Importance of Prospective Randomized Controlled Trials - Essay Example

Importance of prospective randomized controlled trials in relation to make decisions on radiation therapy for cancer patients. In medical science randomized controlled trials are known to provide the most reliable information, specially related to the efficacy of treatments. However due to aggressive nature of the cancer treatments ethical issues are also common. This encourages investigators to involve in observational studies that are ethically sound but produce less reliable information due to compounding factors and possible bias. This discussion paper emphasizes the importance of randomized controlled trials in deciding radiation therapy options and articulating the information for successful clinical trials addressing the ethical issues. Introduction Randomised controlled trials are expected to provide most reliable results for medical treatments. However due to its complexity and ethical issues researchers make ways to improve observational and retrospective studies for reliable findings. Radiation therapy is one of the main and routinely performed treatments in the treatment regime for cancer. It is generally administrated to reduce the size of the tumor and shrink it before the surgery and to destroy any remaining malignant cells after surgery. Radiation therapy is also used to control metastasis and reduce the pain. However the requirement of the radiation therapy is different in different cancers to get the optimal outcome. As an example Internal radiation or brachytherapy is more effective and convenient in cervical and prostate cancers than conventional external radiation therapy1 Similar to that administration methods, dose, treatment duration and after care differ from patient to patient based on the stage of cancer, age of the patient, tumor size, health of the patient, location, type etc. Although radiation treatment options for some cancers are well established still there is a wide gap to be fulfilled by research. Both observational (longitudinal or follow-up) studies and randomized controlled trials are conducted to find out the optimal radiation therapy practices and long term effects such as survival rates and quality of life and cumulative effect when combined with other treatments. However randomized controlled trials may help to identify the most appropriate radiation therapy method for optimal result than other research methods. Many examples can be shown in the literature. The usual treatment for Nasopharyngeal carcinoma was radiotherapy with the maximum survival rate of 60%. Chemotherapy was not administrated due to lack of evidence of observational studies. The US Intergroup Trial 00-99 was the first randomized study with tested combination effect of radiation therapy and chemotherapy for patients with Nasopharyngeal cancer. Combined treatment increased survival rate by 25% than the patients who received only radiation therapy. The objective of this discussion paper is to evaluate randomized controlled trials over observational studies in relation to establish optimal treatment criteria for radiation therapy and to find out how to address the ethical issues. TYPES OF RADIATION THERAPY Proposals for randomisation methods In a way observational or follow-up studies are easy to carry out as it does not need restrictions and debatable experimental treatments. Therefore ethical issues are also less complex. They are more suitable to find out the long-term impact of the treatment such as disease free survival rate, recurrence rate, disability rate etc. However a large number of participants is required to be recruited and usually take long time to obtain an outcome. The main problem arises in observational studies is higher chance of being influenced by the compounding factors which are usually cannot be controlled in such setting. Researches engage in observational studies often mentioned about the possibility of masking of the actual impact of the radiation therapy due to compounding factors although they have taken all possible measures to adjustment. The other problem is reliability of data and selection biasness. Not like randomized trials, in observational studies data are usually collected via self reporting (sending back questionnaires via post) and medical records. But in randomized trials , since number of participants are low, direct methods such as x- rays, MRI, Blood tests, and clinical examinations are deployed. Those direct methods are more reliable and uniform. Self reported progress more likely to be self perceived than the factual. As an example self reporting of pain after radiation therapy has a higher possibility of subject biasness whereas direct biochemical methods (measuring of inflammatory bio markers etc.) may provide unbiased results. Selection biasness is also possible in observational studies as the selected sample has a higher chance to be deviated from the general representation of the society (missing some groups or over representation). A recent research has identified that there are about 20 morphologically distinct subtypes of breast cancers with various molecular, biochemical and prognoses levels.The authors predict difference in response to treatment and further suggested clinical trials. Two retrospective studies published in the Journal of Clinical Oncology showed that prostate cancer patients who have taken statins during there treatment (time of the surgery) period have 30% reduction in biochemical recurrence than that of the prostate cancer patient who did not take statins at the time of the surgery. The protective effect is statistically significant. However the authors suggested possible selection biasness and recommended randomized controlled trials for confirmation.  In 2009 at the annual meeting of the American Urological Association(AUA), AUA spokesperson J. Brantley had emphazide the importance of RCT to decide on treatments.by saying "From here forward, we have to put more emphasis on well-designed clinical trials” Randomize trials provide chance to test the effect of different doses (treatment level) which may help to identify the most effective dose. Ethical considerations for randomization Randomized trials required subjects to undergo different experimental treatments which may have not been fully studies and sometime have a potential for adverse effects. Specially, treatments of cancer are as aggressive as the disease. All of the conventional treatments have significant undesirable side effects such as damaging to healthy body tissue and vulnerable for other systemic disorders. Moreover lower doses may be ineffective in controlling the disease while producing adverse effects. Further more delaying for treatments (due to participate in trials) can be life threatening specially in patients with past spreading cancers. Therefore trials on cancer treatments gain more ethical attention and the same reason encourages researchers to conduct prospective or cross sectional studies than controlled trials. Degree of uncertainty or unpredictability of the outcome is one of the main ethical considerations for the approval. A group of scientists widely reviewed the ethical issues in randomized control trials and published a guide to overcome ethical issues. They have intensely compared different research methods and elaborated the importance of conducting randomized trials to draw conclusions in medical field. There are adequate evidence for randomized trials that had been keenly planned to overcome ethical issues and finally achieve the objectives. In those studies investigators had reduce the degree of uncertainty by analyzing related literature extensively and justifying the benefit over risk for the participant as well as the society. Test treatments were selected based on the satisfactory assumptions derived by the literature. Following are recommended to minimize the ethical considerations. • Providing a strong justification for the required research (benefit over risk) • Patients should not lose out in prospect by taking part in a trial. If the study uses generally available treatments patients benefit. If treatments are new make sure that the expected outcome is higher or at least equal to the conventional treatments. • Patients must be given as much information to understand their role in the study. • Patients are least alarmed and understand the issues most clearly when they have encountered the concept of comparative trials before. • Clinical trials should start early in the life of a new treatment. Optimal approach to randomization Many types of randomization methods are employed in research including, simple randomization, randomizes blocked designs, crossover studies, double blind studies and randomized follow-up studies where subjects participated in a randomized controlled trial are further observed for extended period. As these is a vast difference between cancers, there is no generally accepted research design for radiation therapy. Researches have to be designed accordingly towards most accurate findings. However the following recommendations can be considered. Respect the ethical aspects Eliminate all possible biasness by carefully manipulating the research design The degree of uncertainty should be reduced as much as possible by extensively studying the previous literature and through designing. Effect of the known and suspected compounding factors should be avoided either by research design or statistical modeling. (if possible double blind placebo controlled or blocked designs are appropriate) From the above cross over studies are generally not appropriate for radiation therapy since such a treatment with unfavorable side effects cannot be repeated without a known benefit and wash-out is not possible between treatments. Double blind placebo control trails can be tested for the patients with cancers that are spreading slowly and if the trial period is short. Any effective conventional treatment should not be delayed for controls to test a new treatment. Instead subjects can be treated with combine treatment (conventional and new) if risk of combine therapy is uncomplicated. Randomized blocked designs can be modulated to test different treatment methods such as internal and external radiation therapy. Zelens design (getting consent to participate in placebo or treatment group after randomization) and blinding (patient is unaware whether they are given placebo or treatment) can be used to address ethical issues in critical situations such as resentful demoralization and Hawthorne effect. Accuracy of the results from randomised trials In medical research RCT known to have the highest accuracy when compared to observational and other research methods. There are adequate instances that conventional aggressive cancer treatments decided based on the observational studies later have changed to less aggressive and similar or more effective treatments due to the findings of the clinical trials. For many years treatment for the Colorectal Liver Metastases was aggressive treatment combination of liver resection, chemotherapy and radiotherapy however the survival rate was low. The effect of pre-operative chemotherapy was evaluated later by Nordlinger et al using a well designed randomized controlled trial participating 364 patients. Pre-operative chemotherapy provided high survival rate proposing a change to the treatment order. Another randomized clinical follow-up trial conducted between 1979-1984 found there is no significant benefit on relapse rate and survival rate from radiation therapy given to patients in Stage II and III Renal Adenocarcinoma though it was the common practice at the time due to lack of evidence. It was also found high doses of radiation exposed by the patient led to develop lot of unfavorable complications without getting any health benefit. Limitations In addition to ethical consideration randomized controlled trials encounter problems including difficulty of finding participants in rare type of cancers and highly spread cancers. In these cases observational studies are the next best alternative. Conclusion Randomized controlled trials provide the most reliable and detailed information about the efficacy of medical treatments which cannot be fulfilled by observational studies. Although Radiation therapy provides adverse side effects making ethical issues, investigators should not be discouraged to conduct clinical trials considering the importance and possibility to address most of the ethical concerns. References 1. Janet M. Torpy; Alison Burke; Richard M. Glass, Radiation Therapy 2005;294(10):1296 (doi:10.1001/jama.294.10.1296) JAMA Ackermann TF. Medical research, society and health care ethics. In: Gillon R, editor. Principles of health care ethics. Chichester: Wiley, 1994:873–84. Antman K. A comparison of randomized vs concurrent controls. Proceedings of the American Association of Cancer Research 1983;24:146. Baum M. The ethics of clinical research. In: Byrne P, editor. Ethics and law in health care 1. Chichester:Wiley, 1990. Chalmers I, Chalmers TC. Randomisation and patient choice. Lancet 1994;344:892–3. Cassileth BP, Knuiman MW, Abeloff MD, Falkson G, Ezdinli EZ, Mehta CR. Anxiety levels in patients randomized to adjuvant therapy vs observation for early breast cancer. Journal of Clinical Oncology 1986;4:972–4. Freedman N. A response to a purported ethical difficulty with randomised clinical trials involving cancer patient. Journal of Clinical Ethics 1992;3(3):231–4. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. British Journal of Cancer 1976;34:585–612. Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC,Hewison J,Thornton J. Ethical issues in the design and conduct of randomised controlled trials. Health Technol Assessment 1998; 2(15). Stufken, J. (1996). "Optimal Crossover Designs". in Ghosh, S. and Rao, C. R.. Design and Analysis of Experiments. Handbook of Statistics. 13. North-Holland. pp. 63--90. Heckman, J. (1979) Sample selection bias as a specification error. Econometrica, 47, 153–61. Assimilation bias" is another term used for biased interpretation of evidence. (Risen & Gilovich 2007, p. 113) Sackett, D.L. Bias in analytic research. Journal of Chronic Diseases, 1979; 32: 51-63. Introduction to the Special Issue Dedicated to Marvin Zelen , Lifetime Data Analysis, Issue Volume 10, Number 4 / December, 2004. DOI 10.1007/s10985-004-4769-7, Pages 321-323 Jeffrey A. Sonnenfeld, "Shedding Light on the Hawthorne Studies," Journal of Occupational Behavior, Vol. 6, 1985, p. 125.  Synchronous Colorectal Liver Metastases: Triumph Of Prospective Randomized Trials Over Observational Bias Leads To Paradigm Shift Vijay P. Khatri, MBChB, FACS Ann Surg Oncol. 2009 July; 16(7): 1762–1764. Published online 2009 March 17. doi: 10.1245/s10434-009-0369-9 7. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-16.  A Randomized Trial of Postoperative Radiotherapy Versus Observation in Stage II and III Renal Adenocarcinoma A Study by the Copenhagen Renal Cancer Study Group 1987, Vol. 21, No. 4 , Pages 285-289 Mogens Kjaer1, Peter Iversen2, Valdemar Hvidt3, Eywin Bruun4, Poul Skaarup5, Jørgen Bech Hansen6, Peter L. Frederiksen7 Randomized Trial of Radiotherapy Versus Concurrent Chemoradiotherapy Followed by Adjuvant Chemotherapy in Patients With American Joint Committee on Cancer/International Union Against Cancer Stage III and IV Nasopharyngeal Cancer of the Endemic Variety Joseph Wee, Eng Huat Tan, Bee Choo Tai, Hwee Bee Wong, Swan Swan Leong, Terence Tan,Eu Tiong Chua, Edward Yang, Khai Mun Lee, Kam Weng Fong, Hoon Seng Khoo Tan, Kim Shang Lee,Susan Loong, Vijay Sethi, Eu Jin Chua, David MachinJournal of Clinical Oncology, Vol 23, No 27 (September 20), 2005: pp. 6730-6738 © 2005 American Society of Clinical Oncology.  DOI: 10.1200/JCO.2005.16.790  Read More