Eduard Vrdoljak

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

BACKGROUND Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING F Hoffmann-La Roche, Michelangelo Foundation.

Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

PURPOSE We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. PATIENTS AND METHODS A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m(2) intravenously on day 1) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14) or capecitabine alone (2,500 mg/m(2) on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death. RESULTS There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible. CONCLUSION This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial

BACKGROUND Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. METHODS In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. FINDINGS Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. INTERPRETATION These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. FUNDING F Hoffmann-La Roche.

Cancer epidemiology in Central and South Eastern European countries

Aim To collect cancer epidemiology data in South Eastern European countries as a basis for potential comparison of their performance in cancer care. Methods The South Eastern European Research Oncology Group (SEEROG) collected and analyzed epidemiological data on incidence and mortality that reflect cancer management in 8 countries – Croatia, Czech Republic, Hungary, Romania, Poland, Slovakia, and Serbia and Montenegro in the last 20-40 years. Results The most common cancer type in men in all countries was lung cancer, followed by colorectal and prostate cancer, with the exception of the Czech Republic, where prostate cancer and colorectal cancer were more common. The most frequent cancer in women was breast cancer followed by colorectal cancer, with the exceptions of Romania and Central Serbia where cervical cancer was the second most common. Cancer mortality data from the last 20-40 years revealed two different patterns in men. In Romania and in Serbia and Montenegro, there was a trend toward an increase, while in the other countries mortality was declining, after increasing for a number of years. In women, a steady decline was observed over many years in the Czech Republic, Hungary, and Slovakia, while in the other countries it remained unchanged. Conclusions There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors which provides a clear challenge to prevention. There are some differences in incidence and mortality that cannot be explained by exposure to known risk factors or treatment availabilities.

Phase II study of bevacizumab in combination with capecitabine as first-line treatment in elderly patients with metastatic colorectal cancer.

The relative survival of elderly patients with metastatic colorectal cancer (mCRC) is generally worse than that of younger patients because of more advanced stage at presentation, comorbidity and reduced use of optimal therapy. We conducted a prospective phase II trial of the combination of bevacizumab and capecitabine in elderly patients with mCRC. In total 41 patients aged more than or equal to 70 years with mCRC, who had not received chemotherapy earlier for metastatic disease, were enroled. Patients received capecitabine (1000 mg/m2 twice daily on days 1–14) and bevacizumab (7.5 mg/kg of body weight on day 1). The treatment cycles were repeated every 3 weeks. The overall response rate was 65%, including 13% of patients with a complete response and 53% of patients with a partial response. A further 13% of patients maintained stable disease. The median progression-free survival was 11.5 months and the median overall survival was 21.2 months. Despite the advanced age of participants, the rate of bevacizumab-related and capecitabine-related adverse events was consistent with that reported earlier in the general mCRC population. The combination of bevacizumab and capecitabine is effective and has a favourable tolerability profile and should be considered as an option for the initial treatment of mCRC in elderly patients.

A prospective characterization of the resolution of ixabepilone induced peripheral neuropathy: data from a large registrational program in patients with metastatic breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6140 Background: Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented. Methods: Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN. Results: Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048). ![][1] PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049). Conclusions: Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140. [1]: /embed/graphic-1.gif

Bisphosphonates and vascular endothelial growth factor-targeted drugs in the treatment of patients with renal cell carcinoma metastatic to bone.

Skeletal involvement is common in patients with renal cell carcinoma (RCC): ∼30% of patients with metastatic RCC (mRCC) will develop bone metastases. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear-cell RCC (m-ccRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and the monoclonal antibody bevacizumab, became the therapy of choice for patients with m-ccRCC. Besides the undisputed efficacy of TKI in the treatment of m-ccRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, a relatively common practice in the treatment of such patients is bone-directed therapy with bisphosphonates (BPs). Recent evidence shows a potentially synergistic effect on efficacy but also the potential for increased toxicity of combining TKIs and BPs. This review article highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients.

Ixabepilone plus capecitabine improves progression free survival in patients with metastatic breast cancer resistant to taxanes: a pooled analysis from two phase III trials.

Abstract #2015 Background:
 Patients (pts) with MBC whose tumors are resistant to taxanes (T) have limited therapeutic options. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts resistant to (study 046, JCO, 2007), or pretreated with anthracycline (A) and T (study 048). Pts whose tumors were resistant to A/T were also allowed to enter the 048 trial. In 048, ixa + C, compared to C alone, also demonstrated significant increases in progression-free survival (PFS, HR 0.79 [0.69-0.90)]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Here we present a pooled analysis from the 2 studies of clinical outcomes (ORR, PFS, and OS) in patients with a strict definition of resistance to T.
 Methods:
 1973 pts with MBC previously treated with an A and T, were randomized in phase III trials to receive either ixa (40 mg/m2 IV over 3h Q3w) + C (1000 mg/m2 PO BID x14d Q3w) or C alone (1250 mg/m2 PO BID x14d Q3w). For both studies, resistance was defined as disease progression up to 4 months following T in the metastatic setting and up to 12 months following adjuvant T therapy. Due to the similarity of the study populations, individual pt data from both studies was pooled to better evaluate treatment effect within pre-planned patient subgroups.
 Results:
 1337 pts from the 2 studies were T resistant and randomized to ixa + C or C alone. ORR and PFS favored ixa + C in this pt population, and there was a trend towards increased OS, which did not reach statistical significance (see table).
 Conclusion:
 Ixa + C is the first combination to show a clinical benefit of PFS in pts with MBC resistant to T (following a strict definition of resistance). The benefit seen in this pooled analysis was consistent with that observed in the resistant pt population from the individual studies as well. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2015.

Adjuvant endocrine therapy for perimenopausal women with early breast cancer

Adjuvant treatment with aromatase inhibitors (AIs) improves outcomes in postmenopausal women with hormone-sensitive early breast cancer compared with tamoxifen. However, AIs should not be used in premenopausal women because they can paradoxically increase estrogen secretion and may therefore stimulate tumor progression. In perimenopausal women undergoing treatment for breast cancer, it can be difficult to determine true menopausal status because adjuvant chemotherapy, tamoxifen, and gonadotropin-releasing hormone analogues can induce transient (or permanent) ovarian suppression. How can one determine whether these women are truly postmenopausal and therefore candidates for AI therapy? A panel of experts in the field of endocrine therapy in breast cancer met in Dubrovnik, Croatia, on October 23, 2006, to discuss this clinical dilemma. This report summarizes the conclusions and recommendations that arose from this discussion.

Optimizing treatment for patients with metastatic renal cell carcinoma in the central and Eastern European region

Introduction: Belarus, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Republic of Moldova, Romania, Russian Federation, Serbia, Slovakia, Slovenia and the Ukraine represent a collection of Central and Eastern European (CEE) countries in which the epidemiology and treatment of cancer varies greatly between and within countries. Current challenges include non-adherence to current treatment guidelines, restrictions in access and reimbursement for new therapies, and a lack of basic oncology programs. Metastatic renal cell carcinoma (mRCC) is a malignancy with historically poor prognosis. In CEE countries, the incidence and mortality rates of mRCC are among the highest in the world. Fortunately, mRCC represents a cancer for which a number of new targeted therapies have recently demonstrated benefit, resulting in new evidence-based treatment guidelines. Incorporating these mRCC treatment recommendations into the routine care of patients with mRCC in CEE countries would represent a major step forward for cancer care in this region. Areas covered: This review discusses the unique challenges faced by the aforementioned Eastern European countries in the treatment of metastatic renal cell cancer, in an attempt to assist health-care providers in providing the best care possible for their European patients. Expert opinion: Despite a wealth of clinical trial data supporting the use of targeted therapies for first-line treatment of mRCC, cytokine-based immunotherapy is still used in some of these European countries. With implementation and adherence to existing guidelines, treatment can be clinically and economically optimized in patients with mRCC from this region.