primeLINES CLINICAL OPINION POLL

APRIL 2010 Issue

PHARMACEUTICAL NEWS

Expanded Indication for Erlotinib in Lung Cancer

On March 18, 2010, the European Medicines Agency (EMEA) adopted a positive opinion regarding a variation to the marketing authorization of Roche’s erlotinib (Tarceva^®) in lung cancer. The new indication states that single-agent erlotinib may be used as maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with stable disease after 4 cycles of standard platinum-based first-line chemotherapy. This positive opinion is based on data from the phase III SATURN study, which demonstrated that treatment with erlotinib was associated with a statistically significant improvement in both progression-free survival (PFS) and overall survival (OS) when compared to placebo in patients with advanced NSCLC who had received standard platinum-based first-line chemotherapy. Erlotinib was previously indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen, and in combination with gemcitabine for the treatment of patients with metastatic pancreatic cancer.

The US Food and Drug Administration (FDA) made a similar decision on April 16, 2010, also approving the use of erlotinib as maintenance therapy in NSCLC.

New Six-Month GnRH Agonist Approved for Palliative Treatment of Advanced Prostate Cancer

On March 11, 2010, the FDA approved Watson Pharmaceuticals’ triptorelin pamoate for injectable suspension 22.5 mg (Trelstar^®), making this formulation the first and only 6-month intramuscular gonadotropin releasing hormone (GnRH) agonist for the palliative treatment of advanced prostate cancer. The approval is based on a phase III study that demonstrated that administration every 6 months with triptorelin pamoate for injectable suspension 22.5 mg produced a mean testosterone serum level well below castration levels associated with androgen deprivation therapy. First approved in the United States in 2000, triptorelin pamoate for injectable suspension is currently available in 1-month (3.75 mg) and 3-month (11.25 mg) forms; however, the new, longer-acting 6-month formulation is designed to provide patients and physicians with a more convenient therapeutic option that is well tolerated and as effective as previous formulations.

CONFERENCE NEWS

Highlights from the 7^th European Breast Cancer Conference

Approximately 5000 breast cancer specialists, medical professionals, researchers and breast cancer patient advocates from around the world gathered in Barcelona, Spain, March 24 - 27 for the 7^th European Breast Cancer Conference (EBCC), jointly organized by the European Breast Cancer Coalition (EUROPA DONNA), the European Society of Breast Cancer Specialists (EUSOMA), and the European Organisation for Research and Treatment of Cancer (EORTC) Breast Group. Continuing with the goal to successfully promote multidisciplinarity, collaboration, and strong partnerships, the format of this year’s conference incorporated all of the essential elements common to past EBCC programs: Plenary sessions, teaching lectures, clinical science and keynote symposia, Oxford-type debates, “Challenge the Expert” sessions and patient management workshops. Topics discussed at the meeting included prevention and early diagnosis of breast cancer, locoregional therapy in both the early and metastatic settings, the role of gene profiling to guide therapeutic decision making, and the importance of biology in individualizing the therapeutic approach for each patient. In addition, the following areas of interest were highlighted during the conference: Pregnancy and breast cancer, CNS metastases, multitargeted therapy, cardiology for oncologists, the management of side effects and—last but not least—obstacles currently encountered in academic research.

During the conference several abstracts and posters were presented; reports of particular interest included:

• Phase III trial results demonstrated similar efficacy and significantly less toxicity with vinorelbine (Navelbine^®) and trastuzumab (Herceptin^®) compared with docetaxel (Taxotere^®) and trastuzumab in patients with HER2-positive locally advanced or metastatic breast cancer. The authors concluded that vinorelbine plus trastuzumab should be considered a potentially better first-line treatment option for this patient population.
• Patients who are newly diagnosed with unifocal and unilateral breast cancer often request contralateral prophylactic mastectomy at the time of diagnosis due to overestimated risk of contralateral breast cancer. In a study involving 27 patients who initially wanted contralateral prophylactic mastectomy, only 4 patients actually went through with the procedure. The remaining 23 patients decided not to undergo surgery, and stated that they were pleased to have been given a year to reconsider the facts and options.
• Expression of PARP was detected by immunohistochemistry in patients with all subtypes of early breast cancer enrolled in the phase III GeparTrio trial. Analysis of tissue microarrays from core biopsies demonstrated that high PARP expression was significantly correlated with an aggressive biologic tumor pattern, and cytoplasmic PARP expression predicts pCR to neoadjuvant taxane-anthracycline-based chemotherapy.

A “Metastatic breast cancer guidelines workshop” was organized by the European School of Oncology’s Metastatic Breast Cancer Task Force. This session highlighted several issues encountered in the management of patients with metastatic breast cancer, including the role of maintenance therapy and how many lines of therapy should be administered. Special emphasis was placed on the needs of the patient with metastatic breast cancer, from the perspective of both patient and physician.

FROM THE LITERATURE

Is MRI Alone a New Standard of Care for Screening of Women at Elevated Risk for Breast Cancer?

A family history of breast cancer is thought to be a major risk factor for the development of breast cancer; indeed, most guidelines recommend screening for at-risk women starting at age 25 or 30 years, as opposed to routine screening beginning at 50 years of age. In current clinical practice, the combination of annual mammogram and magnetic resonance imaging (MRI) is used in women with a genetic susceptibility to breast cancer since the diagnostic accuracy of MRI is enhanced with mammography. Ultrasound has been suggested as an alternative to MRI, but there is no definitive evidence that ultrasound is an equal replacement for MRI and whether it is useful in women who undergo MRI screening. In the March 20 issue of the Journal of Clinical Oncology, Kuhl et al report results of the prospective multicenter screening EVA (EVAluation of imaging methods for secondary prevention of familial breast cancer) trial, designed to investigate the respective cancer yield and diagnostic accuracy of mammography, MRI, and ultrasound, used alone or in different combinations, for screening women at elevated familial risk of breast cancer. A secondary objective of the trial was to investigate the cancer yield of additional half-yearly screening with ultrasound and clinical breast examination (CBE).

The analysis cohort, consisting of 687 asymptomatic women considered to have a ≥ 20% lifetime risk of developing breast cancer, underwent 1679 annual screening rounds consisting of CBE, mammography, ultrasound, and quality-assured MRI. A subcohort of 371 patients chose to undergo additional half-yearly screening with ultrasound and CBE for a total of 869 screening rounds. After a median follow-up of 29 months, 27 of 687 (3.9%) women were diagnosed with breast cancer: 11 women with ductal carcinoma in situ (DCIS) and 16 with invasive cancers. It is interesting to note that all cancers were diagnosed during the annual screening rounds; no interval cancers occurred, and no cancer was identified during the half-yearly screening rounds. The cancer yield of ultrasound alone and mammography alone was equivalent, with a non-significant increase if both methods were combined. The cancer yield of MRI alone was significantly higher, and there was no significant improvement by adding mammography or ultrasound. The positive predictive value was highest for MRI (48.0%), followed by mammography (39.1%) and ultrasound (35.7%). Although clinical examination was positive in 110 screening rounds, only one of these palpable abnormalities corresponded to breast cancer, the rest were benign changes. Another 26 cancers were clinically occult at the time of diagnosis. This yields a sensitivity of only 3% and a positive predictive value (PPV) of 0.9% for CBE. The authors concluded that, in women at elevated familial risk for breast cancer, annual quality-assured MRI screening (use of standardized MR-BIRADS interpretation criteria and interpretation of at least 200 MRIs per year and verifiable experience with MR-guided biopsies) was able to shift the distribution of screen-detected breast cancers toward the preinvasive stage, and neither mammography nor annual or half-yearly ultrasound or CBE added to the cancer yield achieved by MRI alone.

J Clin Oncol. 2010;28(9):1450-1457.

An accompanying editorial by Jan Klijn in the same issue of Journal of Clinical Oncology acknowledges the merits of EVA, but also critically discusses limitations of this study. First and foremost, the study population evaluated in EVA was very heterogeneous in terms of patients with a personal history of breast cancer (31%) and numbers of BRCA1/2 gene mutation carriers (9%), making results of the EVA trial difficult to directly compare with other trials where the proportion of BRCA mutation carriers was higher. Second, the lack of interval cancers observed in EVA must be noted since in all the related studies, with the exception of one study , interval cancers were observed. Klijn explains that the average growth rate of the breast cancers observed in the EVA trial was lower than the tumor growth rate in the other studies (probably because of the lower incidence of BRCA mutation–associated cancers, which have a faster growth rate), positively affected both the interval cancer rates and the tumor stage at diagnosis. Finally, when compared to the EVA trial, the low PPV of MRI reported in earlier publications may be explained by inconsistent definitions of parameters (ie, PPV percentages when based on Breast Imaging Reporting And Data System [BIRADS] scores 0, 3, 4, and 5 versus BIRADS scores 4 and 5).

No other large prospective studies have shown such high sensitivity of MRI for both invasive cancer and DCIS as has been shown by Kuhl et al, and Klijn states that results from the EVA trial contribute to the accumulating evidence that MRI is not only the most important screening modality in gene mutation carriers, but also in women with a familial risk without a documented BRCA1/2 mutation and a cumulative life-time risk of 20% to 50%. However, many radiologists and oncologists remain hesitant to abandon mammography based on the following: the combination of MRI and mammography has demonstrated significant superiority to either screening modality alone in other large studies, the number of screen-detected DCIS cases across all published studies is still very small, and practical experience utilizing MRI is extremely variable.

J Clin Oncol. 2010;28(9):1441-1445.

Irradiation for Inner-Quadrant Breast Cancer Increases Cardiovascular Mortality

It has been reported that radiation therapy to the left breast is associated with an increased risk of cardiovascular mortality, likely caused by toxicity of ionizing radiation to the heart. However, with modern radiation techniques and generalization of cardiac protection for left-sided breast cancer, this risk substantially decreased. In addition to tumor side, tumor location within the breast can also influence heart exposure, and radiotherapy (RT) to the inner quadrants may also be associated with increased irradiation to the heart and greater cardiovascular mortality compared to RT administered to outer-quadrant tumors. In the March issue of Annals of Oncology, Bouchardy et al reported results from a large observational study evaluating the effect of inner quadrant radiotherapy on cardiovascular mortality risk. Of 1245 women treated mostly with breast conserving surgery and irradiated for primary node-negative breast cancer from 1980 to 2004, 393 (32%) had tumors in the inner quadrants and 852 (68%) in the outer quadrants. After a mean follow-up of 7.7 years, 28 women died of cardiovascular disease (19 women with cardiac disease and 9 of other vascular disease), 91 women died of breast cancer, and 36 women died of other causes. Cardiovascular mortality rates were higher among patients with inner-quadrant tumors when compared with patients with outer-quadrant tumors (6.2% versus 1.2%; P = .002), and patients with inner-quadrant tumors had a 2.3-fold increased risk of death from cardiovascular disease. Additional analysis by periods with different radiation protocols indicated that the excess of cardiovascular mortality was limited to women diagnosed during 1988-2004, when the boost dose was increased from from 10 to 16 Gy. Interestingly, cardiovascular mortality risk for inner-quadrant tumors was not increased during 1980-1987 when internal mammary lymph node chain (IMC) irradiation was high and boost dose was low (10 Gy). The risk of cardiovascular mortality associated with inner-quadrant tumors was similar for left-and right-sided breast cancer. As previously reported in this study, patients with inner-quadrant tumors had an increased risk of breast cancer–specific mortality and an increased risk of overall mortality compared to patients with outer-quadrant tumors. In contrast with other studies, patients with left-sided breast tumors had no excess of cardiovascular mortality compared to patients with right-sided tumors. The authors conclude that women receiving radiotherapy for inner-quadrant breast tumors have a considerably increased risk of cardiovascular mortality, probably linked to higher radiation exposure to the heart due to the site of boost. Though the present results should be confirmed in further studies, this adverse event should be taken into account and the benefit of such irradiation should be weighed against the risks. As for patients with left-sided breast cancer and patients with inner-quadrant tumors, the heart should be adequately shielded during radiotherapy.

Ann Oncol. 2010;21(3):459-465.

Optimal Timing of Adjuvant Chemotherapy in Colorectal Cancer

Treatment of stage III colorectal cancer (CRC) with adjuvant chemotherapy, usually administered within 8 weeks after curative surgery, has been a standard of care. However, several reasons may delay initiation of adjuvant chemotherapy. The results of various studies investigating if delaying initiation of adjuvant CT affects survival are contradictory. To address this issue, Des Guetz et al performed a meta-analysis of all published studies comparing delayed chemotherapy with standard of care. However, only eight studies (N = 13,158) were included in the main meta-analysis to evaluate the survival effect of delaying adjuvant chemotherapy for more than 8 weeks in patients with stage II/III colon or rectal cancer; this cutoff was selected as it was the most frequently used among studies. Statistical analysis of these studies demonstrated that delaying the initiation of chemotherapy for more than 8 weeks after curative surgery was associated with a worse overall survival (P = .001) and relapse free survival. The authors conclude that, whenever possible, adjuvant chemotherapy should be initiated within 8 weeks of curative surgery for colorectal cancer; delaying therapy for more than 12 weeks poses a significant question of effectiveness.

Eur J Cancer. 2010;46(6):1049-1055.

Toxicity the Determining Factor in Choosing Chemotherapy for Advanced NSCLC?

Patients with advanced NSCLC are typically given palliative chemotherapy with one of the platinum doublets as current standard of care; however in phase II studies, similar responses have been observed with the non-platinum regimen of gemcitabine plus paclitaxel. Treat et al conducted a prospective randomized phase III trial comparing overall survival, efficacy, and toxicity of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus standard of care combination of paclitaxel plus carboplatin (PC) in patients with locally advanced or metastatic NSCLC. A total of 1135 patients with stage IIIB (with pleural or pericardial effusion), stage IV, or recurrent NSCLC were randomly assigned to one of the three treatment arms: GC, GP, or PC. Patient characteristics were well-balanced, and the number of treatment cycles administered did not vary by treatment group. Median follow-up was 8.2 months, and median survival was 7.9 months for GC, 8.5 months for GP, and 8.7 months for PC. There were no statistically significant differences between individual treatment groups, and the P value for overall comparison was 0.693. The overall response rates (complete response plus partial response) were 25.3% for GC, 32.1% for GP, and 29.8% for PC; in addition, the clinical benefit rates (complete response plus partial response plus stable disease) of the three treatment arms were similar and exceeded 60%. Median time to progression (TTP) was 4.3 months for GC, 4.5 months for GP, and 4.7 months for PC. Patients receiving PC experienced more neurotoxicity and alopecia, while the GC arm was associated with greater myelosuppression and reduced median dose intensity. These findings demonstrate that the use of cytotoxic doublets in the treatment of patients with advanced or metastatic NSCLC result in comparable efficacy in terms of overall survival, response rates, and TTP, though distinct toxicity profiles are associated with each regimen. Until molecular selection strategies have improved, differences in toxicity should be the primary consideration when selecting therapy in this patient population.

Ann Oncol. 2010;21(3):540-547.

CA125 Doubling Time during Surveillance in Ovarian Cancer

Monitoring serum CA125 as an indicator of ovarian cancer recurrence has been widely accepted, however, a recently completed randomized trial (MRC-OVO5/EORTC 55955) has revealed that early re-treatment on the basis of rising CA125 alone in the absence of symptoms confers no survival benefit, nor proves to be advantageous in quality of life. This leads to the conclusion that there is no value in routine measurement of CA125 during surveillance after achievement of complete response following front-line therapy. Despite these results, it is likely that many clinicians will continue to monitor CA125 and may well consider the rate of rise in CA125 levels an important parameter. Han et al recently conductd a study to determine the independent prognostic significance of CA125 kinetics during surveillance in patients with ovarian cancer who had completed first-line chemotherapy. A clinical information of 296 patients with ovarian cancer treated in Royal Marsden Hospital London from 1994-2003 were initially obtained via a 2-staged chart review of patients who met criteria for CA125 progression and doubling during surveillance following first-line therapy. The median age of patients was 61 years. The majority of these patients were diagnosed with high stage (stages III and IV) and high grade (grade 2 and 3) ovarian cancer; nearly half of these patients underwent optimal cytoreduction and almost all were treated with platinum-based chemotherapy. Seventy-three percent of patients ultimately achieved post-treatment CA125 levels within normal limits (<35 u/mL), while 27% had CA125 above normal levels. With a median follow-up of 4.2 years, a total of 258 deaths occurred in this group of 296 patients. The median survival of patients with a short CA125 doubling time (≤40 days) was 10.6 months compared to 22.1 months in patients with a doubling time of >40 days. A univariate analysis demonstrated that age, high-grade, suboptimal cytoreduction, short CA125 doubling time (≤40 days), short time to progression (≤180 days), and high CA125 at progression (≥77 u/mL) were significantly associated with poor survival in these patients; however, a multivariate analysis found that a short CA125 doubling time and a short time to disease progression were the only independent adverse prognostic factors (P = .001). Second stage review identified 28 new patients who met criteria for CA125 doubling and provided a confirmatory set that supported the adverse survival trend for patients with short CA125 doubling time. Although findings from this study provide no data to support that early re-introduction of systemic therapy based on the rate of rise of CA125 levels influences patient outcomes , the authors highlight that analysis of CA125 kinetics (ie, doubling time) in asymptomatic patients relapsing after first-line chemotherapy provides prognostic significance and should be used in the individualized therapeutic decision-making process.

Eur J Cancer. 2010 Mar 18. [Epub ahead of print]

ADDITIONAL PUBLICATIONS WORTH READING

• Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: importance of heterogenicity [heterogeneity - title correction later published]. Nat Rev Clin Oncol. 2010;7(3):139-147. This review article discusses recently established and investigational strategies in the therapy of breast cancer in the context of currently accepted breast cancer subtypes: hormone receptor–positive, HER2-amplified, and triple-negative.
• Licitra L, Locati LD, Greco A, Granata R, Bossi P. Multikinase inhibitors in thyroid cancer. Eur J Cancer. 2010;46(6):1012-1018. This review focuses on the molecular basis of thyroid carcinogenesis and summarizes the results of studies evaluating the use of multitargeted tyrosine kinase inhibitors in advanced thyroid cancer.
• Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7(3):163-172. This review article discusses current treatment options for patients with advanced pancreatic cancer, and outlines novel treatment strategies and future directions for this highly lethal solid tumor.
• Tewari KS, Monk BJ. The rationale for the use of non-platinum chemotherapy doublets for metastatic and recurrent cervical carcinoma. Clin Adv Hematol Oncol. 2010;8(2):108-115. This publication proposes a rationale for exploring non-platinum chemotherapy doublets in metastatic and recurrent cervical cancer based on recent clinical trial data.
• Verweij J, Baker LH. Future treatment of soft tissue sarcomas will be driven by histological subtype and molecular abberations [sic]. Eur J Cancer. 2010;46(5):863-868. This manuscript reviews data regarding the increased sensitivity of specific subtypes of soft tissue sarcomas to specific cytotoxic agents, and summarizes the current status of molecularly targeted agents in a variety of soft tissue sarcomas, including gastrointestinal stromal tumors.
• Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: Response Assessment In Neuro-Oncology Working Group. J Clin Oncol. 2010;28(11):1963-1972. Since it has become increasingly apparent that there are significant limitations to the most widely used criteria for assessing response to therapy in high-grade gliomas, the Response Assessment in Neuro-Oncology Working Group presents updated response assessments for the evaluation of therapies in high-grade gliomas incorporating MRI characteristics to address the recognized and accepted limitations of the current Macdonald Criteria.

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