Post-menopausal Early Breast Cancer Patients May Benefit From Switching to Exemestane After Two Years of Treatment with Tamoxifen

New research has found that switching post-menopausal women with early breast cancer to the drug exemestane (Aromasin®, Pfizer, USA) after two or three years of tamoxifen rather than keeping them on tamoxifen for five years improves the chance of remaining cancer free and reduces the risk of death for at least the next six years.

“These findings have confirmed that the strategy of switching to exemestane mid-way through the five-year tamoxifen treatment plan provides a clear and durable benefit for relapse and overall survival,” the study’s leader, Professor Charles Coombes, head of oncology at Imperial College in London, told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany. “We found that six years after changing treatment, women who got exemestane were 18% more likely to remain disease free and were 14% less likely to die than those who stayed on tamoxifen.”

Breast cancer is the leading cancer in women, with 1.29 million cases diagnosed worldwide every year. About 75% of breast cancers are oestrogen-receptor positive, meaning that oestrogen plays in important role in promoting the growth. Such tumours are usually treated with anti-oestrogen drugs.

Tamoxifen, also known by the trade names Nolvadex, Istubal, and Valodex, is the oldest of these. The drug blocks the tumour’s ability to use oestrogen and is the standard treatment after surgery in women who have early-stage breast cancer. It is normally taken for five years.

Exemestane belongs to a newer class of anti-oestrogen drugs known as aromatase inhibitors, which interfere with the function of aromatase, an enzyme responsible for the production of oestrogen. Aromatase inhibitors are accepted as an alternative to tamoxifen for post-menopausal women, but the question of how best to use these drugs remains under investigation.

The study tested whether switching to exemestane after two or three years of tamoxifen was more effective in the long term than continuing with tamoxifen for the remainder of the five years of treatment. The results presented in Berlin update findings reported previously, providing evidence based on a longer follow-up to produce a more robust estimate of the strategy’s effect on survival and disease recurrence and give a clearer picture of the long-term side effects.

“Our earlier analysis, based on a shorter follow-up, had shown a clear relapse advantage but until now, the magnitude and duration of the overall survival benefit had been uncertain. These updated results show that the relapse improvement does not seem to diminish over time and have clarified that the survival advantage is robust and enduring.”

The study, which has the longest follow-up of any trial to date investigating the impact of switching from tamoxifen to an aromatase inhibitor, involved 4,724 postmenopausal women from 37 countries with oestrogen-receptor-positive or unknown receptor status breast cancer who had their tumours cut out and had remained disease free after two or three years on tamoxifen. About half continued with tamoxifen until they had completed a total of five years of treatment, while the other half were switched to exemestane for the remaining period of treatment. The women were followed for an average of 91 months.

The 18% improvement in disease-free survival is derived from a hazard ratio of 0.82, while the 14% improvement in overall survival is calculated from a hazard ratio of 0.86.

“Practice changed in many countries after our early findings were released in 2004, from using five years of tamoxifen to the current recommended treatment strategy of switching these patients to exemestane or another aromatase inhibitor after two or three years of tamoxifen. The issue that has yet to be clarified is whether starting with tamoxifen and then switching is better than starting with an aromatase inhibitor,” Coombes said.

Cancer Research UK and Pfizer Ltd., which makes exemestane, funded the study.

For more information:

• Abstract no: 5010. Breast Cancer proffered papers session, Tuesday 09.00-11.00 hrs CEST (Hall 1)

Also read these PubMed Abstracts

• Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review. Cancer Treat Rev. 2008 Apr;34(2):157-74. Epub 2007 Dec 31. Review.
• Spicer J, Ellis P. Towards optimal endocrine therapy for hormone-sensitive breast cancer: initial versus sequential adjuvant aromatase inhibition.
  Cancer Lett. 2007 Apr 1 8;248(2):165-74. Epub 2006 Aug 21. Review.

Bevacizumab Data Gives Hope to Colorectal Cancer Patients with Liver Metastases

New data from several studies presented at the joint multidisciplinary meeting of ECCO 15 (European CanCer Organisation) and ESMO 34 (European Society for Medical Oncology) in Berlin, Germany, confirm unique benefits of bevacizumab (Avastin®, Roche, Basel, Switzerland), an antibody that specifically binds and blocks VEGF (vascular endothelial growth factor), and capecitabine (Xeloda®, Roche, Basel, Swizerland), a highly effective targeted oral chemotherapy offering patients a survival advantage when taken on its own or in combination with other anticancer drugs, in treatment of colon cancer.

Colorectal cancer is the second most common cause of death from cancer across all tumor types in Europe and is the third most commonly reported cancer in the world.

Bevacizumab in combination with chemotherapy led to shrinkage or disappearance (overall response rate) of liver metastases (disease that has spread to the liver) in 78% of patients with advanced colorectal cancer. As a result, one third (33%) of patients who were initially unable to undergo surgery were eligible to undergo a potentially lifesaving surgery. Complete surgical removal of the metastases was achieved in 56% of all bevacizumab-treated patients.

II BOXER study
The multicentre phase II BOXER study, a single arm phase II study, investigated the efficacy and safety of bevacizumab in combination with oral capecitabine and intravenous oxaliplatin (NO16968 XELOX trial, an open-label, randomised, phase III study of oral capecitabine in combination with intravenous oxaliplatin versus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for patients with stage III colon cancer who have undergone surgery) in patients considered unsuitable for upfront resection (surgical removal) of their liver metastases.

Response rates in this trial were measured by RECIST criteria. Secondary objectives of BOXER trial included complete resection rate, safety and feasibility of the regimen, PFS and overall survival.

“The data from BOXER shows that bevacizumab in combination with standard chemotherapy has the ability to shrink metastatic lesions which might allow surgical removal and therefore offer a potential for cure for patients with advanced disease,” explained Professor David Cunningham, Head of the Gastrointestinal Unit at the Royal Marsden Hospital, UK.

First BEAT
Data from the large, observational First BEAT phase IV trial assessing the safety and efficacy of bevacizumab in almost 2,000 previously untreated patients with mCRC in combination with a variety of standard chemotherapies, showed that bevacizumab -based treatment delivers the same benefits to all patients including those aged above 65 years who represent the majority of people with advanced colorectal cancer. This is an important finding as older patients are often under-represented in clinical trials. The study results showed that the time patients lived without their disease advancing (PFS) was similar across age groups – 10.8 months for those below 65 years, 11.2 months for those between 65 and 74 years and 10 months for those 75 years and older.

The most common chemotherapy regimens combined with bevacizumab in First BEAT were FOLFOX, XELOX, FOLFIRI (oxaliplatin, fluorouracil and irinotecan) and capecitabine. The primary endpoint of First BEAT was safety and secondary objectives were PFS and overall survival.

NO16968 (XELOXA) study
Patients taking capecitabine with oxaliplatin immediately after surgery live disease free for longer compared to those treated with commonly used chemotherapy regimen. New results for capecitabine in early colon cancer were also presented at the ECCO 15 - ESMO 34 meeting. The pivotal NO16968 (XELOXA) study, the largest-ever study of patients with stage III colon cancer, showed that the three year disease-free survival (DFS) for patients receiving XELOX was 70.9%, superior to the 5-FU/LV arm (66.5%) (HR=0.80 (95% CI: 0.69-0.93), p=0.0045). The DFS result obtained with XELOX is similar to that shown in trials evaluating the use of FOLFOX in patients with stage III colon cancer.

"We know that XELOX helps keep patients free from recurrence of their cancer longer,’’ said Dr Dan Haller, Professor of Medicine, University of Pennsylvania. "These results now confirm that patients have an additional option for the treatment of stage III colon cancer. In these potentially curable patients, XELOX offers the additional benefit of an oral medication, Xeloda."

"Colorectal cancer sadly claims more than 600,000 lives each year, despite the treatment advances made in the last decade” said William M. Burns, CEO of Roche’s Pharmaceuticals. “Today’s announcements about Avastin and Xeloda are therefore very welcome news for patients and their families as they offer more options for fighting this disease and hope that some patients may even have the potential to be cured” he added.

Images courtesy American Society of Clinical oncology (ASCO) and Roche Pharmaceuticals.

Cetuximab plus Chemotherapy may Reduce Advanced Lung Cancer Death Risk

Patients with advanced non-small cell lung cancer who are given cetuximab (Erbitux, Merck KgA), an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, in addition to chemotherapy are 13% less likely to die than those who receive chemotherapy alone, regardless of which chemotherapy is used, new research finds. They also experience slower disease progression and an increased chance of tumor shrinkage.

While a large study last year found that patients lived five weeks longer when the targeted drug cetuximab was added to a particular chemotherapy combination, it has not been clear whether it matters which chemotherapy combination the drug is added to, how its addition affects disease progression and what the exact magnitude of the survival benefit is.

Researchers combined the data from four trials that investigated the addition of cetuximab to various different platinum-based chemotherapy combinations in first-line treatment of advanced non-small cell lung cancer. The findings of the meta-analysis, which included a total of 2,018 patients, were presented in Berlin on Tuesday at Europe’s largest cancer congress, ECCO 15 – ESMO 34 (the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology).

Meta-analyses, which integrate the results of several studies, are important for corroborating the findings of key studies and give a more accurate estimate of a drug’s true effects. “We found that patients who got cetuximab had a 13% lower chance of dying within the three years of follow-up compared with those who got chemotherapy alone,” said Professor Jean-Louis Pujol, chair of thoracic oncology at Montpelier Academic Hospital and professor of medicine at Montpelier University in France. “For lung cancer, considering that this disease is very resistant to treatment and that the prognosis is very poor, an improvement of that magnitude is meaningful. It’s about the same as what you get from giving chemotherapy after surgery and that’s accepted as standard treatment.”

The median survival, a more crude measure of the drug’s effect on death, was 9.4 months in the chemotherapy alone group and 10.3 months in the chemotherapy plus cetuximab group.

The meta-analysis also uncovered a 10% improvement in progression free survival, which measures the length of time a patient survives before the cancer gets worse. None of the individual studies were powerful enough to identify any effect on this outcome on their own, as it is difficult to observe this in lung cancer because the disease progresses so quickly.

The study also found that patients who received the addition of cetuximab were 48% more likely to experience tumour shrinkage.

“Fewer than 30% of patients with advanced non-small cell lung cancer respond to chemotherapy, so even though adding cetuximab increases the chance by another 48%, pushing the response rate up to about 45%, this shows than non-small lung cancer remains a disease that is very resistant to treatment,” Prof Pujol said.

The benefits for all these outcomes were seen across all subtypes of the disease. Lung cancer is particularly difficult to treat and is the leading cause of cancer death worldwide, killing an estimated 1.31 million people a year. Patients with advanced disease have few treatment options and about 70% of them die within one year of diagnosis. Fewer than two percent survive five years. Platinum-based chemotherapy is the standard treatment.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and most patients have tumours that over-express the epidermal growth factor receptor (EGFR). Cetuximab belongs to a new class of anti-cancer drugs known as monoclonal antibodies and works by blocking the EGF receptor to interrupt uncontrolled cell division.

Studies of other EGFR blockers have not shown any benefit when they are combined with chemotherapy in first-line treatment of advanced non-small cell lung cancer, although they have been shown to help in second-line treatment. One explanation for why cetuximab has shown benefit in this case while the other drugs targeting the receptor haven’t could be because it blocks the receptor in a different location. The drug is currently used to treat metastatic colorectal cancer and head and neck cancer. Frequent side effects include an acne-like rash.

“We now have enough evidence to recommend cetuximab for patients with advanced non-small cell lung cancer and we have confirmation that it doesn’t matter what kind of chemotherapy it is used with,” Prof Pujol said. “What we now need to investigate is whether this drug could also help at early stages of the disease.”

The study was funded by a grant from Merck KGaA, which makes cetuximab.

For more information:

• Abstract no: 9009. Lung Cancer II session, Tuesday 09.00 hrs CEST (Hall 15.2)

Also read these Pubmed Abstracts:

• Reade CA, Ganti AK. EGFR targeted therapy in non-small cell lung cancer: potential role of cetuximab. Biologics. 2009;3:215-24. Epub 2009 Jul 13
• Belani CP, Schreeder MT, Steis RG, Guidice RA, et al. Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer. 2008 Nov 1;113(9):2512-7
• Borghaei H, Langer CJ, Millenson M, Ruth KJ, et al. Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. J Thorac Oncol. 2008 Nov;3(11):1286-92

Images courtesy American Society of Clinical oncology (ASCO)

Society to Fund Research Focused on Long-Term and Late Effects of Cancer Treatment

Over the past decades, cure rates for many cancers have improved dramatically. The harsh reality is, however, that too many cancer survivors suffer serious side-effects of their curative treatments. Toxic side-effects can occur months or years after the treatments are finished, sometimes as chronic conditions, sometimes life-threatening, but always unacceptably reducing a patient's quality of life.

While research continues to seek new safe and effective drugs, what patients need now is for current therapies to be made less harmful without sacrificing their effectiveness.

In a new initiative, The Leukemia & Lymphoma Society (LLS), the world's largest voluntary health agency dedicated to blood cancer founded in 1949 and headquartered in White Plains, NY, will invest in research designed to discover the biological mechanisms that cause late effects, and to develop and test measures to prevent or at least significantly reduce toxicities. LLS is seeking requests for proposals from scientists studying these issues.

The pediatric cancer story has shown us that the goal is achievable. Years of research and clinical trials enabled survival rates to reach nearly 90% for children with acute lymphocytic leukemia. But then the medical and research community recognized that the serious late effects were severely impacting quality of life. High-dose radiation treatments, once thought critical to cures, have been eliminated for most children, significantly reducing cognitive deficits and other once common side-effects.

Now The Leukemia & Lymphoma Society has set a goal of doing for all cancer patients, regardless of age, what has been achieved for many children -- survival with good quality of life.

The initiative is being led by Anna T. Meadows, M.D., medical director of the Cancer Survivorship and Living Well After Cancer Program at the Children's Hospital of Philadelphia. Dr. Meadows is an internationally recognized pioneer in late effects research; she helped quantify the serious consequences of high-dose radiation and eliminate it from curative treatments for most children with leukemia and lymphoma.

"We must find the answers and test them as soon as possible," says Dr. Meadows. "We must be determined and courageous - funders, researchers, and patients alike - because survival is just the first part of the struggle to cure cancer; the quality of that survival matters."

Bevacizumab study does not meet primary endpoint, but results suggest future trials may hold promise for early-stage colon cancer treatment

Adding bevacizumab to standard adjuvant chemotherapy does not improve disease-free survival for early-stage colon cancer. This is the primary conclusion from the complete results from the first, randomized phase III trial of bevacizumab (Avastin, Roche) in early-stage colon cancer, known as NSABP C-08, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Genentech and NCI, and will be presented on Sunday, May 31, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida.

NSABP C-08 was the first study to report results on the use of bevacizumab as an adjuvant treatment. Bevacizumab targets the vascular endothelial growth factor (VEGF) receptor, a key driver of tumor angiogenesis – an essential process in the development and maintenance of blood vessels which is required for a tumor to grow and to spread (metastasize) to other parts of the body.

The results of the NSABP C-08 trial have found that adding bevacizumab to standard adjuvant chemotherapy did not improve disease-free survival (the time that patients are free of tumor recurrence) in early-stage colon cancer

The current study enrolled 2,710 patients who were randomized to receive six months of standard adjuvant chemotherapy or six months of adjuvant chemotherapy combined with bevacizumab plus an additional six months of bevacizumab after the chemotherapy had ended.

All patients in the study had stage II or stage III disease and first had surgery to remove their tumors. After a median follow-up of three years, the investigators found that 77.4 percent of patients in the experimental group (bevacizumab) were alive and free of disease, compared with 75.5 percent of patients in the control group, a difference that was not statistically significant. There were no unexpected side effects in either arm and the toxicities from bevacizumab were well tolerated.

“One interesting effect was that during the year that patients were receiving bevacizumab we saw a benefit in disease-free survival (DFS) that subsequently diminished when follow-up was completed,” said Norman Wolmark, MD, chairman of the Department of Human Oncology at Allegheny General Hospital and the study’s lead author. Patients receiving bevacizumab treatment had a 40 percent lower risk of cancer returning, however, this initial improvement over chemotherapy alone gradually diminished over time.

Commenting on the trial, Walmark continued “Our overall conclusion is that bevacizumab was not effective as an adjuvant treatment for early-stage colon cancer, but the transient benefit we saw in patients who received bevacizumab illustrates that we have more to learn about how this reagent works, and we need to design more clinical trials to determine how it can be used most effectively.”

No new safety signals for bevacizumab were observed in the study and careful review of the data did not provide evidence that cancer returns faster or more aggressively after bevacizumab therapy was stopped.

“These results are encouraging and suggest that Avastin may have an important role in early cancer treatment. We are committed to the ongoing program of Avastin in early-stage cancers and believe that these results could help us optimize the use of Avastin for the benefit of patients,’’ noted William M. Burns, CEO of the pharmaceutical division of Roche, a leader in research-focused healthcare.

Study Results
The NSABP C-08, a two-arm randomized prospective multi-center Phase III study evaluated the use of bevacizumab plus chemotherapy (mFolfox6 + bevacizumab/mFF6+B) for the treatment of Stage II or III adenocarcinoma immediately following surgery (adjuvant therapy) compared to chemotherapy alone (mFolfox6/mFF6). The study showed the addition of one year of bevacizumab to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS). However, during the year of bevacizumab treatment there was an early and significant improvement in disease-free survival that diminished over the course of the study.

Disease-Free Survival was measured from the date of randomization to the date of any type of cancer recurrence or death from any cause. Patients enrolled in the study were randomized after surgery to receive either FOLFOX chemotherapy alone for six months or FOLFOX in combination with bevacizumab (intravenously every two weeks) for six months, followed by an additional six months of bevacizumab monotherapy. Patients continue to be followed for overall survival, a secondary endpoint of the study.

Overall in the study, there was 12 percent improvement in DFS that was not statistically significant (hazard ratio=0.89, p=0.15; risk reduction 11 percent). In the first year of the study, while patients received bevacizumab in addition to a standard six-months of adjuvant chemotherapy, disease-free survival improved by 67 percent compared to chemotherapy alone (hazard ratio=0.60; risk reduction of 40 percent). However, this early improvement in DFS began to diminish after the first year, and overall DFS was not improved.

NSABP C-08 included a comprehensive safety analysis that showed no new or unexpected safety events related to bevacizumab in the study. Specific severe (Grade 3 or greater) adverse events (AEs) that occurred with increased frequency in patients who received bevacizumab versus chemotherapy alone were: hypertension (12 percent vs. 1.8 percent), pain (11.1 percent vs. 6.3 percent), proteinuria (2.7 percent vs. 0.8 percent) and wound-healing complications (1.7 percent vs. 0.3 percent).

Other trials and standard of care
Bevacizumab is currently approved for metastatic colorectal, breast, and lung cancers and other trials are ongoing to evaluate it as an adjuvant treatment for a variety of solid tumors. Therapy with bevacizumab is the standard of care in advanced colon cancer treatment which will be further confirmed throughout the ASCO meeting with 53 efficacy and safety data presentations including more than 6,000 patients.

In addition to early-stage colon cancer, bevacizumab is being studied as an adjuvant treatment in other early-stage diseases: HER2-negative breast cancer, HER2-positive breast cancer, and non-squamous, non-small cell lung cancer. Approximately 26,000 people are expected to participate in bevacizumab based adjuvant studies, making the bevacizumab development program one of the most comprehensive undertakings in cancer research since chemotherapy. The Avastin (bevacizumab) development program includes more than 450 clinical trials worldwide in approximately 30 different tumor types.

More than 500,000 patients have been treated with bevacizumab so far. A comprehensive clinical program with more than 450 clinical trials is investigating the use of bevacizumab in various tumor types (including colorectal, breast, lung, brain, gastric, ovarian, prostate and others) and different settings (advanced or early stage disease).

Mode of Action
The precise mode of action of bevacizumab helps control tumor growth and metastases with only a limited impact on side effects of chemotherapy.

The drug has proven survival benefits across multiple tumor types and is approved in Europe for the treatment of the advanced stages of four common types of cancer, including colorectal cancer, breast cancer, lung cancer and kidney cancer. These types of cancer collectively cause nearly 3 million deaths each year in the US alone.

In the US, bevacizumab was the first anti-angiogenesis therapy approved by the FDA and is now approved for the treatment of four tumor types: breast, colorectal, glioblastoma, and non-small cell lung cancer (NSCLC).

For further information:

• American Society for Clinical Oncology
• Wolmark, G. Yothers, M. J. O’Connell, S. Sharif, J. N. et al. A phase III trial comparing mFolfox6 to mFolfox6 + bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 N. Plenary presentation, Sunday, May 31, 3:15 PM EDT, Level 2, West Hall D2. Plenary Session, Lead Author: Norman Wolmark, MD, Allegheny General Hospital Pittsburgh, Pa. Abstract No# LBA4

Other, related, abstracts

• A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4000 First Author: D. KerrCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
  Meeting:2009 ASCO Annual Meeting Abstract No: 4001 First Author: S. TejparCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4002 First Author: A. D. RothCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)

Folfox Background information:

• Wikipedia (Definition)
• Cancer Research UK
• NCI – National cancer Institute

Colorectal Cancer:

• Medical Oncology (at Boomja.com)
• Goldberg RM, Therapy for Metastatic Colorectal Cancer The Oncologist Vol. 11, No. 9, 981-987, October 2006

Pharmaceutical information:

• EMEA - European Public Assessment Report (bevacizumab)
• Highlights of Prescribing Information USA (bevacizumab)