primeLINES CLINICAL OPINION POLL

SEPTEMBER 2010 Issue

FROM THE LITERATURE

Is Sentinel Lymph Node Biopsy Accurate in Women with Multiple Synchronous Breast Tumors?

Sentinel lymph node biopsy (SLNB) has become the standard of care in women with unifocal breast cancer, demonstrating a high degree of accuracy and a low false-negative rate. However, the accuracy of SLNB has not been adequately studied in women with preoperatively diagnosed multiple synchronous tumors (MST) in the same breast (ie, multifocal or multicentric disease). These patients have historically been excluded from prospective studies of SLNB. The 2005 American Society of Clinical Oncology guideline recommendations for SLNB in early breast cancer indicated that SLNB can be used in women with multicentric breast cancer through intradermal, subdermal, or subareolar injection techniques, but with limited level of evidence. In an effort to clarify this issue, a prospective multi-institutional study called “The Interest of Axillary Sentinel Lymph Node Biopsy in Multiple Invasive Breast Cancer” (IGASSU) was conducted in patients with preoperatively diagnosed MST. All patients underwent initial surgery, SLNB, and systematic axillary lymph node dissection (ALND). To date, this is the largest prospective trial to address this question.

The IGASSU study enrolled 211 assessable patients between March 2006 and August 2007, and among those patients, 197 (93%) had a sentinel lymph node (SLN) identified. Most importantly, among 108 patients with a negative SLN, 13.6% had a false-negative result (ie, the SLN was negative but subsequent ALND detected tumors in other nodes). In a univariate analysis of clinicopathologic risk factors, external tumor location (whereas “internal” was defined as internal quadrant and/or upper or uber quadrant and/or retroareolar) was the sole factor significantly associated with a higher false-negative rate (22% for external vs 7% for other location), and these external tumors were generally smaller than tumors in other locations. Based on the high false-negative rate observed in this study, which was substantially higher than that reported in other, smaller studies (<10%), the authors concluded that SLNB should not be recommended for any patient with MST, and not even for those with small tumors.

Ann Oncol. 2010;21(8):1630-1635.

Are Anthracyclines a Missed Opportunity in HER2-Positive Metastatic Breast Cancer?

Anthracyclines are among the most active chemotherapy agents in breast cancer. However, due to the high rate of cardiotoxicity with concomitant use of trastuzumab (Herceptin^®) in patients with HER2-positive metastatic breast cancer (MBC), the use of anthracyclines has declined in this patient population, despite the fact that anthracycline-based therapy may represent valuable treatment options for patients resistant to anti-HER2 therapy and availability of less toxic liposome-encapsulated doxorubicin. Based on current practice guidelines, patients are considered eligible for treatment with anthracyclines if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed 12 months or more after their last dose. Montemurro et al conducted a retrospective study to assess the use of anthracyclines after failure of a first-line trastuzumab-based regimen for MBC in patients who would be eligible for additional therapy with an anthracycline.

Among 450 patients in a multi-institutional database who received at least one trastuzumab-based regimen for HER2-positive MBC, 321 patients were considered eligible for anthracyclines. Of these patients, 190 had progressive disease during initial trastuzumab-based therapy and received further treatment. Use of an anthracycline was particularly infrequent (12%) in patients who had been exposed to these drugs in adjuvant setting, but was more frequent in anthracycline-naïve patients (31%). In fact, about one-third of dying patients never received an anthracycline throughout their entire disease course. In conclusion, the authors indicate that, based on findings of their analysis, the role of anthracyclines in HER2-positive MBC should be redefined.

Oncologist. 2010;15(7):665-672.

Safety of Sunitinib and Sorafenib in Patients with mRCC and Renal Insufficiency

The antiangiogenic agents sunitinib (Sutent^®) and sorafenib (Nexavar^®) are now widely used to treat metastatic renal cell carcinoma (mRCC), but their safety profile in patients with renal insufficiency has not been adequately studied. Impaired renal function is often an issue in patients with advanced mRCC, particularly following nephrectomy. Moreover, both of these agents are associated with some renal toxicity. Therefore, Khan et al sought to assess, retrospectively, the safety of these agents in patients with pre-existing renal insufficiency and those who developed renal insufficiency during treatment. They studied the medical records of 39 patients, of whom 21 had pre-existing renal insufficiency and 18 developed renal insufficiency during treatment. Renal insufficiency was defined as serum creatinine ≥1.9 mg/dL or creatinine clearance (CrCl) <60 mL/min/1.73 m² for >3 months before treatment. Among patients with pre-existing renal insufficiency, serum creatinine increased in 57%, and 48% of patients required dose reductions. Among patients who developed renal insufficiency during treatment, the median increase in serum creatinine was 0.8 mg/dL (range, 0.3 mg/dL - 2.8 mg/dL) and median decrease in CrCl was 25 mL/min (range, 8.5 mL/min - 64.8 mL/min). Within the entire cohort, 24% of patients had a partial response, 62% had stable disease, and median progression-free survival was 8.4 months.

Based on this retrospective analysis in a limited number of patients, the authors concluded that sunitinib and sorafenib can both be safely administered to patients with renal insufficiency, provided renal function is adequately monitored. For those patients who develop increase serum creatinine during treatment, dose modifications may be required for continuation of therapy. Notably, dose reductions were required more often among patients treated with sunitinib. In addition, it appears that the clinical benefit of these agents is not compromised in patients with renal insufficiency despite dose modifications.

Ann Oncol. 2010;21(8):1618-1622.

Have Therapeutic Anticancer Vaccines Finally Come of Age?

On April 29, 2010, sipuleucel-T (Provenge^®), an autologous dendritic cell–based vaccine, became the first therapeutic anticancer vaccine to receive US Food and Drug Administration (FDA) approval for advanced cancer. After more than 30 years of research and many disappointments, this was no doubt an important milestone. Sipuleucel-T was approved for patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC) based on a large multicenter, placebo-controlled, phase III trial reported by Kantoff et al. That study demonstrated a 4-month improvement in median overall survival (25.8 months versus 21.7 months) with a hazard ratio of 0.77 (P = .02). However, despite this apparent success, these results continue to raise many fundamental questions about how to design and test therapeutic vaccines, their clinical benefits, and the best place in therapy to use them.

In his editorial, Dan Longo highlighted some of these issues. First and foremost, he pointed out that the clinically meaningful 4-month improvement in overall survival associated with sipuleucel-T came without evidence of a measurable antitumor effect. Only 1 patient had a partial response by RECIST, and only 3% of patients had a ≥50% reduction in PSA. Moreover, there was no improvement in time to progression. An improvement in survival without a measurable antitumor effect raises concerns that there may have been an imbalance between the treatment groups in some, as yet unknown, prognostic factor. Indeed, this is not an isolated finding. He points out that another prostate cancer vaccine (PROSTVAC^®-VF) prolonged median survival by more than 8 months in a randomized phase II trial without improving progression-free survival.

The second issue has to do with where therapeutic vaccines make most sense in the treatment continuum and how best to test them. It is well documented that patients with advanced metastatic cancer have a number of disease-associated immune defects. Therefore, the vaccine strategy must somehow overcome these daunting challenges. Dendritic cell–based vaccines attempt to overcome defective antigen presentation, but can they also overcome the other immune-suppressive mechanisms that are geared up to prevent an effective T-cell−mediated immune response? In light of this, Dr Longo argued that it may make more sense to test therapeutic vaccines in the adjuvant setting. This, however, presents a whole new set of challenges in terms of demonstrating a treatment benefit, and the landscape is littered with failed adjuvant vaccine trials for melanoma.

Finally, Dr Longo addressed the issue of cost and where sipuleucel-T may ultimately fit in the treatment paradigm for CRPC. Unfortunately, the cost of this therapy ($93,000 for 1 course of therapy) may limit its use, particularly in light of the recent success of other novel agents being tested in CRPC. For example, recent studies have shown that CRPC is still dependent on androgens, and drugs like abiraterone, which blocks synthesis of androgens, are proving effective in this setting. Thus, the success of sipuleucel-T in CRPC should be viewed as a first step rather than the final chapter in this story. It remains to be seen where therapeutic vaccines will ultimately find their place in the treatment of cancer.

N Engl J Med. 2010;363(5):411-422.

N Engl J Med. 2010;363:479-481 (editorial).

Predicting Survival for Recurrent Glioblastoma

Glioblastoma multiforme is an aggressive brain tumor, and despite advances in first-line therapy that typically involves surgery, radiotherapy, and chemotherapy, nearly all patients will have tumor recurrence within 1 to 2 years. At the time of tumor recurrence, additional systemic and local therapies, as well as repeat surgery, are commonly considered. While each of these therapies has potential benefits, each also carries associated risks, particularly surgery.

Previous retrospective studies have shown that preoperative Karnofsky performance status (KPS), extent of surgical resection, age, and time interval between first and second operations were significantly associated with overall survival in patients undergoing second surgical resection for glioblastoma. However, these studies did not provide guidelines regarding which patients will benefit from repeat surgery. The ability to reliably predict survival outcomes prior to performing additional surgery would help guide treatment decisions. Therefore, Park et al sought to develop an easy to use and reliable prognostic scoring system for use in counseling such patients.

Based on data from 34 patients, the authors showed that 3 factors were significantly associated with poor postoperative survival in a multivariate Cox model. These factors were tumor involvement of eloquent/critical brain regions (P = .021), KPS ≤80 (P = .030), and tumor volume ≥50 cm³ (P = .048). Each of these factors was assigned 1 point on a 3-point scale, which defined 3 distinct prognostic subgroups identified as good (0 points), intermediate (1 to 2 points), and poor (3 points). In the initial cohort of 34 patients, median postoperative survival for each of these subgroups was 10.8 months, 4.5 months, and 1.0 month, respectively (P<.001). The scale was then validated based on a separate cohort of 109 patients, and again the scale identified three statistically distinct subgroups within the validation cohort with median survival times of 9.2 months, 6.3 months, and 1.9 month, respectively (P<.001). Considering these definitive results, this simple scale appears to be quite robust in terms of its ability to predict survival outcomes in this setting. Therefore, it may be useful in counseling patients regarding their treatment options for recurrent glioblastoma and in designing future clinical trials.

J Clin Oncol. 2010;28(24):3838-3843.

Less Intense Therapy for Early-Stage Hodgkin Lymphoma

Approximately 30% of patients diagnosed with Hodgkin lymphoma have early-stage disease and a favorable prognosis. These patients are typically treated with either the current standard of care—4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field radiation therapy (RT)—or with chemotherapy alone, an approach that remains controversial. However, these regimens are associated with significant acute toxicity, and RT is associated with the development of secondary solid tumors 5 years to 25 years after initial treatment. One of the key objectives in the treatment of Hodgkin lymphoma is to reduce the intensity of first-line therapy as much as possible while maintaining tumor control. This is most relevant for early-stage disease with a favorable prognosis where overall survival can be compromised by late treatment-related mortality. Therefore, Engert and colleagues conducted a multicenter, randomized trial to compare standard therapy with less intense chemoradiotherapy. In the HD10 study, patients with clinical stage I or II disease and no clinical risk factors were randomized to either 2 or 4 cycles of ABVD followed by either 20 Gy or 30 Gy of RT. The primary outcome was freedom from treatment failure at 5 years. This potentially practice-changing trial demonstrated that 2 cycles of ABVD was noninferior to 4 cycles, and 20 Gy of RT was noninferior to 30 Gy. Importantly, the lower intensity regimen (2 cycles of ABVD plus 20 Gy RT) resulted in significantly less acute toxicity. Overall, grade 3 or 4 adverse events occurred in 52% of patients treated with 4 cycles of ABVD compared to 33% of patients receiving 2 cycles (P<.001), and acute grade 3 or 4 toxicity was also higher among patients treated with 30 Gy of RT (8.7% versus 2.9%; P<.001). Survival outcomes were comparable between treatment groups, but longer follow up is needed to fully assess the long-term effects of these treatments. Nevertheless, this study clearly suggests that patients with early-stage Hodgkin lymphoma may benefit from less intense chemoradiotherapy.

N Engl J Med. 2010(7);363:640-652.

BRIEF REPORTS

Circulating MicroRNAs: Will They Be Breast Cancer’s “PSA”?

Biomarkers increasingly play an important role in the diagnosis and management of cancer. Perhaps the best known example widely used in clinical practice is prostate-specific antigen (PSA) for prostate cancer. Today, a new class of biomarkers is emerging based on microarrays to detect genetic signatures and assays that can detect circulating tumor cells or tumor-associated microRNA (miRNA). MicroRNAs are small noncoding sets of 19-24 nucleotides associated with miRNA expression of downstream gene targets including transcription factors, oncogenes, and tumor suppressor genes. Their expression could be measured by using a quantitative polymerase chain reaction method. The report by Heneghan et al describes a unique miRNA (miR-195) in the blood that can discriminate breast cancer from a variety of other solid tumors or healthy controls with a sensitivity of 88% and >90% specificity. In an accompanying editorial, Jeffrey Ross acknowledges the great potential of this technology, which has achieved levels of predictive accuracy never achieved with conventional immunohistochemical biomarkers. He states that there is growing excitement about the potential of miRNA markers for early diagnosis of breast cancer and for resolving borderline clinical imaging studies, but he cautions that larger confirmatory studies will be needed before miRNA is ready for routine clinical practice.

Oncologist. 2010;15(7):673-682.

Oncologist. 2010;15(7):656.

Exciting Times in the Management of Chronic Myelogenous Leukemia

In this review, Rao et al summarize the progress that has been made in the last 10 years with respect to the treatment of chronic myelogenous leukemia (CML). Small-molecule tyrosine kinase inhibitors (TKIs) directed against the Bcr/Abl oncogene, including imatinib (Gleevec^®/Glivec^®), nilotinib (Tasigna^®), and dasatinib (Sprycel^®), have significantly improved clinical outcomes and changed the natural history of the disease. As a result, the role of stem cell transplantation in CML has been redefined. The second-generation TKIs (nilotinib and dasatinib) have activity against imatinib-resistant mutations and have recently demonstrated superiority to imatinib in newly diagnosed chronic-phase CML. A growing body of evidence suggests that second-generation TKIs may eventually replace imatinib as the standard of care for newly diagnosed CML. In fact, nilotinib recently received FDA approval as first-line therapy. Other novel TKIs with activity against the T315I mutation are showing promise as salvage therapy. The authors discuss practical considerations such as guidelines for monitoring responses to imatinib therapy, criteria for choice of second-line therapy, management of the adverse events associated with TKIs, and quality-of-life issues. Preserving fertility and strategies for management CML during pregnancy are discussed.

Pharmacotherapy. 2010;30(9 Pt 2):77S-101S.