Download 6 Toxic effect of chemotherapy dosing using actual body weight in

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