 2011;86(4):277-288.
  • An Evolving Role of Circulating Tumor Cells in Breast Cancer. This review article examines the current and evolving state of knowledge regarding the role of circulating tumor cells (CTCs) in breast cancer progression and metastasis and the value of CTCs as a prognostic factor in early and advanced disease. Patholog Res Int. 2011;2011:621090.
  • Recommendations from European LeukemiaNet for the Management of Philadelphia-Negative Classical Myeloproliferative Disorders. This article presents critical concepts and recommendations for the management of polycythemia vera, essential thrombocythemia, and primary myelofibrosis based on two consensus conferences convened by the European Leukemia Network. Topics include disease monitoring, definition of response, recommended first-line and second-line therapy, and special issues. J Clin Oncol. 2011;29(6):761-770.

 
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UPCOMING prIME EVENTS

Key Questions About Biosimilars: The Experts' Opinions
Satellite Symposium at the 16th Congress of the European Association of Hospital Pharmacists
30 March 2011
Vienna, Austria
Expert PracticeSM in Breast Cancer
2 April 2011
Lisbon, Portugal
Expert PracticeSM in Hematology
9 April 2011
Brussels, Belgium


12th Annual Palm Beach Cancer Symposium
28 April 2011
Fort Lauderdale, Florida,
United States

OTHER prIME ACTIVITIES

Breast Cancer Virtual Journal Club: Eribulin as Single-Agent Treatment for Metastatic Breast Cancer
prIME Oncology Case in Oropharyngeal Cancer
Expert Perspectives in Oncology: Contemporary Approaches in Targeting Angiogenesis
 
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