National Discussion on Proper Use and Support of Oral Chemotherapy in Cancer Care

The growing use of oral chemotherapeutics brings clinical benefits but also raises questions in prescribing, adherence, accessibility and long term follow-up care.

Therfore, US Oncology, Inc. partnered with the Association of Community Cancer Centers, Association of Oncology Social Work, American Society for Clinical Oncology, Community Oncology Alliance, Oncology Nursing Society and the National Patient Advocate Foundation in hosting a panel discussion on Capitol Hill to examine the benefits of oral chemotherapy in cancer care, as well as challenges in its prescribing, accessibility and adherence in the current health care system.

"US Oncology recognizes the benefits of oral chemotherapy treatments and supports their use in that many patients have benefited from their convenience; ease of administration; and in some cases, lessened side effects when compared to traditional chemotherapy," said Leonard Kalman, M.D., Chairman of US Oncology's Public Policy Steering Committee. "As more patients request this therapy option, it is critical that patients and their physicians be fully informed and supported when it comes to effective prescribing, access to care and dosing adherence. We applaud our partners in the oncology community for coming together to address this issue."

Oral Agent in Cancer Care
The panel discussion, entitled "Oral Agents in Cancer: Their Impact on the Treatment of Patients and Providers," featured perspectives from practicing medical oncologists, oncology nurses, oncology social workers and a chemotherapy patient who was unable to access her prescribed oral chemotherapy medication following an insurance coverage denial. As the panelists explained, all healthcare stakeholders must work together to ensure that these life-saving treatments are properly prescribed and administered, effectively covered and financially obtainable for patients as the oral chemotherapeutics market grows.

US Oncology's OncologyRx Care Advantage™ national oral oncology specialty pharmacy service provides this type of financial, administrative and clinical support to cancer patients in need. By working directly with various charitable foundations, the program has provided more than $15 million in drug co-pay assistance to cancer patients since its inception in August 2006. OncologyRx Care Advantage also provides home delivery of prescribed oral cancer therapies, utilizes oncology certified nurses to proactively monitor patient compliance and help manage side effects, and gives patients 24-hour access to oncology certified pharmacists to answer their medication and dosing questions.

Patient Adherence
With intravenous chemotherapy, cancer care providers are able to monitor treatment on site and ensure that patients properly follow to their dosing amount and schedule. However, when patients take their own oral chemotherapy treatments at home, other factors may come into play, such as forgotten doses, omitted doses, emotional factors and other priorities. Adequate patient education and follow-up are critical to make certain patients receive the full treatment they need.

Healthcare providers play a unique and important role in assisting patients' healthy behavior changes. Panelists noted that widespread success in oral chemotherapy treatment will call for improved patient access to treatments; a new level of integration in care among physicians, pharmacists and other clinicians involved with the patient's care; and a new infrastructure in care for prescribing, education and support.

The problem of poor adherence has been a well-recognized problem [1,2,3,4]. Research investigating the effects of nonadherence suggest that in the United States alone, every year more than 125,000 deaths are caused by this phenomenon, accounting for upwards of 10% to 25% of all hospital and nursing home admissions. [5]. These numbers suggest that a patient’s poor or nonadherence is one of the largest and most expensive disease categories in the US. But patient nonadherence is not limited to medications alone. Patients may ‘forget’ to keep their appointments, to follow recommended dietary, adhere to other lifestyle changes, or fail to follow – in some case deliberately sabotage - other aspects of treatment or recommended preventive health practices. As a result, the actual implications of nonadherence go far beyond the financial aspect of patients’ failing to take medication.

"As more cancer patients are likely to look to oral chemotherapy as a more convenient and less invasive treatment option, we need to ensure that systematically, we are ready to meet their needs and providers' needs in terms of ready access to treatment; comprehensive information; and full administrative, clinical and social support throughout the course of treatment," added Dr. Kalman. "We look to the steps we have taken with OncologyRx Care Advantage as a model for this type of support, and we hope the broader healthcare community and policymakers will join us in exploring similar strategies to advance treatment success more broadly in this important area of care."

For more information
[1] Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, Md: Johns Hopkins University Press; 1979:1-18.
[2] Blackwell B. Drug therapy: patient compliance. N Engl J Med. 1973;289:249-252.
[3] Fawcett J. Compliance: definitions and key issues. J Clin Psychiatry. 1995;56(suppl1):4-8.
[4]Davis MS. Variation in patients' compliance with doctors' orders: medical practice and doctor-patient interaction. Psychiatry Med. 1971;2:31-54.
[5] Smith DL. Compliance packaging: a patient education tool. Am Pharm. 1989;NS29(2):42-45, 49-53.

Also:

• Onco’Zine – The International Cancer Network

Study of New Treatment for Advanced Melanoma Shows Rapid Shrinking of Tumors

Researchers have made significant advances in the treatment of metastatic malignant melanoma – one of the most difficult cancers to treat successfully once it has started to spread – according to a study presented 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, in Berlin, Germany.

In the phase I extension study, researchers have seen rapid and dramatic shrinking of metastatic tumors in patients treated with a new compound that blocks the activity of the cancer-causing mutation of the BRAF gene, which is implicated in about 50% melanomas and 5% of colorectal cancers. In new results from 31 melanoma patients with the BRAF mutation who were treated with 960mg of PLX4032, twice a day, 64% (14) of the 22 patients who could be evaluated so far met the official criteria for partial response (this involves the diameter of tumors shrinking by at least 30% for at least a month). A further six of the 22 patients also showed a response, but, at the time of the congress presentation, it was too early to say whether the tumors’ would shrink far enough to meet these criteria.

Dr Paul Chapman, an attending physician on the Melanoma/Sarcoma service at Memorial Sloan-Kettering Cancer Center (New York, USA) and who was one of the leaders of the trial, told a news briefing: “We are very excited about these results. Of the 22 patients we have been able to evaluate so far, 20 have had some objective tumor shrinkage. This is impressive as they all had metastatic disease and most of them had failed several prior therapies. A lot of these patients were pretty sick but many of them had a significant and rapid improvement in the way they function. We’ve had patients come off oxygen and we’ve got several patients who have been able to come off narcotic pain medication soon after starting treatment.”

The trial is investigating PLX4032, a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene, in patients with the BRAF mutation, and results from the first 55 patients were reported at a cancer meeting earlier this year (ASCO 2009). These data had been aimed at finding the best dose of PLX4032 to give to patients. However, the phase I extension data reported at ECCO 15 – ESMO 34 focuses on a subsequent group of an additional 31 patients who were all treated at the maximum tolerated dose of the drug (a 960 mg pill twice a day). All the patients had the BRAF mutation.

Dr Chapman said: “What makes this treatment different from standard chemotherapy is that standard chemotherapy attacks the machinery involved in cell division; so to stop the cancer cells dividing uncontrollably, most standard chemotherapy aims to block the mechanism of division by interfering directly with DNA replication or with microtubules in the dividing cells. PLX4302 is different because it attacks the genetic program that is causing the cells to divide uncontrollably, and we think the BRAF mutation is driving that program. The drug is blocking the genetics of the tumor, rather than trying to interfere with the proliferation of the cells and, as a result, there are fewer side effects, although there are some. We are seeing some pretty dramatic and rapid responses, and they are occurring in sites where we rarely see responses to chemotherapy, such as in the bone.

“There are some important caveats. All these patients had failed previous therapies, either chemotherapy or treatment with Interleukin 2, as well as surgery. However, we know that only 10-30% of patients will respond to standard chemotherapy, so it’s not surprising that our patients had not responded, or have responded and then the cancer has recurred. In our study 64% of patients have had a partial response, but because we are only treating patients with the BRAF mutation, we are cutting out about 40% of melanoma patients who do not have this mutation and whom we know will not respond to this treatment. That is one reason why we are seeing a much higher response than with conventional treatments.

“Also, we don’t know yet how long these responses will last, and we have had patients whose cancer has progressed after initially responding; so we are putting a lot of effort in to studying the patients who do relapse, trying to understand how their tumors have become resistant.

“In addition, one of the main side effects we’ve seen is that some patients develop early, non-melanoma skin cancers such as squamous cell skin cancer. We are very vigilant about this and although they are very easy to cut out, it’s something we are keeping a close eye on.”

Dr Chapman and his colleagues are planning a phase II trial of 90 patients starting at the end of this year. In addition, a large phase III randomized controlled trial involving several hundred patients is planned to start either at the end of this year or beginning of next year involving centers in North America, Europe and Australia.

Dr Chapman said it was too early to be talking about a cure for advanced melanoma, but that this drug had potential. “Most of us think that a drug like this would ultimately be part of the regimen, but that we might need additional drugs with it to complete the cure. Right now we are seeing dramatic responses but it’s too early to say whether we’ve actually cured people because most patients still have evidence of some level of tumor on their skin. I think this is a huge step forward; whether or not it will be sufficient by itself really remains to be seen.”

Clinical trials to support a registration program for product approval are targeted to start shortly. Plexxikon Inc and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

For more information:

• Abstract no: 6 BA. Presidential session IV, Thursday, 9.30-11.15 hrs CEST (Hall)
• Plexxikon, Inc. Berkeley, CA, USA)
• Onco'Zine - The International Cancer Network

Also read these PubMed abstracts:

• Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008 May;6(5):751-9. Epub 2008 May 5.
• Hersey P, Bastholt L, Chiarion-Sileni V, Cinat G, Dummer R, et al. Small molecules and targeted therapies in distant metastatic disease. Ann Oncol. 2009 Aug;20 Suppl 6:vi35-40.

Images courtesy American Society of Clinical oncology (ASCO).

Trastuzumab plus Standard Chemotherapy Provides Unprecedented Survival Benefit for Patients with HER2-positive Advanced Gastric Cancer

A detailed analysis of the Phase III ToGA study, the first randomized Phase III clinical trial investigating the use of trastuzumab (Herceptin) in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive gastric cancer, revealed an unprecedented survival benefit for patients when trastuzumab, a humanized antibody designed to target and block the function of HER2, was added to standard chemotherapy regimen containing capecitabine (Xeloda) or intravenous 5-FU and cisplatin.

The analysis evaluated patient benefit according to the level of HER2 identified in their stomach tumour. Overall survival for patients with high levels of HER2 receiving Herceptin was 16 months on average versus 11.8 months for patients receiving chemotherapy alone.

These results were presented at the joint 15th Congress of the European CanCer Organisation (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO) in Berlin, Germany. They illustrate the importance of an individualized approach to patient care and the opportunity that a targeted medicine may offer.

The rationale for conducting this trial was based on the knowledge that the targeted therapy trastuzumab has demonstrated unprecedented efficacy in the treatment of HER2-positive breast cancer. In addition, the overexpression of HER2 was also observed in stomach cancer.

In the ToGA study, patients were randomized to receive one of the following regimens as their first line of treatment:

• A fluoropyrimidine (capecitabine or intravenous 5-FU) and cisplatin every 3 weeks for 6 cycles. Most patients were receiving Xeloda and cisplatin as chemotherapy
• Trastuzumab 6mg/kg every 3 weeks until disease progression in combination with a fluoropyrimidine and cisplatin which was stopped after a maximum of for 6 cycles

The primary objective of the study was to demonstrate superiority in overall survival of the trastuzumab containing treatment arm compared to the chemotherapy alone arm. The pre-planned interim analysis was triggered by the occurrence of 347 events. Secondary endpoints for the study included progression-free survival, overall response rate, duration of response, safety and quality of life. In the ToGA study, no new or unexpected side effects were observed.

For overall survival, the Hazard Ratio was 0.74 (CI 0.60, 0.91) with a highly significant p-value of p=0.0046 corresponding to a 26% reduction in the risk of death. All patients who were included the study to receive trastuzumab had a median overall survival increase by 2.7 months to 13.8 months. The response rate was increased with trastuzumab from 34.5 % to 47.3%. Patients with tumors exhibiting higher levels of HER2 experienced even greater benefit from the addition of trastuzumab.

“It is now clearly proven that Herceptin prolongs the lives of patients suffering from HER2-positive gastric cancer. As an investigator on this study and a treating physician, it is very rewarding to see a new effective treatment option emerging”, said principle investigator, Professor Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium. “The results of the ToGA study reinforce the need for early and accurate HER2 testing of all advanced gastric cancer patients.”

Based on the significant findings of the ToGA study, Roche has submitted a label extension application with the EU Health Authorities for use of trastuzumab in HER2-positive advanced gastric cancer. Applications for label extension in other regions of the world will follow as soon as possible.

“We are pleased to see the impressive benefit that the targeted therapy Herceptin provides for patients with HER2-positive stomach cancer. That this benefit is even greater in patients with higher levels of HER2demonstrates the significant advances through personalized medicine”, commented William M. Burns, CEO of Roche’s Pharmaceuticals Division, “Herceptin will become the new standard of care and will make an important contribution to helping these patients.”

Stomach cancer is the second most common cause of cancer-related death worldwide with over 1,000,000 new cases diagnosed each year. Stomach cancer is associated with poor prognosis and early diagnosis is challenging because most patients do not show symptoms until the later stages. Around 16% of stomach tumors express high levels of HER2 (IHC 3+ or IHC2+/FISH+).

Pemetrexed First Agent Approved in Europe as Maintenance Therapy for Advanced, Nonsquamous Non-Small Cell Lung Cancer

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has granted approval for the use of pemetrexed for injection (Alimta ®, Eli Lilly and Company) as monotherapy for maintenance treatment of patients with other than predominantly squamous cell histology in locally-advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has not progressed immediately following platinum-based chemotherapy. This approval is based on data that showed pemetrexed improved overall survival in other than predominantly squamous NSCLC patients in the maintenance setting.

Globally, lung cancer is the most common form of cancer and the biggest killer, causing 1.3 million cancer deaths annually. This is more than breast, colon and prostate cancer taken together. About 85 - 90 percent of all lung cancers are non-small cell lung cancer (NSCLC). Survival rates are very poor.

Major disease forms
Non-small cell lung cancer (NSCLC) is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most predominant is squamous cell carcinoma (also known as epidermoid carcinoma) which accounts for 30 - 40% of all NSCLC cases. Formed from round cells that replace damaged cells along the epithelium of the main, lobar or segmental bronchi, this disease is a relatively slow growing carcinoma with a relatively good prognosis. Recurrence rates for resected squamous cell carcinoma are relatively low compared top other types of NSCLC, with distant metastases less common given the same treatment at the same stage.

Also referred to as nonsquamous histology, adenocarcinoma, which account for more than half of all NSCLC diagnoses, usually arises from mucus-producing cells of the lung. Aproximately two-thirds of adenocarcinomas develop in the outer regions of the lung, while the remaining one-third develop centrally. The majority of adenocarcinomas are asymptomatic until they have progressed to an advanced stage. As a consequence, the prognosis is generally worse compared to that of squamous cell carcinoma. On the other hand, once diagnosed, adenocarcinomas generally respond better to treatment than other NSCLC histologies.

Squamous cell carcinoma tends to metastasize in the bone, adrenal glands, liver, small intestines and brain. Because this disease is almost always caused by smoking, occurrence has decreased over the past 30 - 35 years.

Other types of NSCLC include bronchoalveolar carcinoma (BAC), a subclassification of adenocarcinoma with distinct clinical and pathologic properties and large cell carcinoma.

The majority of patients with NSCLC eventually develop metastatic disease or disease that is not a candidate for surgical interventions. this makes them potential candidates for systemic therapies. However, the decision on whether a patient receives therapy, greatly depends upon a number of factors, including the disease stage. In general, the more advanced the disease is, the more likely that a physician will prescribe a drug therapy.

Staging of Lung Cancer
Lung Cancer is often classified according to the American Joint Commitee on Cancer (AJCC) TNM staging system, and has five-tier staging, starting at 0 and rising to the severity of stage IV.

The primary T1 tumor, generally smaller than 3 centimeter, is usually easy to define on computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET).

TNM stage T3 tumors include tumors of any size with direct extension into the chest wall, diaphragm, mediastinal pleura or pericardium. Stage T4 tumors invade the mediastinum, great vessels, trachea, oesophagus and vertebral bodies.

Lung cancer in metastatic stage becomes aggressive. In this stage a therapy to shrink tumour size, stabilize the disease and relieve debilitating symptoms, with minimal toxic effects of the drug is required. Pemetrexed is the most promising molecule in that aspect. The drug provides better survival, progression free time and response and has superior tolerability than other cytotoxic drugs used for the same condition.

Mechanism of action
Pemetrexed is a multitargeted antifolate currently approved for first-line treatment of advanced, other than predominantly squamous NSCLC in combination with a platinum-based chemotherapy, and as a single agent in the second-line setting for advanced, other than predominantly squamous NSCLC patients with recurrent disease. Pemetrexed is chemically similar to folic acid and is in the class ofchenotheray drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).

Improve Overall Survival in a Maintenance Setting
The concept of maintenance therapy represents a paradigm shift in the treatment of advanced, other than predominantly squamous NSCLC.

Traditionally, patients who respond to first-line chemotherapy are monitored until the disease recurs and are then treated with a second-line regimen. In maintenance therapy, rather than halting further treatment until disease progression, patients who respond to a first-line therapy are treated immediately with a maintenance regimen.

"The idea behind ALIMTA as maintenance therapy for nonsquamous, non-small cell lung cancer is to treat patients immediately following their initial course of therapy, in an effort to prolong survival," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader at Lilly. "The study that led to this approval was the first that showed improved overall survival in the maintenance setting for NSCLC. This was also the third trial to show the benefit of tailoring ALIMTA treatment to the nonsquamous NSCLC patient population."

Overall survival data for pemetrexed as a maintenance therapy for NSCLC was presented on May 31, 2009, at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Chandra P Belani M.D.

The trial compared efficacy with respect to overall survival of pemetrexed plus best supportive care versus placebo plus best supportive care in 663 patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based induction chemotherapy. Pemetrexed was not included among the induction regimens studied in the maintenance trial. The trial supported two previous studies looking at the use of histology to tailor treatment for patients with advanced, other than predominantly squamous NSCLC.

Patients in the trial were treated with pemetrexed (500 mg/m2 on day one of each 21-day cycle) plus best supportive care or placebo plus best supportive care. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Pemetrexed was initially approved by the FDA in 2004 for the treatment of mesothelioma, with subsequent approval for second-line treatment of NSCLC.

This latest approval for pemetrexed - the fourth in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on May 29, 2009, and the recent approval by the U.S. Food and Drug Administration (FDA) of pemetrexed for maintenance therapy in advanced, nonsquamous NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Apart from the existing approvals in the EU and U.S. for the use of pemetrexed in the treatment of patients with locally-advanced or metastatic other than predominantly squamous NSCLC, pemetrexed is also approved, in combination with cisplatin, in both the EU and U.S. for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

For more information:

• Official Lilly Physician Resource for pemetrexemed
• Commitee for Medicinal Products for Human Use Post-Authorisation Summary of Positive Opinion for Alimta (EMEA)
• American Cancer Society: Lung Cancer - Non-Small Cell
• C. P. Belani, T. Brodowicz, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). Abstract #CRA8000. 2009 American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA8000).
• C.P. Belani. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC. ASCO 2009 Annual Meeting. Oral presentation (Oral Presentation Chair(s): Jyoti D. Patel, MD; Karen L. Reckamp, MD)
• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (Version 2.2006). Non-Small Cell Lung Cancer.
• Staging of non-small cell lung cancer (NSCLC)
• About the TNM System (Blog)
• American Joint Committee on Cancer: PowerPoint Presentation; Staging Lung Cancer.
• Mayo Clinic: Lung Cancer
• Lung Cancer Alliance

Also read these PubMed abstracts:

• Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C. Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Jul 3. [Epub ahead of print]
• Bobin-Dubigeon C, Amiand MB, Herrenknecht C, Bard JM. Development and validation of an improved liquid chromatography-mass spectrometry method for the determination of pemetrexed in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 21. [Epub ahead of print].
• Belli C, Fennell D, Giovannini M, Gaudino G, Mutti L. Malignant pleural mesothelioma: current treatments and emerging drugs. E xpert Opin Emerg Drugs. 2009 Jun 24. [Epub ahead of print]
• Racanelli AC, Rothbart SB, Heyer CL, Moran RG. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 2009 Jul 1;69(13):5467-74. Epub 2009 Jun 23.
• Vlastos F, Hillas G, Vidal P, Lacomme S, Galateau-Sallé F, et al. Survey and Biological Insights of Pemetrexed-Related Therapeutic Improvement in Mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort. J Thorac Oncol. 2009 Jun 19. [Epub ahead of print]
• Comella P, Chiuri VE, De Cataldis G, Filippelli G, Maiorino L, et al. Gemcitabine combined with either pemetrexed or paclitaxel in the treatment of advanced non-small cell lung cancer A randomized phase II SICOG trial. Lung Cancer. 2009 Jun 20. [Epub ahead of print]
• Scagliotti GV, Ceppi P, Capelletto E, Novello S. Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. Review.

How to help your patients:

• Encourage your patients to have an open, honest talk with you. Tell them that they should feel free to ask any question that’s on their mind, no matter how small it might seem. Also, encourage your patients to talk to other healthcare professionals, including nurses, social workers, and other members of the healthcare team.

Patient resources:

• ASCO’s Guideline on Adjuvant Treatment for Lung Cancer

Images courtesy American Society of Clinical oncology (ASCO)

Escalated Dose-Intensified Combined Modality Treatment Shows Survival Benefit In Patients With Early Unfavourable Hodgekin Lymphoma

With more than 7,500 participants from more than 100 European and non-European countries in attendance, the 14th congress of the European Hematology Association (EHA), which was held in Berlin, Germany, from June 4 – 7, 2009, proved record-breaking. The delegates gathered in Berlin to share the most recent developments in hematological research and improvements in care.

The program included sessions on clinical and laboratory hematology and covered all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.

The program featured a session, presented by Prof. Peter Borchmann on behalf of the German Hodgkin Study Group / GHSG (abstract number 0553) discussing an analysis of Dose-Intensified Combined Modality Treatment In Patients With Early Unfavourable Hodgekin Lymphoma (HL).

As a result of intensified medical research, Hodgkin's lymphoma has become one of the most curable tumors in adults. Today, about 80% - 90% of patients experience long-term disease free survival (DFS). This is mainly the result of numerous large clinical trials initiated by the German Hodgkin Study Group and other organizations, taking place since the late 1970's, using risk-adapted, highly effective therapy modalities. From the late '70s nearly 15,000 patients have been randomized and treated in these prospectively randomized trials.

Risk Groups
Patients with Hodgkin lymphoma are divided in three risk groups according to the initial staging and additional clinical risk factors: early favorable, early unfavorable and advanced-stage risk groups.

Abstract 0553 (Interim Analysis of the GHSG HD14 Trial for Patients With Early Unfavourable HL) compared the results of the arms of the GHSG HD14 trial. The rational of this trial was to improve the prognosis of patients with early unfavorable disease by comparing the old standard treatment, 4 courses of ABVD (adriamycin, bleomycin, vinblastine, and dacarbacine) followed by localized radiotherapy (30 Gy IF-RT), with a more intensive chemotherapy regimen consisting of 2 cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by 2 cycles of ABVD and the same radiotherapy as in the standard arm.

Treatment-associated toxicities
A previous GHSG trial (GHSG HD11) compared 4 cycles of ABVD with BEACOPP, followed by either 30 or 20 Gy IF-RT. This trial showed no difference with respect to outcomes, and despite excellent initial remission rates, approximately 15% of patients with early unfavorable-stage HL relapsed within 5 years and another 5% suffered from progressive disease. Nevertheless, these good results of the GHSG trials are threatened by treatment-associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies.

Improving trial results
The GHSG HD14 trial showed a significantly better outcome in terms of progression-free survival in the more intensive escalated BEACOPP regimen than the standard regimen of 4 cycles of ABVD in patients with early unfavorable Hodgkin's lymphoma (HL).
The study, conducted by the German Hodgkin Study Group (GHSG), included 1645 patients in 346 centres. These patients had early unfavorable Hodgkin's lymphoma, clinical stage 1 or 2 and risk factors, including large mediastinal mass, extranodal disease, high erythrocyte sedimentation rate, and 3 or more areas affected.

Interim analysis
After the third interim analysis with 1127 patients, researchers decided to terminate the GHSD HD14 trial early because of the significantly better outcome for patients treated with BEACOPP compared to ABVD. The interim results showed that progression free survival (PFS) was significantly better for patients treated with the hybrid regimen than for patients treated with 4 courses of ABVD. After 3 years, progression-free survival was observed in 97% of patients in the escalated BEACOPP group and 91% in the ABVD group.

Furthermore, the interim analysis showed freedom from treatment failure to be 95% in the escalated BEACOPP group versus 91% in the ABVD group. Overall, there were more patients with progressive disease, relapse and a higher mortality in those receiving 4 cycles of ABVD. These results prompted the GHSG to adopt a regimen of two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy radiotherapy as the new standard treatment for patients with early unfavorable Hodgkin's lymphoma.

Escalated BEACOPP, compared to standard BEACOPP, uses a higher doses of etoposide (200 vs 100 mg/m2), doxorubicin (35 vs 25 mg/m2), cyclophosphamide (1200 vs 650 mg/m2), with added granulocyte colony-stimulating factor support. Combined with local irradiation, the escalated regimen showed superior disease control compared with ABVD. Patients experienced more hematological adverse events in the escalated BEACOPP group compared to the ABVD group. This included leukopenia (22% vs , including 81%), thrombocytopenia (<1%>

Predisposition to Myeloproliferative Neoplasms
An unrelated presentation by Prof. Nick Cross, Salisbury, United Kingdom, discussed research aimed to understand what causes a group of related conditions known collectively as myeloproliferative neoplasms (abstract number 0555).

Researchers have found a common genetic 'signature' that predisposes to these disorders. The predisposition is relatively subtle and so it cannot by itself be used to predict whether anyone will develop disease or not, but it is an important step towards understanding why some people get cancer and why others do not. In the future it is possible that the abnormality we have found might be combined with other genetic and environmental risk factors to enable much better predictions of disease susceptibility to be made.

Myeloproliferative neoplasms or MPNs are conditions of the blood that are related to leukemia but in effect they are a very mild form that resembles the first steps towards cancer. They are characterised by the overproduction of red and white blood cells, which increases the risk of strokes and heart attacks. Many cases of MPDs are caused by a mutation in a gene called JAK2. When the JAK2 gene has mutated, it sends abnormal messages to the blood stem cells to produce more and more blood cells.

Scientists have found that a particular region of chromosome 9 that carries the JAK2 gene is predisposed to acquiring mutations, but only in individuals with a particular genetic makeup. It is likely that this finding will lead to a much better understanding of how the JAK2 gene mutations happen and why they lead to an increased risk of someone developing an MPD.

The study, carried out at the Wessex Regional Genetics Laboratory in Salisbury and the University of Southampton, has proved that people carrying this mutation-prone region of DNA on chromosome 9 that includes the JAK2 gene have triple the risk of developing an MPD. The chromosome 9 variant is present in 40% of the population in the United Kingdom but only 1 in 20,000 people develop an MPD each year. Nonetheless, the new research has confirmed that the inheritance of this genetic variant can contribute to inherited susceptibility to develop an MPD.The study found that the link was especially strong in polycythaemia vera (PV), one of the main three MPDs.

Professor Nick Cross, from the University of Southampton (University RoadSouthampton SO17 1BJ, United Kingdom, Tel. +44 (0)23 8059 5000, Fax +44 (0)23 8059 3131) who led the research team, said: “This research provides strong evidence that at least half of the cases of PV diagnosed each year are linked to an inherited genetic variant on chromosome 9. Whilst this risk is still very small it nonetheless confirms that individual susceptibility to acquiring cancer-causing mutations is linked to genetic inheritance. Now that we have this evidence we can carry out studies to determine exactly how the variant contributes to this risk.”

Dr Shabih Syed, Scientific Director at UK-based Leukaemia Research who sponsored the reserach, adds: “This is a very important step forward in our knowledge of the causes of myeloproliferative disorders. It helps us to understand why some people might be predisposed to acquiring genetic mutations that lead to cancers.”

For more information:

• 14th Congress of the Europan Hematology Association (EHA): Presentations.
• Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group Journal of Clinical Oncology. 1998 Vol 16, 3810-3821.
• Patrice Carde P, Cavalli F, Diehl V, Franklin J. Is escalated BEACOPP a standard therapy for advanced Hodgkin's disease? The Hematology Journal (2000) 1, 282 ± 290.
• Jones AV, Chase A, Silver RT, Oscier D, Zoi K, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nature Genetics 41, 446 - 449 (2009) Published online: 15 March 2009

Read these PubMed abstracts:

• Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5
• Bosetti C, Levi F, Ferlay J, Lucchini F, Negri E, La Vecchia C. The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe. Ann Oncol. 2009 Apr;20(4):767-74. Epub 2008 Dec 16.
• Eich HT, Müller RP, Engenhart-Cabillic R, Lukas P, Schmidberger H, et al. Involved-node radiotherapy in early-stage Hodgkin's lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG). Strahlenther Onkol. 2008 Aug;184(8):406-10.
• Ben Arush MW, Shafat I, Ben Barak A, Shalom RB, Vlodavsky E, Ilan N. Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study. Pediatr Hematol Oncol. 2009 Jun;26(4):157-64.
• Gobbi PG, Valentino F, Danova M, Morabito F, Rovati B, et al. Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma. Oncol Rep. 2009 Apr;21(4):1029-35.
• Wood AD, Chen E, Donaldson IJ, Hattangadi S, Burke KA, et al. Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling. Blood. 2009 Jul 1. [Epub ahead of print].
• Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009 May 26. [Epub ahead of print]

What to tell your patients:

• US National Cancer Institute: Definition Hodgkin Lymphoma
• Mayo Clinic: Definition Hodgkin Lymphoma
• WikiPedia: Definition Hodgkin Lymphoma
• LymphomaInfo.Net: Definition Hodgkin Lymphoma
• The Leukemia & Lymphoma Society (USA): Definition Hodgekin Lymphoma
• SteadyHealth.com: Definition of Myeloproliferative Neoplasms.
• UptoDate for Patients: Overview of Myeloproliferative Neoplasms.

Illustrations courtesy of the European Hematology Association.

Test Identifies Low-risk Subgroup in HER2-positive Breast Cancer

HER2, human epidermal growth factor receptor 2, is a protein found on the surface of breast cancer cells. When functioning normally, HER2 is a key component in regulating cell growth. However, when altered, extra HER2 protein receptors may be produced.

This overexpression of HER2 is considered a negative prognostic factor and associated with increased cell growth and reproduction, often resulting in a more aggressive form of breast cancer with increased disease recurrence and worse prognosis. Studies show that HER2/neu is overexpressed in approximately 15-20% of invasive breast cancers. Because HER2+ tumors tend to grow and spread more quickly than tumors that are not HER2+, accurate and timely diagnostic procedures are crucial.

High Risk
There are a number of different kinds of breast cancer and each is treated differently. Patients with Her2+ breast cancer are generally classified as high risk. As a result, current treatment guidelines recommend adjuvant trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990, co-marketed by F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) and chemotherapy as the best treatment option for all HER2-positive breast cancer patients at high risk of relapse, increasing their chance of living longer. At the same time, results from the HERA-trial (HERceptin Adjuvant), a randomized, two-arm, open label study of the efficacy, safety and tolerability of trastuzumab compared to observation in women who have completed standard adjuvant treatment of HER2 positive primary breast cancer, showed that 74% of patients remained distant recurrence-free at 3 years without trastuzumab.

A highly sensitive prognostic tool
Dr. Michael Knauer, MD, from the Netherlands Cancer Institute presented the results from a study investigating the benefits of a highly sensitive diagnostic assay during the 2008 San Antonio Breast Cancer Symposium (SABCS). In the study, researchers used MammaPrint®, (Agendia BV, Amsterdam Science Park, Kruislaan 406, NL-1098 SM Amsterdam, The Netherlands), a prognostic genomic test developed with micro-array technology that has the potential to greatly improve risk assessment and treatment decision making for early breast cancer, to identify a subgroup of patients with low risk and favorable outcome. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine. This prognostic signature of genetic 'fingerprint' is validated as an independent prognostic indicator for patients with up to three positive lymph nodes.

Knauer showed that the highly accurate MammaPrint was able to differentiate between patients at high risk for recurrence and a low risk subgroup of HER2+ patients. The assay helped uncover a substantial group of traditionally miscategorized low risk HER2+ patients.

Study results
In the study population of 169 HER2+ patients, Mammaprint, the first ‘in vitro diagnostic multivariate index assay’ (IVDMIA) cleared by the U.S. Food and Drug Administration (FDA) designed to identify patients with early metastasis, classified 16 percent of patients as having a good prognosis signature with a 10-year distant disease-free survival (DDFS) of 89 percent, even in the absence of (neo)adjuvant trastuzumab and chemotherapy, compared to 84 percent of patients classified as having a poor prognosis signature with a DDFS of 64 percent. Additionally, in a subgroup of highly endocrine responsive HER2/neu positive patients, MammaPrint low risk patients had no relapse.

All 169 patients with HER2-positive breast cancer were selected from a pooled dataset of 1280 patients with known HER2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.

The strength of the assay is underscored by the 70 gene panel unique to the test and a resulting gene profile that covers all molecular pathways associated with breast cancer.

Personalized medicine
MammaPrint accurately identified a subgroup of patients with a good clinical outcome in HER2+ early breast cancer. These patients will be further studied in the ongoing MINDACT-trial (EORTC 10041/ BIG 3-04), a multicentre, prospective, phase III trial coordinated by the EORTC (European Organisation for Research and Treatment of Cancer) and run under the BIG and TRANSBIG network, which will accrue 6000 node-negative patients designed to determine the prospects of withholding chemotherapy and/or trastuzumab in HER2+, MammaPrint low risk patients.

This study compares MammaPrint to traditional clinical-pathological methods to assess the risk of breast cancer recurring in women with lymph node negative disease. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the traditional selection for adjuvant chemotherapy is far from accurate.

Based on the initial results with MammaPrint, it is hypothesized that using the genomic test in addition to traditional methods will result in more accurate risk assessment. It is expected that 10% to 20% of patients with node negative breast cancer will, in the future, safely be able to avoid chemotherapy and its potential side effects.

The current trend in research cancer is to develop ways of individualizing breast cancer treatment. This goal toward ‘personalized medicine’ requires better identification of type of systemic treatment and better identification of patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy.

MammaPrint may be one of the tools helping to realize these goals.

For more information, read:

• Knauer M, Cardoso F, Mook S. et al. Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature. SABCS, Saturday, December 13, 2008 - 7:00 AM Poster Session IV: Late Acceptances (7:00AM-9:00AM). Abstract 4171.

Watch:

• Options for HER2+ Breast Cancer (video).

Also review PubMed abstracts:

• Haibe-Kains B, Desmedt C, Piette F, et al. Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics. 2008 Aug 21;9:394. Free Full Text Article (PDF);
• Mook S, Schmidt MK, Viale G, et al. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2008 Jul 27. [Epub ahead of print];
• Cardoso F, Van't Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008 Feb 10;26(5):729-35.
• Marchionni L, Wilson RF, Marinopoulos SS et al. Impact of gene expression profiling tests on breast cancer outcomes. Evid Rep Technol Assess (Full Rep). 2007 Dec;(160):1-105;
• Mook S, Van't Veer LJ, Rutgers EJ et al. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 2007 May-Jun;4(3):147-55;
• Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002 Dec 19;347(25):1999-2009.

More information:

• EORTC – The Mindact brochure.
• EORTC – The Mindsact website.
• Clinical trial: Trastuzumab in Treating Women With Primary Breast Cancer (EORTC, NCIC, BIG); Phase III.

Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.

Triple-negative breast cancer: risk factors to potential targets

Breast cancer is not one single disease, but knows different subgroups originating in the breast. Triple-negative breast cancer, one of these subgroups, has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, of the basal-like subtype and refers to a specific subtype of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu.

Depending on its stage of diagnosis, triple-negative breast cancer can be extremely aggressive and is more likely to recur and metastasize than other subtypes of breast cancer. It typically is responsive to chemotherapy, although it can be more difficult to treat because it is unresponsive to the most effective receptor targeted treatments

Late last year, researchers from the Indiana University Department of Medicine, Melvin and Bren Simon Cancer Center, Indianapolis, led by Dr. Bryan Paul Schneider MD, reported details of a new studies and findings in the area of breast cancer risk factors. The results were published in the journal Clinical Cancer Research.

Commenting on the research results, Schneider explained: ‘We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms.’

The established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay.

‘Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets,' Schneider said.

For more information, read:

• Schneider BP, Winer EP, Foulkes WD, Garber J, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 2008 Dec 15;14(24):8010-8
• Click here to contact the author.

Also read PubMed abstracts:

• Liu ZB, Liu GY, Yang WT, Di GH, et al. Triple-negative breast cancer types exhibit a distinct poor clinical characteristic in lymph node-negative Chinese patients Oncol Rep. 2008 Oct;20(4):987-94.
• Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008 Jan;52(1):108-18. Review.
• Sasa M, Bando Y, Takahashi M, Hirose T, Nagao T Screening for basal marker expression is necessary for decision of therapeutic strategy for triple-negative breast cancer. J Surg Oncol. 2008 Jan 1;97(1):30-4.
• Rakha EA, El-Sayed ME, Green AR, Lee AH, et al. Prognostic markers in triple-negative breast cancer. Cancer. 2007 Jan 1;109(1):25-32

See online video:

• CNN's Dr. Sanjay Gupta looks into tripple-negative breast cancer, an aggressive and drug-resistant form of cancer affecting black women.
• About tripple-negative breast cancer on Truveo.
  

Preliminary Study Results Demonstrate that Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of zoledronic acid, a bisphosphonate used for the treatment of bone metastases in advanced breast cancer, suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Bisphosphonates may therefore offer an (neo)adjuvant therapeutic strategy of potential importance.

“Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,” said Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom. Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, which is evaluating the effect of zoledronic acid on breast cancer.

Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be 'practice changing,' Coleman said. The AZURE trial, a prospective, randomized, open label, clinical trial , enrolled 3,360 women with stage II/III breast cancer to determine whether treatment with zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve disease outcomes. Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group. After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8% in the chemotherapy arm and 10.9% in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9% in the chemotherapy group and 65.3% in the combination group. “Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,” said Coleman.

For more information

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE, The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101; SABCS, December 10-14, 2008.