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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE - 560 041, KARNATAKA ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the candidate and address (in block letters) DR. SHIVANAND .T.CHAVAN PG IN GENERAL SURGERY ROOM #86, VIVEK P.G. HOSTEL KIMS, HUBLI - 580 021 2. Name of the institution KARNATAKA INSTITUTE OF MEDICAL SCIENCES (K.I.M.S.) HUBLI - 580 021 3. Course of study and subject M.S. – GENERAL SURGERY 4. Date of admission to the course 17TH AUGUST 2013 5. Title of the topic “THE RELATIONSHIP BETWEEN BODY COMPOSITION AND RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN WOMEN WITH OPERABLE BREAST CANCER ” BRIEF RESUME OF INTENDED WORK 6. 6.1 Need for the study: Obesity is associated with several factors involved in carcinogenesis and cancer progression,including insulin resistance, lower adiponectin levels, and higher levels of leptin, plasminogen activator inhibitor-1, A comprehensive literature review concluded that women with breast cancer who are overweight or gain weight after diagnosis are at greater risk for recurrence and death . Although there are many population studies using well-defined criteria for obesity, there are few studies that evaluate body composition in patients with a high body mass index (BMI). Patients with the same BMI may have wide variations in their body composition of skeletal muscle and adipose tissue. Because of the obesity epidemic in the developed world, studies endogenous sex steroids, and chronic inflammation . In addition to increasing the risk for incident breast cancer, obesity also adversely affects patients receiving definitive treatment. using BMI alone may be under-reporting patients with sarcopenia. Sarcopenia can be defined as muscle mass greater than two standard deviations below that of healthy adults and has been associated with both physical decline and mortality in noncancer and cancer patients. In patients with chemotherapy-resistant metastatic breast cancer being treated with capecitabine, sarcopenia predicted greater treatment toxicity and a shorter time to tumor progression . In another small exploratory study of 24 stage II and stage III breast cancer patients receiving adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide , patients with toxicity had a lower lean body mass than patients with no toxicity . A potential consequence of a low lean body mass in relation to a person's height and weight could be a low volume of distribution of cytotoxic chemotherapy drugs in proportion to the body surface area (BSA), resulting in greater treatment toxicity. Our study will use the same data source of operable breast cancer patients as Litton et al. comparing overweight and obese groups of operable breast cancer patients with those of normal weight. A higher BMI was associated with a lower pathologic complete response (pCR) rate to neoadjuvant chemotherapy (NC) and a shorter overall survival (OS) time. Obese patients had a significantly shorter survival time than did normal or underweight patients . 6.2 REVIEW OF LITERATURE: 1. Overweight, operable breast cancer patients treated with NC had a lower pCR rate than those with a normal BMI. The PFS interval was significantly longer in sarcopenic patients with a normal BMI than in those with an overweight BMI. This is consistent with previous studies and supports the concept of overweight and obesity as being poor prognostic factors in patients with breast cancer. Unlike other studies, however, we found that, among patients with a normal BMI, the pCR rate was significantly higher in those who were sarcopenic, and a shorter OS time was associated with a higher skeletal muscle index and adipose tissue mass. More research is required to evaluate the negative impact of sarcopenic obesity on prognosis and the contributors to better response rates in operable, normal weight breast cancer patients with sarcopenia. . Rob C.M. van Kruijsdijk,1 Elsken van der Wall,2 and Frank L.J. Visseren1 Departments of 1Vascular Medicine and 2Pathology and Medical Oncology, University Medical Center Utrecht, the Netherlands 2. From July 1996 to March 1999, 168 patients were considered for enrollment onto this phase III study . None of these patients had received prior therapy for breast cancer. Six patients were deemed ineligible. Reasons for ineligibility included age older than 75 years in one patient, nonassessable disease (no discrete focal mass) in three patients, comorbidity (poor cardiac function) in one patient, and presence of metastatic disease (cytology confirmed supraclavicular lymph node involvement) in one patient. Therefore, 162 patients were enrolled. All of these patients completed four initial cycles of CVAP chemotherapy and therefore were suitable for the first evaluation of clinical primary tumor response. Three of these patients declined further chemotherapy (one patient had previously experi- enced a grade 3 neutropenic event; however, the other two patients felt subjectively that cumulative toxicity was intol- erable); hence, 159 patients underwent further treatment stratification. Fifty-five patients were assigned four further pulses of docetaxel after failure of their breast cancers to demonstrate a clinical response after the initial CVAP chemotherapy. Of the 104 patients with primary breast cancers that did demonstrate a clinical response after four initial pulses of CVAP chemotherapy, 52 were randomized initial CVAP chemotherapy did subsequently achieve a clinical response (cPR or cCR) after four further cycles of docetaxel. In randomized patients, four further cycles of docetaxel administered after initial CVAP chemotherapy re- sulted in a significantly enhanced (P .001) overall clinical response rate when compared with that achieved after eight cycles of CVAP (94% v 66%). Using an intention-to-treat analysis, significance is preserved (P .03). J Clin Oncol 20:1456-1466. © 2002 by American Society of Clinical Oncology. 3.Adipose tissue dysfunction, as a consequence of obesity, is likely to play a role in carcinogenesis, by affecting insulin resistance and the production of several adipokines and inflammatory cytokines. Though the precise mechanisms may differ between different types of cancer, it is plausible that these mechanisms synergistically contribute to the increased cancer risk. While understanding the link between obesity and cancer might provide therapeutic targets, lifestyle improvement remains the most important component in preventing obesityrelated morbidity and mortality. This needs to be addressed in intervention studies. Cancer Epidemiol Biomarkers Prev 2009;18:2569-2578. Published OnlineFirst September 15, 2009. 4. The measurement of body mass index (BMI), as a standard method to detect obese or overweight people, has been widely accepted to have an effect on the development and prognosis of breast cancer. High BMI has been associated with a higher risk of breast cancer in multiple studies . Obesity is also associated with advanced disease at diagnosis and with a poor prognosis in both pre-menopausal and post-menopausal women with breast cancer. The underlying mechanism of these effects remains unknown. Most investigators believe that higher BMI is related to higher circulating concentrations of sex hormones, insulin and insulin-like growth factor, which lead to a distortion of the normal balance between cell differentiation and apoptosis and the progression and proliferation of breast cancer cells . Some reports indicate that obese women with cancer would have a relatively poor response to treatment. However, whether BMI affects chemotherapy sensitivity in breast cancer is still unclear. Neoadjuvant chemotherapy (NCT), which provides an opportunity to gain early information about the response to chemotherapeutic drugs, would most likely serve as the best model for a better understanding of this issue. A large study of 1169 breast cancer patients treated with NCT has demonstrated that BMI is associated with the probability of complete pathological response (pCR) . Overweight patients and the combination of overweight and obese patients were significantly less likely to have a pCR. That is the first study to demonstrate the important role of BMI in predicting NCT response in breast cancer. In China, there are less obese people (BMI≥30 according to W.H.O. criteria) compared with western countries. In recent years, with an increasing population of overweight breast cancer patients, this risk factor is playing an increasingly important and indispensable role in breast cancer treatment. The aim of our study is to detect the relationship between BMI and the pathological response to NCT and to determine whether this relationship varies among different subgroups of Chinese women with breast cancer. PLoS One. 2012; 7(7): e41380.Published online 2012 July 25. doi: 10.1371/journal.pone.0041380 PMCID: PMC3405121 Sheng Chen,1,2 Can-Ming Chen,1,2 Ying Zhou,1,2 Ruo-Ji Zhou,2,3 Ke-Da Yu,1,2 and Zhi-Ming Shao1,2,4 5.Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing. Carla M.M.Prado,Vickie E Baracos,Linda J .McCARGAR, Tony Reiman, Marina Mourtzakis, Katia Tonkin, John R.Mackey,Sheryl Koshi, Edith pituskin and Michael B sawyer. Published OnlineFirst April 7, 2009; doi: 10.1158/10780432.CCR08-2242 Clin Cancer Res April 15, 2009 15; 2920 Clinical Cancer Researchclincancerres.aacrjournals.org 6 Toxic effect of chemotherapy dosing using actual body weight in obese versus normalweight patients: a systematic review and meta-analysis shows Obese patients receiving chemotherapy based on ABW experience similar or lower rates of compared with normal-weight patients, and survival outcomes do not differ. K.C.Hourdequin,W.L.scholrod.D.RMckenna,B.L.Piazik and R.larson Ann Oncol (2013) doi: 10.1093/annonc/mdt294 First published online: August 21, 2013 7. From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI of 25 to < 30 kg/m2), or normal/underweight (BMI < 25 kg/m2).The study showed that Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.. Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke Aman U. Buzdar,Shu-Wan Kau, Melissa Bondy,Somdat Mahabir, Gabriel N. Hortobagyi and Abenaa M. Brewster 6.3.OBJECTIVES. OF THE STUDY To compare pathological complete response cases with controls and evaluate associations among a pathological complete response, survival out come , and sarcopenia as well as the combination of both sarcopenia and a BMI > 25 kg/m2. 7. MATERIALS AND METHODS: 7.1 Source of the data: . All admitted female patients of all age groups with locally advanced carcinoma breast STAGE-IIb, IIIa, IIIb, IIIc 7.2 A. Methodology and type of data collection: This study will be conducted in collaboration with Department of Radiology,Pathology at KIMS, Hubli from Nov 2013 to april 2015 (18 months). After approval and clearance from Institutional Ethical Committee, all cases of locally advanced carcinoma breast (IIb, IIIa, IIIb, IIIc ) will be included for the present study. The written informed consent will be obtained from all the patients/ legal representatives of the patient after fully explaining the study procedure to their satisfaction. The clinical history of the disease and any associated complaints will be documented. Relevant investigations done, criteria for selecting the neoadjuvant chemotherapy, frequency of dosing, duration and change in neoadjuvant therapy if any will be recorded. The response of neoadjuvant chemotherapy will be assessed by treatment outcome based on clinical improvement i.e. reduction in size of the tumour,recurrence rate. The adverse events will also be assessed and recorded. The patients will be followed up for appropriate duration. B. Inclusion criteria: 1.All newly diagnosed locally advanced carcinoma breast (STAGE IIb, IIIa, IIIb, IIIc ) 2.female patients of all age groups C. Exclusion criteria: .1.Male patients 2.Recurrent cases 3.Previously received radiotherapy 4.Metastatic 5.pregnant patients 6.Previously operated cases 7.Refused surgery after neoadjuvant chemotherapy 8.Pathologic response assessment for >1yr after neoadjuvant chemotherapy D. Sample size: All admitted cases of locally advance carcinoma breast during the period nov- 2013 To may-2015 in KIMS HUBLI F. Study design: Randamised control trial G. Study period nov 2013 to april 2015 (18 months) H. Place of study KIMS hospital, Hubli 7.3. Does the study require any investigations or interventions to be conducted on patients or other animals? Specify. 1.Routine blood investigations 2.USG 3.Sonomammography 4.CT Abdomen 5.FNAC 6.Core niddle Biopsy 7.histopathologic examination/ Black’s nuclear grading . 7.4. Has ethical clearance been obtained from ethical committee of your institution? Yes. 7.5. Statistical methods involved : The demographic data collected will be analyzed using mean and standard deviation. Percentage pattern will be calculated for profile of locally advance carcinoma breast and neoadjuvant chemotherapy utilization. The data obtained by the various parameters will be statistically evaluated by one way analysis of variance (ANOVA) and p value of less than 0.05 will be considered significant. Wherever necessary data will be depicted using tables and graphs. 100 LIST OF REFERENCES : 1.van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009; 2.J Clin Oncol 20:1456-1466. © 2002 by American Society of Clinical Oncology 18:2569–2578 3.Cancer Epidemiol Biomarkers Prev 2009;18:2569-2578. Published OnlineFirst September 15, 2009. 4.PLoS One. 2012; 7(7): e41380.Published online 2012 July 25. doi: 10.1371/journal.pone.0041380 5. Carla M.M.Prado,Vickie E Baracos,Linda J .McCARGAR, Tony Reiman, Marina Mourtzakis, Katia Tonkin, John R.Mackey,Sheryl Koshi, Edith pituskin and Michael B sawyer Published OnlineFirst April 7, 2009; doi: 10.1158/10780432.CCR-08-2242 Clin Cancer Res April 15, 2009 15; 2920 Clinical Cancer Researchclincancerres.aacrjournals.org 6. K.C.Hourdequin,W.L.scholrod.D.RMckenna,B.L.Piazik and R.larson Ann Oncol (2013) doi: 10.1093/annonc/mdt294 First published online: August 21, 2013 1. 7. Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke 2. 3. Aman U. Buzdar,Shu-Wan Kau, Melissa Bondy,Somdat Mahabir, Gabriel N. Hortobagyi and Abenaa M. Brewster 9 SIGNATURE OF THE CANDIDATE 10 REMARKS OF THE GUIDE NAME AND DESIGNATION OF THE GUIDE CAN BE TAKEN UP FOR STUDY Dr. B.S.MADAKATTI PROFESSOR & HEAD DEPARTMENT OF GENERAL SURGERY K.I.M.S., HUBLI – 580 021 SIGNATURE 11 HEAD OF THE DEPARTMENT Dr. B.S.MADAKATTI PROFESSOR & HEAD DEPARTMENT OF GENERAL SURGERY K.I.M.S., HUBLI – 580 021 SIGNATURE 12 REMARKS OF THE CHAIRMAN AND PRINCIPAL CAN BE TAKEN UP FOR STUDY SIGNATURE