Should Herceptin Be Biven to All Patients with Breast Cancer - Essay Example

Discussion on: “Should Herceptin be given to All Patients with Breast Cancer?” The soaring rates of breast cancer all over the world have instigated researchers to search for novel anti-cancer drugs which not only increase the chances of survival of the patient but also increase the progression time, decrease relapse chances and prevent cytotoxicity of normal tissue. Such a search has led to the invention of Trastuzumab or herceptin. An effective anti-cancer agent, regular recommendation of this drug is surrounded by many controversies because of its high cost, decreased availability, potential life threatening complications and effectiveness only in some patients. In this article, the appropriateness of recommending herceptin routinely for anti-cancer therapy of breast cancer shall be explored through review of literature pertaining to this issue. Herceptin is a recombinant humanized monoclonal antibody that interferes with the receptor HER2 (human epidermal growth factor receptor 2) which is located in the cell membrane and participates in the regulation of cell growth and other aspects of functioning of the cells which are exaggerated or amplified in cancer like adhesion, survival, migration and differentiation (NICE, 2002). The receptors act by communicating signals between inside and outside the cells by turning the genes on or off. In some cancers like the breast cancer, the HER2 receptors are defective and in the on position, causing uncontrollable growth of the breast cancer cells. Thus, it has been thought that targeting HER2 receptors can control the growth and development of breast cancer cells. HER-2 is overexpressed in 20-25 percent of breast cancers which are invasive in nature. It is associated with reduced survival rates and aggressive phenotype (Nahta and Esteva, 2003). The importance of herceptin comes in the wake of decrease in survival rates by 50 percent in those with amplified HER2 receptors (Nahta and Esteva, 2003). It is important to note that in many cases, breast cancer in presented in advanced stages and many of the breast cancers which have been diagnosed in early stages turn metastatic. According to NICE (2002), 16-20 percent of women presenting with breast cancer are in advanced stage and 50 percent of those who have been diagnosed in early stages are likely to develop metastatic breast cancer. Average survival period after development of metastatic cancer is 18- 24 months (NICE, 2002). Also, in some breast tumors, there is amplification of HER2 which contributes to overexpression of HER2 protein which is associated with poorer prognosis (NICE, 2002). The primary goal of any novel anti-cancer therapy is to target specific molecular lesions found in the tumor cells directly, hoping cure of cancer and reduce cytotoxicity of adjacent normal cells. Through advances in molecular biology and immunohistopathology techniques, it has been possible to identify tumor markers which help in the prediction of prognosis and therapeutic response (Nahta and Esteva, 2003). Currently, the first line systemic therapy for those in advanced or metastatic breast cancer with negative estrogen receptor is chemotherapy with either anthracycline-containing regimen or a combination of methotrexate, fluorouracil and cyclophosphamide (NICE, 2002). In those with estrogen receptor positivity status, hormone manipulation therapy is the first line treatment. NICE (2002) recommends that paclitaxel and docetaxel must be instituted in patients with advanced breast cancer in whom initial chemotherapeutic administration has either failed or is considered inappropriate. According to Nahta and Esteva (2003), there are several reasons as to why it has become important to target HER-2 in breast cancer treatment. 1. The levels of HER2 correlate strongly with the pathophysiology and pathogenesis of breast cancer. 2. The levels also correlate with the prognosis of the disease. 3. In cancer cells the level of HER2 with gene amplification is much more than what is seen in normal breast tissue, thus reducing the chances of cytotoxicity of normal breast tissue during administration of treatment with anti HER2 drug herceptin. 4. The receptors are present in very high proportions in the cancer cells and tumor tissues with high expression of these receptors show intense and uniform staining of the tissue immunohistochemically indicating that herceptin will target most of the cancer cells when administered intravenously. 5. the over expression of the receptors is found in both primary tumor tissue and metastatic tissue indicating that herceptin may be effective in all disease states (Nahta and Esteva, 2003). Research in the form of trials have shown that herceptin is a safe medication with reliable pharmacokinetics (Nahta and Esteva, 2003). The response rates to monotherapy are 12-34 percent (Nahta and Esteva, 2003). The response rates are dependent on prior treatment received and the HER2 status. According to Slamon et al (cited in Nahta and Esteva, 2003), combination of herceptin with anthrocycline or paclitaxel has more benefits in terms of longer time to progress, higher response rates and imporved survival rates (Nahta and Esteva, 2003). However, the combination of herceptin with anthrocycline is much avoided because of potential cyclotoxicity. Other chemotherapeutic agents which may be clubbed with herceptin are cisplatin, docetaxel, gemcitabine and vinorelbine (Nahta and Esteva, 2003). Combination sin the phase-3 trial which have found to be beneficial are herceptin with palitaxel and carbiplatin and herceptin with docetaxel and carboplatin. Currently, the optimum duration of herceptin therapy has not yet been ascertained (Nahta and Esteva, 2003). There is not much literature to support the benefits of herceptin therapy in early stages of breast cancer and hence the drug is recommended only in advanced or late stages when other therapies have failed. Herceptin is licensed for use in UK mainly for 2 indications in patients with metastatic cancer and overexpression of HER2 (NICE, 2002). One is for the treatment of metastatic cancer who have not received chemotherapy and in whom it is inappropriate to institute anthracycline. In this situation, it has been recommended to use herceptin with paclitaxel. The second indication is in those with metastatic cancer and who have received atleast 2 chemotherapeutic regimens which have failed. Also, the therapy should have contained anthracycline and a taxane unless they are inappropriate to be instituted. In those with estrogen receptor positive status, appropriate hormonal therapy must have been tried. In these situations, herceptin is recommended to be instituted as monotherapy (NICE, 2002). Herceptin is administered through intravenous routes. The initial loading dose is 4mg per kg body weight, on top of which the patients should be given 2 mg per kg body weight of medication every week until disease progression (NICE, 2002). Herceptin is associated with many adverse reactions, the most important of which are cardiac toxicity (Seidman, Hudis, Pierri, et al, 2002). The effect is worst when given in combination with anthracycline and cyclophosphamide (27%). When given with paclitaxel the risk is only 13 percent and when given alone, it is 3-7 percent (Seidman et al, 2002). Thus, it is imperative that herceptin must be initiated only after cardiac screening with echocardiography. Other side effects include intolerance and risk of cardiomyopathy. Treatment with herceptin is very costly and hence many public health funding organizations question the need for this therapy in the wake of perceived poor prognosis of advanced breast cancer. It has been estimated that a full course of treatment will cost about 70,000 US dollars (Fleck, 2006). In Australia, the cost is 50,000 A dollars. In the United Kingdom, the cost of treatment for one year has been estimated to be 20,000 pounds (BBC News, 12th April, 2006). The famous The Herceptin Judgement of 2006 could cost the National Health Service about 100 million pounds a year (BBC News, 2006). According to Nahta and Esteva (2003), herceptin combination with other chemotherapeutic agents increases the rates of response to treatment, increases the time of progression and increases survival rates by 2 times. The authors also opined that majority of cancer patients who have initially responded to the drug are likely to begin to progress again within just one year. From the above discussion, it is evident that not all breast cancers have increase in the HER2 receptor amplification status and thus targeting this receptor in all patients with breast cancer is inappropriate. There is not much evidence to support the usefulness of herceptin therapy in early breast cancer and most of the trials have been on advanced and metastatic cancer states. Thus, it is imperative that this drug is recommended only in advanced malignancy. Also, due to potential toxicity, moderate response rate and high cost of treatment, this drug is approved to be used only alone or with pacitaxel, only after appropriate and established first line therapies have failed. Thus, it can be said that herceptin should not be given to all patients with breast cancer. References BBC News. (2006). Q&A: The Herceptin judgement. 12th April, 2006. Retrieved on 16th November 2009 from http://news.bbc.co.uk/2/hi/health/4684852.stm Fleck L (2006). The costs of caring: Who pays? Who profits? Who panders?". Hastings Cent Rep., 36 (3), 13–7. National Institute foe Clinical Excellence (2002). Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Retrieved on 16th November 2009 from http://www.nice.org.uk/nicemedia/pdf/advancedbreastcancerno34PDF.pdf Nahta, R. and Esteva, F.J. (2003). HER-2-Targeted Therapy – Lessons Learned and Future Directions. Clinical Cancer Research, 9, 5078 – 5048 Seidman, A., Hudis, C., Pierri, M.K., et al. (2002). Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience. Journal of Clinical Oncology, 20, 1215–1221. Read More