TEAM Study of Adjuvant Endocrine Treatment for Breast Cancer Reveals the Cost of Patient Non-compliance

The largest study in the world of treatments for post menopausal, hormone positive breast cancer has shown that patients who continue to take exemestane or tamoxifen do significantly better than patients who start to take one drug (or tamoxifen followed exemestane) but then stop.

Professor Cornelis van de Velde, principal investigator at the central data office for TEAM (tamoxifen exemestane adjuvant multinational) trial 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, that differences in compliance between the nine countries involved in the trial shed light on the role that it played in patient outcome.

In the Dutch/Belgian part of the TEAM trial, more patients were node positive compared to those in other countries (and were therefore at higher risk of recurrences), because the existing Dutch treatment guidelines (which have since been changed) indicated that only ‘high risk’ patients should receive chemotherapy, endocrine treatment or both. Yet despite this handicap, recurrences of breast cancer in The Netherlands and Belgium were 12% for patients using tamoxifen and 9% of patients using exemestane compared to 8% and 7% internationally. This is probably due to better compliance with treatment in The Netherlands, which was significantly better than in other countries.

“Across the whole study, up to a cut-off point of two years nine months, non-compliance amongst women on tamoxifen was 19.8% and 12.9% for women on exemestane. However, these percentages were considerably lower in the Dutch/Belgian part of the TEAM trial where non-compliance was 14% for tamoxifen and 9% for exemestane Patients who stopped study treatment (tamoxifen or exemestane) had significantly higher chance of a recurrence; the chance was between four and five times higher among this group than among those who continued their treatment. This underlines the need for good information for patients concerning the side-effects of drugs and treatment efficacy,” said Prof van de Velde, who is Professor of Surgery at the Leiden University Medical Centre (Leiden, The Netherlands) and President of the European Society of Surgical Oncology. Compliance with medication in the TEAM study was lower than in any previous study of adjuvant aromatase inhibitors.

The TEAM study is a randomised phase III clinical trial comparing the efficacy of the aromatase inhibitor exemestane versus the current “gold standard” treatment tamoxifen as adjuvant endocrine therapies for hormone sensitive early breast cancer in postmenopausal women. After two years nine months a total of 9,779 women had been included in the trial from nine countries: France (1230 patients), Germany (1480), Greece (211), Japan (184), The Netherlands (2753), Belgium (414), UK/Ireland (1275), and the USA (2232).

The trial was started in 2001 but in 2004, based on results from another trial (Intergroup Exemestane Study) that showed a significant survival advantage for patients on exemestane, the TEAM study was changed so that patients receiving tamoxifen were switched to exemestane after having been in the trial for between two and a half to three years. The results presented today relate to data on disease-free survival in patients on the trial for no longer than two years nine months and they focus particularly on issues of compliance in the Dutch/Belgian TEAM patients, as well as on side effects, and disease-free and overall survival across the whole of the study.

Prof van de Velde noted: “Adverse side effects were the main reasons why patients discontinued their treatment – about half of all patients who discontinued did so because of side effects. Out of all the patients in the study, 6.3% discontinued tamoxifen and 4.4% discontinued exemestane because of side effects."

Adverse side effects included heart, skin, hormonal, digestive, metabolic, neurological, muscle and skeletal problems. Exemestane was associated with significantly higher rates of arthralgia, carpal tunnel syndrome, diarrhoea and high cholesterol levels, but with significantly lower rates of hot flushes, vaginal bleeding and discharge, and thromboembolism than tamoxifen. Fractures and heart problems were similar between the two groups.

“The safety profile has been better for exemestane than for tamoxifen and I think this is a contributory factor to the lower discontinuation rates amongst the patients on exemestane,” Van de Velde said.

After two and three-quarter years of follow-up, among the women on exemestane there were 11% fewer cases of a local recurrence of the tumour, distant metastases, breast cancer in the other breast (contralateral breast cancer) and deaths occurring without a relapse of the disease,than among the women on tamoxifen (352 in the exemestane patients and 388 in the tamoxifen patients). There were no differences between the two groups for time to contralateral breast cancer or overall survival, and no unexpected safety issues were reported. Patients aged 70 or over and women with breast cancer that had spread to only one to three lymph nodes had a significantly better disease-free survival on exemestane than on tamoxifen.

“The current analysis covers a short period of time with relatively few deaths occurring and this makes it difficult to see significant differences between the two groups. However, the data from TEAM indicate that early use of exemestane in these high risk patients appears to be safe and a more effective endocrine treatment than tamoxifen for reducing breast cancer recurrence,” said Prof van de Velde. “The study is continuing and the next end point has already been reached, so that we now have enough events to conclude whether starting with tamoxifen and switching to exemestane is better or worse than starting with exemestane. These results will be presented at the San Antonio breast cancer symposium in December.”

For more information:

• Abstract no: 2BA. Presidential session, Tuesday 12.30-14.30 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

• Fallowfield LJ, Bliss JM, Porter LS, Price MH, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006 Feb 20;24(6):910-7

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.