Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
Knowledge is treasure of a wise man. The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help ones reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journalsNo manuscriptsNo authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Reviews
Year : 2009 | Month : April | Volume : 3 | Issue : 2 | Page : 1449 - 1454

Novel Aromatase Inhibitors

SHARMA R*, CHOPRA V S**, SHARMA C L***

*(MD) Former Senior Demonstrator, PG Dept of Pharmacology and therapeutics, Govt Medical College, Jammu, J&K-(India). Presently, clinical pharmacologist in J&K Health Services, **Prof. and Head PG Deptt of Pharmacology and therapeutics, Govt. Medical College, ***Lt.Col., 166 Military Hospital Satwari - Jammu, Army Medical Corps-(India)

Correspondence Address :
Dr.Rashmi Sharma,(MD) 216-A, Last Morh,
Gandhi Nagar, Jammu-Tawi. J&K–(India).
Pin:180004,E-mail:rashmichams@yahoo.com

Abstract

Oestrogen receptors are expressed in 2/3rd of all breast cancers and the oestrogen mediated growth stimulation through these receptors causes the progression of hormone sensitive breast tumours. Tamoxifen has played a significant role in the treatment of metastatic and early breast cancers, as well as in preinvasive ductal carcinova in situ. The occurance of adverse effects like hot flushes, vaginal dryness, thromboembolism and endometrial cancer with the use of tamoxifen, together with the fact that some patients are refractory to treatment or may develop resistance, generated interest in the inhibition of oestrogen synthesis by aromatase inhibitors (AI) and inactivators . There are two types of AI- irreversible steroidal activators and reversible nonsteroidal imidazole-based inhibitors. The three novel third generation oral AI and inactivators like, anastrozole, letrozole and steroidal exemestane are very effective in reducing oestrogen levels in postmenopausal women, with minimum toxicity. Moreover, their long half life allows once daily administration, leading to better patient compliance. Inhibition of the aromatase system, in particular, with third-generation aromatase inhibitors and inactivators, appears to be associated with statistically significant improved survival of patients with advanced breast cancer, as compared to standard hormonal treatments. Introduction of the novel AI in the treatment of breast cancer has truly increased the hope of longer and better disease-free survival for these patients.

Keywords

Anastrozole, Letrozole, Exemestane

Oestrogen receptors (ER) are expressed in 2/3rd of all breast cancers and oestrogen mediated growth stimulation through these receptors causes the progression of hormone sensitive breast tumours. This can be ameliorated either by receptor blockade with the use of antioestrogens or by the inhibition of oestrogen synthesis by aromatase inhibitors (AI) and inactivators, which blocks oestrogen production in both the tumour cells as well as in the surrounding tissues (1).

Since it’s introduction in 1973, tamoxifen has played a significant role in the treatment of metastatic and early breast cancer, as well as in preinvasive ductal carcinova in situ. Though it has beneficial effects on the bone and in lipid metabolism, the occurence of adverse effects like hot flushes, vaginal dryness, thromboembolism and endometrial cancer with the use of tamoxifen, together with the fact that some patients are refractory to treatment or may develop resistance to it, justify the need to develop new agents with an improved therapeutic index (2),(3).AIs act by suppressing the conversion of androgen substrates into oestrogen by inhibition of aromatase, thereby leading to regression of ER positive tumour cells (4) (Table/Fig 1)

AIs can be categorized by their generation and by their mechanisms of action. The aromatase enzyme is required for the last step in oestrogen biosynthesis(5).There are two types of AIs, irreversible steroidal activators and reversible nonsteroidal imidazole-based inhibitors. Steroidal agents such as exemestane, have an androgen structure and they bind irreversibly to the catalytic site of aromatase (competing with the natural aromatase substrate androstenedione) (5). Nonsteroidal imidazole-based agents like the second-generation agent aminoglutethimide and the third-generation agents, anastrozole and letrozole, reversibly interact with the cytochrome P450 moiety of the enzyme (5).

Both the first generation AIs, aminoglutethimide and the second generation steroidal AI formestane (introduced in late 1970’s and early 1990’s respectively), were less potent inhibitors of aromatase and oestrogen suppression, which provided the incentive for the development of the third generation Ais (4). The three novel third generation oral AI and inactivators approved for use by FDA – USA, include nonsteroidal agents anastrozole (Arimidex), letrozole (Femara) and steroidal exemestane (Aromasin) (2).These are more potent and safer than progestins and aminogluthetimide. Moreover, these are highly selective for the aromatase enzyme without affecting mineralocorticoid or glucocorticoid synthesis .These are very effective in reducing oestrogen levels in postmenopausal women, with minimum toxicity (6). Moreover, their long half life allows once daily administration, leading to better patient compliance (1). In the present article, we are reviewing the novel third generation AIs.

Search Methodology
Prominent oncology and general/internal medicine journals (MEDLINE, EMBASE and PUBMED) were searched for review papers and clinical trials published on AIs. The data was collected and summarized in the present article (Table/Fig 2).

Anastrozole
It is well absorbed orally with Cmax (maximum concentration) at 3 hours and with a terminal half life of 40-50 hours. More than 80% is metabolized by the liver by N-dealkylation and hydroxylation. 10% is excreted unchanged in urine. It is a potent AI (~ 97%) and provides near maximal suppression of oestrogen to below detectable levels. It is well tolerated (1).

A major clinical programme consisting of two large multicentre trials viz. the North American trial and TARGET (tamoxifen or anastrozole randomised group efficacy and tolerability) trial has demonstrated the superiority of anastrozole over standard endocrine therapy tamoxifen for first line treatment of post menopausal women with hormone sensitive advanced breast cancer(7),(8). Clinical trials have also demonstrated significant benefits with anastrozole, as compared to the standard second line agent megestrol acetate, which led to its approval by US FDA for second line use in post menopausal women with advanced breast cancer, progressing after prior tamoxifen treatment(9). In the long term, prospects may also exist for using anastrozole as a neo-adjuvant agent (4).The two studies comparing the efficacy of anastrozole (1 mg daily) with that of megestrol acetate (160 mg daily), did not report a statistically significant difference between the two groups, although results for each end point were numerically superior for anastrozole (10),(11). In a subsequent pooled analysis of these two trials conducted at a median follow-up of 31 months, a statistically significant survival advantage was found for anastrozole (12).The most common adverse events reported in women taking anastrozole, were asthenia, nausea, headache, hot flashes, and pain (13).

Letrozole
It is an oral, highly potent (>99.1%) and reversible AI. It’s bioavailability is 100% and it is unaffected by food. It is rapidly absorbed, with a half life of 48 hours. It has a high volume of distribution and 60% plasma protein binding. It is metabolized by P450 (CYP3A4 and CYP2A6) to a secondary alcohol, which is excreted in urine. Its levels are suppressed by tamoxifen by a mean of 35-40%, when administered together (1).On comparison with aminoglutethimide and megestrol acetate respectively, in different trials in post menopausal women with metastatic breast cancer previously treated with tamoxifen, letrozole demonstrated clinical superiority in terms of prolonged time to progression and treatment failure, as well as in improved survival (6). Dombernowsky, et al compared two doses of letrozole with megestrol acetate as second-line therapy in postmenopausal women (14). Letrozole, at a dose of 2.5 mg, produced a significantly higher overall objective response rate (ORR) (24%) than megestrol acetate (16%; p = 0.04) and 0.5mg of letrozole (13%; p = 0.004). A significant dose effect on overall survival was observed with the higher letrozole dose, as compared to the lower dose of letrozole. However, Buzdar and colleagues showed no statistically significant differences among the three treatment groups for overall objective tumour response (15). A dose-response relationship was not noted in the second study. However, 0.5 mg of letrozole was found to be superior to megestrol acetate in TTP and TTF (time to treatment failure). The most frequent adverse events reported in women treated with letrozole were hot flashes, nausea, diarrhoea, musculoskeletal pain, dyspnea, and headache (14), (15).

In an open-label, randomized, phase IIIB-IV study, anastrozole (1 mg daily) was compared with letrozole (2.5 mg daily) in 713 postmenopausal women with advanced breast cancer, whose disease became resistant to tamoxifen used, either as adjuvant therapy or for advanced disease (16). Approximately half the patients had an unknown oestrogen-receptor status, TTP, clinical benefit, TTF, duration of response and duration of clinical benefit. However, the secondary end point OR rate statistically significantly favoured letrozole; but, this benefit was not seen in women with oestrogen-receptor-positive disease (17).Nausea was more common with anastrozole (11%) than with letrozole (8%) (16). Letrozole was compared with tamoxifen in one study, in which it demonstrated statistically significant superiority in ORR, clinical benefit, TTP and TTF (18),(19).

In the National Cancer Institute of Canada (NCIC) MA17 trial, a double-blinded, placebo-controlled trial designed to test the effectiveness of 5 years of letrozole therapy in postmenopausal women with breast cancer who had completed 5 years of tamoxifen, an estimated 4-year disease-free survival rate of 93% was noted in the letrozole group, versus 87% in the placebo arm (20). No statistically significant difference in overall survival was apparent at the time of this analysis. Low-grade hot flashes and arthritis were more common in the letrozole arm. No statistically significant difference in the new diagnosis of osteoporosis was observed (5.8% in the letrozole arm versus 4.5% in the placebo arm; p = 0.07). Given the positive results of the trial, it was terminated.

In a retrospective analysis of 95 patients with breast cancer who were postmenopausal and had failed after tamoxifen therapy, 2.5 mg of letrozole daily was quite effective as second line therapy in postmenopausal patients (21).Median TTP time to progression was 10 months and overall ORR was 21%, with a complete response rate of 9%. Th median overall survival was 36 months. Treatment failure was seen in 76% of patients.

Exemestane
It is an analogue of the aromatase subtrate androstenedione and is an irreversible AI (97.9%). Because of their steroidal structure, exemestane and its 17-hydroexemestane metabolite have the potential for androgenic effects. The binding of exemestane to the androgen receptor is about 0.2% that of dihydrotestosterone, but the affinity of 17-hydroexemestane for the androgen receptor is about 100 times that of the parent compound (5). The recommended dosage of exemestane is 25 mg orally, once daily, after a meal(21). It is rapidly absorbed, with peak plasma concentrations of 17 µg/L within one to two hours (21).A steady state concentration is achieved within seven days. Exemestane is extensively metabolized by cytochrome P450 3A4 and aldoketoreductases (21). The metabolites are either of lower potency or inactive and are excreted equally in urine and faeces (22). Exemestane has a half-life of 27h (22),(23).Oral clearance of exemestane is reduced in the presence of significant hepatic or renal disease. The therapeutic implications of this are considered minor because of its relatively large safety margin and minor side-effects (24).

It has been demonstrated that exemestane has a better clinical efficacy as compared to aminoglutethimide or megestrol acetate in phase II and III trials,. In a clinical trial, 25 mg of exemestane, daily, was compared with 40 mg of megestrol acetate, four times daily (5). Exemestane was associated with statistically significant benefits in the duration of clinical benefit, TTP, TTF and survival time. The most frequently reported adverse events in women treated with exemestane were low-grade hot flashes, nausea, and fatigue. Greater weight gain was reported in patients treated with megestrol acetate (5). The steroidal agent, exemestane was compared with tamoxifen in a randomized European Organization for Research and Treatment of Cancer (EORTC) phase II/III trial (25). In the phase II portion of the study, exemestane produced an ORR of 40.9% and a clinical benefit of 55.7% as compared to 13.6% and 42.4%, respectively in the tamoxifen group (25). However, the results of ongoing phase III clinical trials comparing it with tamoxifen, are awaited (26).

The Letrozole, Exemestane and Anastrozole Pharmacodynamics (LEAP) study was conducted in 96 healthy postmenopausal women to assess the pharmacodynamic differences between the three AIs at the 12th and 24th week. Exemestane produced a significant decrease in HDL-C levels associated with an increase in the ApoB: ApoA-1 ratio. However, no significant differences in the changes in nonHDL-C concentrations were observed between the treatment groups (27).

In another two-year trial enrolling 147 patients, exemestane reduced HDL levels by 6-9%, with no major effects on serum lipids, coagulation factors or homocysteine levels (28).

The Greek sub-study of TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial evaluated the effects of either adjuvant exemestane or tamoxifen therapy on the lipid profile in 176 postmenopausal early breast cancer patients (29). After a study period of one year, exemestane was found to have a neutral effect on total cholesterol and LDL and HDL levels. However, tamoxifen on the other hand, increased triglyceride levels, while exemestane resulted in a beneficial reduction(29).

In a randomized trial comparing megestrol acetate with exemestane as second-line hormonal treatment for metastatic disease in 366 patients, there was no incidence of thromboembolic events with the use of exemestane (30). Exemestane is marketed for use only in postmenopausal women. It is contraindicated in pregnant or lactating women (21).No dose adjustment is required in the geriatric population (21). There is no cross-resistance between exemestane and other nonsteroidal Ais (21). Exemestane is currently being evaluated extensively in several studies in postmenopausal women as upfront therapy versus tamoxifen in postmenopausal women with early breast cancer. Efficacy, safety and quality of life (QOL) as end points, are being evaluated in these studies (21) (Table/Fig 2).

Sequential Use of Aromatase Inhibitors:(5)
There is evidence to suggest that steroidal aromatase inhibito, exemestane, is effective after the failure of tamoxifen and megestrol acetate and after failure of tamoxifen and a nonsteroidal aromatase inhibitor (e.g., aminoglutethimide, anastrozole, letrozole). The nonsteroidal aromatase inhibitors were effective after the failure of exemestane . The reason for non-cross-resistance among various AIs, is possibly due to structural differences among aromatase inhibitors (i.e., steroidal versus nonsteroidal imidazole), which may lead to different pharmacokinetic and pharmacologic profiles, or differences in the ways in which these agents interact with the aromatase enzyme. As an example, because of their steroidal structure, exemestane and its 17-hydroexemestane metabolite may have androgenic effects that contribute to antitumour activity. Although clinically important, androgenic adverse events have not been reported at the recommended exemestane dose of 25 mg daily, hypertrichosis, hair loss, hoarseness and acne were reported in about 10% of patients treated with daily exemestane doses of 200 mg or more. It is possible that, although not clinically apparent, recommended doses of steroidal agents may have some androgenic effects.

Breast Cancer Prevention (5),(31),(32),(33)
There is a link between oestrogen exposure and breast cancer development and the antioestrogen tamoxifen has been shown to prevent the development of breast cancer in women with above average cancer risks. As there is evidence that both oestrogens and oestrogen metabolites may initiate breast cancer, AIs may have a role in preventing breast cancer. Moreover, antioestrogens block the action of oestrogens, leaving potentially carcinogenic oestrogen metabolites available to exert their effects. AIs block the formation of oestrogens and therefore, oestrogen metabolites. Data from the ATAC trial demonstrate a greater reduction in the incidence of contralateral breast cancer with anastrozole, than with tamoxifen, particularly in women with hormone-positive disease. However, several trials are currently under way to assess the role of aromatase inhibitors in breast cancer prevention.





Conclusion

The three novel third generation oral AI and inactivators like anastrozole, letrozole and steroidal exemestane are very effective in reducing oestrogen levels in postmenopausal women, with minimum toxicity. Moreover, their long half life allows once daily administration, leading to better patient compliance.

Inhibition of the aromatase system, in particular, with third-generation aromatase inhibitors and inactivators, appears to be associated with statistically significant improved survival of patients with advanced breast cancer as compared to standard hormonal treatments (34). Introduction of the novel AIs in the treatment of breast cancer has truly increased the hope of longer and better disease-free survival for these patients.

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