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Evaluation of exercise tolerance in women receiving surgery and chemotherapy as treatment for stage II… Wiley, Lisa Dawn 1998

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EVALUATION OF EXERCISE TOLERANCE IN WOMEN RECEIVING SURGERY AND CHEMOTHERAPY AS TREATMENT FOR STAGE II BREAST CANCER by LISA DAWN WILEY B.Sc.H., Queen's University, 1993 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES SCHOOL OF HUMAN KINETICS We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y O F B R I T I S H C O L U M B I A March 1998 © Lisa Dawn Wiley, 1998 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia Vancouver, Canada DE-6 (2/88) L ABSTRACT Worldwide, breast cancer is the second-most-common cause of cancer deaths in women (Harvey and Beattie, 1996). It is estimated that by the year 2000, one million women a year w i l l receive a diagnosis of breast cancer, while in Canada alone, the disease develops in 18,400 women every year (National Cancer Institute of Canada, 1997). The development and improvement of new treatment modalities for breast cancer have resulted in increasing cure rates and longer disease-free survival making the outcome of cancer therapy increasingly important. Damaging effects of cancer therapies can occur in the heart and lungs and therefore are thought to impede the patient's functional capacity and ability to exercise. The purpose of this study was to characterize the early changes in functional capacity that occur in women diagnosed with stage II breast cancer, whose treatment involves a schedule of mastectomy and adjuvant chemotherapy. Nine female patients performed the treatment protocol at three different sessions: 1) after diagnosis of breast cancer but before surgery, 2) following surgery but before beginning chemotherapy, and 3) following chemotherapy. Testing sessions involved two protocols and the subjects served as their own controls throughout the three tests. Firstly, resting pulmonary function was assessed using the Spirometry software package on the Medical Graphics C P X - D Metabolic Cart. Forced Vi ta l Capacity ( F V C ) , forced expiratory volume in one second (FEV1) , the ratio of the two ( F E V 1 / F V C ) , and maximal voluntary ventilation ( M W ) were measured. The second protocol was a V02max test on an electronically-braked cycle ergometer (Lode B V Excalibur V2.0) using a Medical Graphics C P X - D Exercise Testing System. Measurements included maximal heart rate ( H R m a x ) , minute ventilation (V E ) , maximal oxygen consumption (V02max), and peak power output (PPO). While cycling, percent arterial oxygen saturation (%Sa02) was monitored with a pulse ii oximeter (Ohmeda Box 3740). Anthropometric measures including height, weight and sum of skinfolds (SOS) were recorded before each test. Data was analyzed using a one-way repeated measures A N O V A design on SPSS and subsequent Tukey H S D post-hoc analyses were performed by hand. A probability value of < 0.05 was considered to provide significance. V 0 2 m a x values, measured both in L/min and ml/kg/min decreased significantly from baseline to the end of chemotherapy (1.70 ± 0.31 to 1.47 ± 0.31 L/min; and 28.3 ± 5.54 to 24.52 ± 6 . 1 3 ml/kg/min, respectively). F E V 1 / F V C and M V V did not change significantly throughout the treatment. PPO, H R m a x , Sa0 2 , and V E also remained unchanged after chemotherapy treatment. Although respiratory function was not affected, the data suggests that breast cancer patients treated with chemotherapy experience a decrease in cardiorespiratory fitness and associated loss of functional capacity. iii T A B L E OF CONTENTS Abstract ii Table of Contents iv List of Tables vii List of Figures ix List of Abbreviations and Symbols x Acknowledgments xi Chapter 1: Introduction 1 Research Hypotheses 5 Limitations 5 Delimitations 6 Chapter 2: Methodology 7 Subjects 7 Experimental Protocol 7 Anthropometry 8 Pulmonary Function 9 Exercise Capacity 9 Daily Activity Log 10 Design and Statistical Analysis 11 Chapter 3: Results 12 Treatment Details 13 iv Timeline For Testing 15 Anthropometry 17 Pulmonary Function 17 Exercise Capacity 18 Activity Levels 20 Smoking Activity 20 Chapter 4: Discussion 22 Summary 31 Recommendations 31 References 33 Appendix A : Review of Literature 41 Treatment of Stage II Breast Cancer 42 Effects of Chemotherapy 44 Pulmonary Effects 45 Cardiac Effects 48 Effects on Exercise Capacity 50 Physiology of Exercise 50 Effects of Exercise Intervention 52 Critique of the Literature 52 What is the Literature Missing? 55 Appendix B : T N M Staging System 57 Appendix C : Five Stages of Breast Cancer 58 v Appendix D : Raw Data 59 Anthropometric Data 59 Pulmonary Function Data i 60 Exercise Capacity Data 62 Activity Data 65 Timeline Data 66 Smoking Data 67 vi L I S T O F T A B L E S Table 1 Surgical Results, individual subject data 13 Table 2 Pathology and Stage of Cancer, individual subject data 14 Table 3 Chemotherapy Details, individual subject data 15 Table 4 Days Between Testing and Treatment, group mean data 16 Table 5 Body Mass and Sum of Skinfolds, group mean data 17 Table 6 Statistical Results, Pulmonary Function 17 Table 7 Pulmonary Function, group mean data 18 Table 8 Measures of Defining Exercise Capacity, group mean data 20 Table 9 Smoking Activity, group mean data 21 Table 10 Pre-surgery Age and Height, individual subject data 59 Table 11 Body Mass (kg), individual subject data 59 Table 12 Sum of Skinfolds (mm), individual subject data 60 Table 13 Forced Vital Capacity (L), individual subject data 60 Table 14 Forced Expiratory Volume in One Second (L), individual subject data 61 Table 15 Ratio of Forced Expiratory Volume in One Second / Forced 61 Vital Capacity (%), individual subject data Table 16 Maximal Voluntary Ventilation (L/min), individual subject data 62 Table 17 Maximal Oxygen Consumption (mL/min), individual subject data 62 Table 18 Maximal Oxygen Consumption (mL/kg/min), individual subject data 63 Table 19 Maximal Heart Rate (bpm), individual subject data 63 Table 20 Ventilation (L/min), individual subject data 64 Table 21 Peak Power Output (watts), individual subject data 64 vii Table 22 Saturation of Oxygen (%), individual subject data 65 Table 23 Daily Activity (Kcal/day) During Study Period, individual subject data 65 Table 24 Pre-Diagnostic Activity Levels (Kcal and Kcal/day), individual subject 66 data Table 25 Number of Days Between Treatments and Testing, individual subject 66 data Table 26 Smoking History, individual subject data 67 viii LIST OF FIGURES Figure 1 Timeline for Testing 8 Figure 2 Changes in Maximal Oxygen Consumption (mL/min) + SE During 19 Stage II Breast Cancer Therapy ix LIST OF ABBREVIATIONS AND SYMBOLS bpm Beats per minute E C G Electrocardiogram F E V 1 Forced expiratory volume in the first second (L) of the F V C F V C Forced vital capacity (L) H R m a x Maximum heart rate (bpm) Kca l Kilocalorie: unit of energy expenditure M V V Maximal voluntary ventilation (L/min) P P O Peak power output (watts) R E R Respiratory exchange ratio rpm Revolutions per minute R R Respiratory Rate %Sa02 Percentage of arterial oxyhemoglobin saturation T N M Breast Cancer Staging System V E Expired ventilation per minute (mL/min) V 0 2 Volume of oxygen uptake (mL/min) V C - w Maximum volume of oxygen uptake (mL/min) x A C K N O W L E D G M E N T S Dr. Don McKenzie M y Committee Dr. Urve Kuusk & Dr. Carol Dingee A n n Knight & Jackie McKnight The Women Dana Reid Diana Jespersen Sheri Niesson Carol Loughren Rob Thurgur M y Parents Katherine Wreford M y advisor, who allowed me to leave every meeting I had with him feeling 100% better than when I arrived Dr. Ken Coutts, Dr. Urve Kuusk, Dr. Jack Taunton whose contributions made this project possible The breast cancer surgeons who believed in our work and provided patients - without which this study could never take place Who provided communication between research and medical practice Who helped me learn more about the disease of breast cancer than any scientific study could ever do We went through this together - and made it! Thank you. Who was always there when I needed her - for everything! A n inspirational colleague and role model Who has an answer for everything and is greatly appreciated Who knew I could do it Who knew I could do it and wished I would hurry up Who provided an excellent example of how to complete a Master's program, yet also provided a social detour x i C H A P T E R 1: INTRODUCTION Worldwide, breast cancer is the second-most-common cause of cancer death in women (Harvey and Beattie, 1996). It is estimated that by the year 2000, one mill ion women a year wi l l receive a diagnosis of breast cancer, while in Canada alone, the disease develops in 18,400 women every year (National Cancer Institute of Canada, 1997). Breast cancer is 200 times more common in women than in men and 400 times more common in women age 50 than in women age 20 (Healey et al., 1993). Estimated deaths from breast cancer in 1997 were 5,100 (National Cancer Institute of Canada). Clearly it is a major health problem. Once a diagnosis of breast cancer is made, tests and examinations are performed to assess the extent or stage of disease. The staging process is very complicated and consists of pathological details of four different stages. Stage I represents early cancer with a small tumour and no spread to the lymph nodes. The tumour becomes progressively advanced in stage n and E I with probable involvement of the lymph nodes, and stage IV refers to metastatic disease that has spread to other areas of the body (Olivotto et a l , 1995). The focus of this paper w i l l be on stage II breast cancer which usually involves a solid tumour two to five centimeters in its greatest dimensions. This does not involve the skin or any of the chest wall such as the pectoralis muscle, and i f lymph nodes are involved they must be movable to be considered stage II (Olivotto et al., 1995). For women with this stage of cancer the average survival five years after diagnosis is 50-70% (Olivotto et al., 1995). The staging system provides a strategy for determining treatment options and for grouping patients with respect to prognosis. Treatment for patients diagnosed with stage II breast cancer usually involves a combination of surgery and chemotherapy, and in some cases is l followed by radiation therapy. Although there are many types of surgery available, a total mastectomy or a partial mastectomy combined with axillary dissection (removal of lymph nodes from the axilla) is commonly performed, depending on where the spread of cancer has occurred (Olivotto et al. 1995). Selection of the appropriate therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, patient age, and how the patient feels about preserving the breast. 'Adjuvant therapy' is treatment given in addition to surgery as a preventive measure in case the cancer is still present. Specifically, adjuvant chemotherapy is given after surgery when there is a risk of cancer cells regrowing as metastases throughout the body (Harvey and Beattie, 1996; Olivotto et al., 1995). Tamoxifen, the most widely used anti-estrogen, may also be included in a patient's treatment protocol following chemotherapy. Recommendation for the use of adjuvant Tamoxifen depends on the stage of the cancer, age, menopausal state and estrogen receptor (ER) status (Olivotto et.al. 1995). Tamoxifen, either alone or combined with chemotherapy, has been found to prolong disease-free survival when administered for five years as adjuvant therapy to pre- and post-menopausal women with axillary lymph node metastases (Baum et al., 1988; Bartlett et al., 1987; National Institutes of Health Consensus Development Conference statement, 1985). Of the single drug therapies, doxorubicin (Adriamycin®) is the most effective, however, multiple drug combinations seem more effective than single-agent therapy (Harvey and Beattie, 1996). The most commonly used combinations of chemotherapeutic drugs are cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) ; cyclophosphamide, doxorubicin and 5-fluorouracil ( C A F ) ; and doxorubicin and cyclophosphamide (AC) (Harvey and Beattie, 1996). Adjuvant combination chemotherapy has been found to prolong disease-free survival for pre- and post-menopausal patients with lymph nodes both positive and negative for metastases. In a study by Bonadonna et al. (1976), patients treated with mastectomy having positive axillary lymph 2 nodes were randomized into those receiving adjuvant chemotherapy with C M F and controls receiving no adjuvant therapy. After 27 months of study, treatment failure occured in 24 per cent of 179 controls and in 5.3 percent of 207 women given chemotherapy. Furthermore, in a trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP-16) , node-positive women 50-59 years of age had improved disease-free and overall survival when treated with tamoxifen and chemotherapy (AC) compared to those treated with tamoxifen alone (Fisher et al. b, 1990). In node-negative patients, a small randomized trial comparing adjuvant chemotherapy with C M F versus no adjuvant therapy showed improved disease-free and overall survival for those receiving C M F (Bonadonna et al., 1986). Finally, in a study at the Mi lan Cancer Institute testing surgery versus surgery plus 12 cycles of C M F in node positive patients, the reduction in failure rate (34%) significantly favoured CMF-treated patients (Bonadonna et al., 1986). The development and improvement of new treatment modalities over the last few decades has resulted in increasing cure rates and longer disease-free survival, making the outcome of cancer therapy increasingly important (Jenney et al., 1995; McKenzie et al., 1995; Sharkey et al., 1993). This combination of surgery and adjuvant chemotherapy is designed to result in complete resolution of the disease, however, it is very aggressive and can result in side effects. The most damaging effects of chemotherapy in women treated for stage II breast cancer occur in the heart and lungs (Harvey and Beattie, 1996; Olivotto et al., 1995). Under disease-free conditions, the transport of oxygen involves ventilation, diffusion from alveoli to pulmonary capillaries, circulation, and delivery of oxygen to the mitochondria (Frontera and Adams, 1986). B y interfering with the transport of oxygen, chemotherapeutic drugs are thought to impede the patients' functional capacities and ability to exercise (Harvey and Beattie; 1996; Olivotto et al., 1995). 3 Acute drug-induced pneumonitis and resulting restrictive and obstructive lung disease have been shown to develop in breast cancer patients treated with chemotherapy (White et a l , 1984; Todd et al., 1993). Further damage to the lung may include chronic pulmonary fibrosis, creating persistent pulmonary function abnormalities (White et al,. 1984). Changes to the heart v tissue from systemic exposure to chemotherapy may also lead to poor oxygen transport. Anthracyclines have been shown to induce stretching of ventricular myocytes which in turn decreases myocardial contractility and impairs blood flow throughout the heart (Stewart et al., 1995). It has generally been accepted that oxygen delivery to the working muscles is the primary determinant of maximal oxygen uptake ( V C - w ) (McArdle et al., 1991). Chemotherapy-induced interference in the delivery of oxygen, either in the respiratory or the circulatory pathways, should therefore become evident through VC>2max and pulmonary function measures. The ability to maintain functional independence and carry out daily activities, whether they be occupational, recreational or social, is important when determining one's quality of life (Winningham, 1991). Few studies, however, have examined the effect that chemotherapy has on functional capacities of women. Baseline measures of exercise capacity patterns during treatment for breast cancer would provide evidence for a pattern of chemotherapy-induced injury. If it can be demonstrated that women undergoing therapy for stage II breast cancer exhibit decreased functional capacities as measured by maximum oxygen uptake and pulmonary function tests, the next step would be to design exercise programs as a cost-effective intervention that would be used to maintain the capacity for self care and physical independence in these women. Therefore the purpose of this study was to characterize the early changes in functional capacity that occur in women diagnosed with stage II breast cancer, whose treatment involved a 4 schedule of mastectomy and adjuvant chemotherapy. Specifically, oxygen uptake (V0 2max) and pulmonary function ( F E V 1 / F V C ) were used to assess functional capacity. R E S E A R C H H Y P O T H E S E S It was hypothesized that: 1) the ratio F E V 1 / F V C (forced expiratory volume in one second/forced vital capacity) would decrease significandy in patients and therefore be lower after the completion of chemotherapy compared to both the pre-surgery and pre-chemotherapy tests 2) post-chemotherapy oxygen consumption ( V 0 2 m a s ) , maximal heart rate (HR) and peak , power output (PPO) values would be significantly lower compared to both the pre-surgery and pre-chemotherapy values. L I M I T A T I O N S The following may affect the ability to generalize to all women diagnosed with stage U breast cancer receiving adjuvant chemotherapy: - small sample size consisting of nine women was a result of recruitment difficulties - women participating in the study volunteered to do so and therefore may have personal qualities which influence their response to treatment that non-volunteers may not possess - drug protocol was difficult to control due to the limited sample size, and although similar, was not the same for all patients - varying lengths of recovery times from surgery and chemotherapy provided inconsistent times between tests - inability to completely control activity levels created small differences in total kilocalories expended between the pre-diagnostic and the treatment period 5 D E L I M I T A T I O N S Women with the following qualities were admitted to the study: - willingness to participate - unilateral disease - no previous breast cancer or chemotherapy treatment - chemotherapy as adjuvant treatment for early stage breast cancer 6 C H A P T E R 2: M E T H O D O L O G Y S U B J E C T S Nine female oncology patients between the ages of 38 and 58 who were diagnosed with stage II breast cancer participated in the study. Subjects were informed about the study following their diagnosis by one of two local breast cancer surgeons who agreed to work in conjunction with the study. The participants were considered "otherwise healthy" meaning that they had no other illness or disease that would interfere with the testing protocol or the results of the study, and that they had no previous history of breast cancer. During the first testing period the study protocol, time commitment, possible risks and benefits, and assurance of confidentiality were explained to the subjects by the principle investigator. Written informed consent was obtained and any questions or concerns that the subjects may have had were addressed. Women wanting to participate but who were receiving radiation treatment following surgery were referred to a different study. Ethical approval for the investigation was given from the University of British Columbia Clinical Screening Committee for Research and Other Studies Involving Human Subjects. E X P E R I M E N T A L P R O T O C O L The experimental protocol was carried out on three separate testing occasions. Testing occurred: 1) after diagnosis of breast cancer, approximately one week before surgery, 2) following surgery but before beginning chemotherapy, and 3) as immediately following chemotherapy that recovery would allow. The mean time from diagnosis to completion of testing, excluding subjects G and I who did not begin the study at diagnosis, was approximately 22.5 weeks and is illustrated in figure 1. Approximate time (wks): 0 1 1 1 1 5 1 1 1 1 10 1 1 1 1 13 1 1 1 1 20 1 1 1 1 25 Treatment: D S B C T E C T Testing: t T t F I G U R E 1: Time Line for Testing D = diagnosis; S = surgery; B C T = begin chemotherapy; E C T = end chemotherapy Individual data for time spent at each stage can be found in Appendix D , Table 25. On the first testing date, subjects were required to read and f i l l out the P A R - Q Physical Activity Readiness questionnaire to ensure the safety of patients exercising during the study. Blood pressure and resting heart rate were recorded from each patient prior to each test. The subjects were informed that i f at any time during the study they felt uncomfortable and wished to stop the testing they could do so. A N T H R O P O M E T R Y Prior to each testing, height, weight (Detecto industrial scale), and sum of skinfolds (SOS) at five sites on the unaffected side (biceps, triceps, subscapular, iliac crest, and medial calf) (Harpenden skinfold calipers, John Bu l l , British Indicators Ltd.) were recorded. 8 P U L M O N A R Y F U N C T I O N Resting pulmonary function was assessed using the Spirometry software package contained on the Medical Graphics C P X - D (St. Paul, Minnesota) Metabolic Cart. The system was calibrated for volume prior to testing using a three-litre syringe. Flow-volume loops were measured for each patient, taking the best of three trials. Forced Vita l Capacity ( F V C ) , Forced Expiratory Volume in one second (FEV1) and Maximal Voluntary Ventilation ( M V V ) were measured. E X E R C I S E C A P A C I T Y The second protocol utilized a Medical Graphics C P X - D (St. Paul, Minnesota) Exercise Testing System to directly measure the functional capacity of the heart and lungs at rest and during exercise to maximum. Following a three minute warm-up period, patients performed a V 0 2 m a x test on an electronically-braked cycle ergometer (Lode B V Excalibur V2.0 , Groningen, The Netherlands) to volitional fatigue. The initial workload was set at 25 watts and increased in ramp fashion following a protocol of 20 watts per minute. Subjects were told to develop a pace between 60 and 80 rpm and were verbally encouraged throughout the test. The pneumotachograph of the system was calibrated with a three litre capacity syringe and the gas analyzers were calibrated with air and gases of known concentration prior to each experiment. Inspired and expired gases were collected and analyzed by 0 2 and C 0 2 fast-response gas analyzers (Medical Graphics Corporation, St. Paul, M N ) on a breath by breath basis. This allowed for the measurement of minute ventilation (V E ) , respiratory exchange ratio (RER) , and respiratory rate (RR). The computer system calculated and displayed the average values every 15 seconds, and output was recorded on a I B M computer interfaced with the metabolic cart. 9 Measurements of expired gas concentrations are known to have errors below 0.1% or even 0.01% using fast-response automated computational systems (Lamarra and Whipp, 1995). For safety reasons, electrocardiographic monitoring ( E C G Lifepak 6®, Physio-Control, Againcourt, Ontario) was performed in conjunction with the test to determine the cardiac response to progressive exercise during the assessment of maximal oxygen consumption. With the use of diaphoretic electrodes (3M), heart rate was continuously recorded, as was percent arterial oxygen saturation (%Sa02) by using a pulse oximeter (Ohmeda Biox 3740, Louisville, CO) . The accuracy of the pulse oximetry is plus or minus three percent (Frownfelter, 1994), and has been validated (r = 0.96) as a measure of arterial hemoglobin oxygen saturation in critically i l l patents (Mihm and Buce, 1985). Maximal values for oxygen consumption were determined by taking the mean of the four highest consecutive 15 second values. Attainment of V02max was considered when at least three of the four following criteria were met: (1) identification of a plateau in oxygen uptake with an increasing workrate, (2) a respiratory exchange ratio greater than 1.15, (3) heart rate greater than 90% of predicted maximum, and (4) volitional fatigue. The reliability of this performance test has been previously confirmed in this laboratory with a high test-retest intraclass correlation coefficient (r = 0.96). D A I L Y A C T I V I T Y L O G Subjects completed a pre-diagnostic activity form on their first testing visit, generally describing what activity they did on a regular basis approximately one year before diagnosis of breast cancer. To determine the influence of exercise or lack thereof, the women kept a daily activity log throughout the entire study period. As with the pre-diagnostic questionnaire, they had to record the type of activity, the length of time it was performed, and subjectively rank the 10 intensity (light, moderate, vigorous or very vigorous). Upon completion of the study, a metabolic equivalent (MET) level for each activity was assigned using the Compendium of Physical Activities (Ainsworth, 1993). From this, energy cost was calculated for each day by multiplying the subject's body mass in kilograms by the assigned M E T value and duration of activity per 60 minutes in order to estimate energy expenditure (Kcal). Totals between each testing period as well as daily totals were calculated. Energy expenditure for the year prior to diagnosis was calculated in the same manner allowing the comparison between the two time periods. DESIGN AND STATISTICAL ANALYSIS A l l descriptive measurement data was analyzed using single factor repeated measures analysis of variance ( R M A N O V A ) . The independent factor was 'test' which therefore consisted of three levels corresponding to the three different testing periods. The main dependent variables to be examined were V 0 2 m a x (L/min), V 0 2 m a x (mL/kg/min), and F E V 1 / F V C , however, F V C , F E V 1 , M V V , H R m a x , V E , S a 0 2 , SOS, and P P O were also measured. Alpha was set at 0.05 to determine significance. Tukey's H S D post-hoc tests were performed to examine the differences within subjects between each of the testing periods. Power of the study for each variable measured was calculated to be between 83 and 93 for ten subjects. 11 C H A P T E R 3: RESULTS Fourteen women volunteered to participate in the study and provided written consent. Following Test 1 and surgery, seven of these women were told they would be treated with radiation and therefore entered another study investigating stage I breast cancer. The remaining seven received chemotherapy and continued with this study. Two other women entered the study after surgery. Since pre-surgery measures were not available for these subjects (G and I), Test 1 values for all variables examined were estimated by determining the average percentage change from pre-surgery (Test 1) to pre-chemotherapy (Test 2) measures of the other subjects, and then adding or subtracting this percentage to or from subject G and H ' s pre-chemotherapy measures (Test 2). This provided a more accurate means of estimation than simply using the mean of all other subjects for that test as both subjects G and I were not representative of the mean. These estimated values are found in bold in all tables, and a total sample size of nine was therefore analyzed. In a repeated measures design, missing data for a single test results in the loss of all data for that subject, consequently calculations were made to avoid sacrificing sample size. It is not expected that estimation of values at one testing point for two subjects w i l l have a large effect on the significance of the overall results. Sum of skinfolds data was difficult to obtain from subject B and therefore this subject was omitted from statistical analysis of this variable (Table 5). A final sample size of nine was obtained. The nine women ranged in age from 38 to 58 years with mean age = 45.2 + 7.29 years, mean height = 166.29 + 5.26 cm (Appendix D, Table 10), and mean weight = 61.04 ± 7.49 kg (Appendix D , Table 11). Seven of the nine subjects were pre-menopausal prior to treatment. Seven subjects were clinically diagnosed with stage U 12 breast cancer, and two with stage I, although all received chemotherapy as adjuvant treatment. Staging details for each subject are summarized in Tables 1 and 2. T R E A T M E N T D E T A I L S Following the procedure of a breast biopsy by one of two local breast cancer surgeons, pathological results and patient-physician consultation determined the type of surgery to be performed. Individual surgical data is summarized in Table 1. Table 1. Surgical Results, individual subject data Subject Surgery Tumour Size (cm) #Nodes Removed # Nodes Positive A r. mastectomy 2.2 15 1 B 1. partial . 2.0 12 0 C 1. partial 2.8 8 0 D r. partial 1.5 14 1 E 1. partial 1.5 11 0 F 1. mastectomy 2.2 15 1 G 1. partial 2.3 ,9 0 H 1. mastectomy 2.0 17 1 I r. partial 2.0 12 . 2 r = right; 1 = left; mastectomy = modified radical mastectomy; partial = partial mastectomy; tumour size = maximum tumour diameter; # nodes removed = axillary lymph nodes removed during surgery; #nodes positive = number of axillary nodes positive for carcinoma Breast tissue and axillary lymph nodes removed during the surgery provided information to determine the stage of breast cancer (Table 2) and adjuvant treatment needed. 13 Table 2. Pathology and Stage of Cancer, individual subject data Subject Type Stage E R Status A IFDC/DCIS T 2 N 1 M O (II) B IFDC T 1 N 0 M 0 (I). - • C IFDC T2N0M0(I I ) • -D IFDC T 1 N 1 M 0 (II) + E IFDC/DCIS TINOMO(I ) -F IFDC/DCIS T 2 N 1 M 0 (II) + G I F L C / L C I S T 2 N 0 M 0 (II) + H IFDC T 2 N 1 M 0 (II) + I IFDC T 2 N 1 M 0 (II) + DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ; I F D C = infiltrating ductal carcinoma; I F L C = infiltrating lobular carcinoma; E R = estrogen receptor; See Appendix B and C for information on pathology and staging Although two of nine patients were clinically diagnosed as having stage I cancer of the breast, all women received adjuvant chemotherapy. Six subjects also received radiation therapy following chemotherapy, but post-radiation results are not available for this analysis. Chemotherapy drug protocols for all patients consisted of either C M F (cyclophosphamide, methotrexate and 5-fluorouracil) or A C (doxorubicin and cyclophosphamide). Appropriate drug combinations, dosage and number of fractions were decided by both the patient and the oncologist after considering many factors including pathology results and potential side effects. A l l treatment protocols were aimed at administering the drugs once every three weeks but in the case of subject A , nausea and low white blood cell count created a one week delay with each treatment resulting in a regime occurring every four weeks. Also , subject A who was the one patient administered C M F , received six treatments and the remaining patients received four. Drug protocols, dosage of drugs and frequency and number of treatments are found in Table 3 for each subject. Doses were given at 100% of the value listed for each drug, unless a lower percentage is specified. Lower doses are administered when the subject is not managing well at 14 the prescribed dose or i f upon returning for a subsequent fraction, a low white blood cell count is found. Table 3. Chemotherapy Details, individual subject data Subject Drug Protocol Dosage/drug (mg/m2) Modifications to Dosage Frequency of Treatments #of Treatment s A C M F 960; 64; 960 n/a 4wks 6 B A C 105;1050 n/a 3wks 4 C A C 73;730 n/a 3wks 4 D A C 98;980 4th=75% 3wks 4 E A C 105;1050 2nd,4th=75% 3wks 4 F A C 90; 900 2nd=75% 3wks 4 G A C 108;1080 2nd=20%;4th=75% 3wks 4 H A C 90;900 2nd=75% 3wks 4 I A C 100;1000 2nd=90% 3wks 4 C M F = cyclophosphamide, methotrexate, & 5-fluorouracil; A C = doxorubicin & cyclophosphamide; Modifications to Dosage = reductions in prescribed dosages for specific treatments; Frequency of Treatments = number of weeks between treatments T I M E L I N E F O R T E S T I N G Time between tests varied between subjects. On average, the women participated in the first test three weeks after being diagnosed. Surgery took place approximately one week following Test 1, and subjects recovered from surgery and were able to perform the second test in approximately two and a half weeks. Exceptions from this included subjects C , E and I who were unable to perform Test 2 until about seven, six and five weeks, respectively, following surgery. These variations occurred due to delays in recovery, removal of drains, and healing processes. The average time between Test 2 and the start of chemotherapy was five days, however, individual data ranged from one to 16 days. Since eight of nine women received four treatments, three weeks apart, and one received six treatments every four weeks, the average time to complete chemotherapy was 73 days. Unlike planned study interventions, Test 3 did not occur 15 immediately following chemotherapy. The women varied in their response to the treatment, and therefore also in their ability to feel comfortable enough to perform the post-chemotherapy test. Consequently, the average time between completion of chemotherapy and Test 3 was 29 ± 19 days, and the range was nine to 73 days. Excluding subject A , who performed Test 3 73 days following the completion of therapy due to a longer period of fatigue and general illness, the average time between completion of chemotherapy and Test 3 was 24 + 11 days with a range of 9 to 38. The mean times are below in Table 4, and individual data can be found in Appendix D , Table 25. For group mean data, times between diagnosis and Test 1 and between Test 1 and surgery involve a sample of n=7 as subjects G and I did not join the study until post-surgery. Table 4 . Days Between Testing and Treatment, group mean data (n = 9) D - T l T l - S S-T2 T 2 - B C T B C T - E C T E C T - T 3 Total Days M E A N 21 * 7 * 25 5 73 29 158 ± S D ± 10 ± 5 ± 15 ± 5 ± 2 3 ± 19 ± 4 5 D = diagnosis; T# = test number; S = surgery; B C T = begin chemotherapy; E C T = end chemotherapy; * n=7 The average time from diagnosis to the completion of the study was 22.5 weeks (158.6 ± 45 days) (Table 4). Excluding subject A who's average time to completion was 252 days, the mean time was 143.0 ± 19 days. Individual subject data for total time from diagnosis to completion of the study can be found in Appendix D , Table 25. 16 A N T H R O P O M E T R Y Body mass did not change significantly from baseline to the end of chemotherapy [F = 0.16, p = .854, ES = 0.777]. Although there was an increase in sum of skinfolds from Test 1 to Test 3, this increase was not significant [ F = 0.71, p = 0.509, ES = 0.570]. Mean group data for both weight and sum of skinfolds is contained in Table 5 below, and individual data is in Appendix D , Tables 11 and 12, respectively. Table 5. Body Mass and Sum of Skinfolds, group mean data (n = 9) Test 1 Test 2 Test 3 Body mass (kg) 60.8 ± 7 . 5 61.3 ± 9 . 0 61.0 ± 9 . 5 Sum Skinfolds (mm)* 70.9 ± 3 2 . 0 63.5 ± 3 8 . 1 77.3 ± 4 1 . 1 * n = 8 P U L M O N A R Y F U N C T I O N Spirometry measures, which included F E V 1 , F V C , F E V 1 / F V C , and M W , were not found to change significantly over the treatment period (Table 6). Table 6. Statistical Results, Pulmonary Function (n = 9) Measure F(2,16) P E S F V C 0.060 0.942 0.675 F E V 1 0.170 0.849 0.626 F E V 1 / F V C 0.170 0.744 0.630 M W 1.94 0.176 0.590 Aside from M W which increased slightly but non-significantly, mean values for the other three variables were remarkably similar between tests (Table 7). Individual pulmonary function data is contained in Appendix D , Tables 13-16. 17 Table 7. Pulmonary Function, group mean data (n = 9) Measure Test 1 (mean ± SD) Test 2 (mean ± SD) Test 3 (mean + SD) F V C (L) 3.62 ± 0 . 7 3.64 ± 0 . 8 3.64 ± 0 . 8 F E V 1 (L) 2.99 ± 0 . 5 2.96 ± 0 . 6 2.97 ± 0.6 F E V 1 / F V C (%) 82.33 ± 3.4 81.78 ± 4 . 4 81.89 ± 5 . 7 M V V (L) 104.56 ± 17.9 107.44 ± 20.7 110.00 ± 16.3 E X E R C I S E C A P A C I T Y Maximal oxygen consumption, expressed both absolutely (L/min) and relative to body mass (ml/kg/min), was the only variable shown to change significantly throughout the testing period [F = 45.67, p = 0.000, ES = 0.757; and F = 17.00, p = 0.000, E S = 0.560, respectively]. Absolute values of V 0 2 m a x decreased consistently from pre-surgery to post-chemotherapy and means of each of the three tests were significantly different from each other. Likewise, V 0 2 m a x relative to body mass decreased, however, pre-chemotherapy values were not significantly different from pre-surgery. Post-chemotherapy values, however, were found to be significantly different from both pre-surgery and pre-chemotherapy V 0 2 m a x . Group means are listed in Table 8 and data plotted in Figure 2 illustrates the changes that occurred. 18 Figure 2. Changes in Maximal Oxygen Consumption (mL/min) ± SE During Stage II Breast Cancer Therapy M 2100' e a n 1900' V O 1 7 0 0 ' 2 + 1500H ± 1300i S E 1100, N « * » * 1 2 3 T e s t Other variables measured during the cycle ergometer test, including V E , H R m a x , P P O , and Sa02, did not change significantly from pre- to post-treatment. Values describing exercise capacity are summarized in Table 8. Both maximal heart rate and peak power output remained very similar throughout the maximal effort tests. Individual data for these measures can be found in Appendix D , Tables 17-22. 19 Table 8. Measures Defining Exercise Capacity, group mean data (n = 9) Measure Test 1 (mean + SD) Test 2 (mean + SD) Test 3 (mean + SD) V 0 2 (L/min) 1.70 ± 0 . 3 1 1.62 ± 0 . 3 3 * 1.47 ± 0.31* + V 0 2 (mL/kg/min) 28.3 ± 5.54 . 26.72 ± 5 . 2 5 24.52 ± 6.13* + H R m a x (bpm) 161 ± 10 161 + 11 159 + 11 V E (L/min) 85.87 ± 14.64 80.03 ± 13.57 75.01 ± 2 0 . 4 1 P P O (watts) 160 ± 2 5 161 ± 2 2 162 ± 3 6 S a 0 2 (%) 96 ± 1 95 ± 3 9 4 ± 3 * significantly different from Test 1 + significantly different from Test 2 ACTIVITY LEVELS Daily activity levels did not change significantly throughout the study period. There was, however, a marginally significant difference between mean group daily activity levels during the study (154 ± 70 Kcal/day) and levels for the year preceding diagnosis (257 ± 147 kcal/day) (t = 2.36, p = .046). Individually, seven of nine subjects had decreased levels of activity from pre-diagnosis, while subjects F and H experienced higher levels of activity during the study period as compared to the year prior to diagnosis of breast cancer. Daily activity levels for both the study period and pre-diagnosis for all subjects can be found in Appendix D , Tables 23 and 24, respectively. SMOKING ACTIVITY A l l subjects were non-smokers at their times of diagnoses, but four had a smoking history. For all four subjects, smoking cessation dates were at least 14 years or more prior to diagnosis. Pre-diagnostic lifetime smoking activity is summarized in Appendix D , Table 26 and group mean data is below in Table 9. 20 Table 9. Smoking Activity, group mean data (n=9) Yrs Smoked Packs/wk Packs/yr Total Packs Smoked Smoke-free yrs Mean + S D 6 ± 3 4 ± 2 1 8 8 ± 1 2 2 1222 ± 8 2 5 19 ± 4 21 DISCUSSION The role for adjuvant chemotherapy in breast cancer therapy is established. Studies in which surgery alone has been compared to surgery plus adjuvant chemotherapy have shown a benefit to the adjuvantly treated patients (Fisher et al., 1980; Meyer et al., 1978; Wheeler, 1979). Reports have shown not only improved relapse-free survival for patients given adjuvant C M F and A C , but also improved local-regional control (Bonadonna et al., 1976). With the recognition of chemotherapy's potent anticancer activity, however, has come an appreciation of its toxicities, the most serious of which affect the heart and lungs. The integrated response of the cardiovascular and pulmonary systems allows for oxygen uptake and delivery to the working muscles during exercise and daily activities. It was therefore thought that determination of maximal oxygen uptake and pulmonary function before and after treatment would provide a measure for chemotherapy-induced heart and lung damage. Now that women are surviving breast cancer and living longer, it is important to determine the impact that chemotherapy has on their lives and their ability to perform every-day activities. As hypothesized, maximal oxygen consumption, expressed both absolutely (L/min) and relative to body mass (mL/kg/min), was found to decrease throughout the testing period. A few of the many factors that are known to effect VC«2max include stroke volume, heart rate, and red blood cell count. Stroke volume is dependent on the contractility of the heart muscle. Numerous studies have p 22 reported anthracycline-induced cardiac damage (Gottlieb et al., 1973; Lefrak et al., 1973; Lenay and Page, 1976; Minow et al., 1977; Bristow et al., 1978), and it appears that the underlying lesion of the anthracyclines is the damaged myocyte which is characterized by a loss of contractile elements (myofibrillar degeneration). This damage could affect the heart's ability to pump blood and therefore lead to reduced oxygen consumption. Red blood cells carry hemoglobin which in turn carry oxygen molecules. Chemotherapy has been shown to decrease red blood cell counts creating potentially anemic situations (Rubin, 1983). A s with decreased contractility, the inability to carry oxygen throughout the body wi l l also affect VO2 values. Only one subject was found to exhibit exercise induced arterial hypoxemia (Sa0 2 < 91%) during the post-surgery and post-chemotherapy tests (Tests 2 and 3). Because her S a 0 2 values were lower than normal both before as well as after chemotherapy, this does not suggest chemotherapy-induced-hypoxemia as a reason for decreased oxygen consumption in her case. In fact, it is more likely that decreased cardiac contractility due to chemotherapy-induced myocyte necrosis produced the significant changes in oxygen consumption values; since oxygen saturation values remained normal throughout the testing for all but one patient, treatment-induced anemia was presumably not the problem. Although it is important to obtain a functional measure of heart damage, other more direct measures exist. Echocardiography, cardiac enzyme monitoring, radionucleotide cardiography and ejection fraction determination have been used in the past. The most accurate, yet most invasive, measure to determine cardiac. damage is endomyocardial biopsy. Any of these measures would help confirm our 23 results obtained by oxygen consumption measures and determine if, in fact, myocyte necrosis did play a role. Maximal heart rate remained unchanged at each test as did peak power output and minute ventilation, suggesting that the subjects' effort was similar for all tests. Study results neither support nor refute the existing literature because there is none. This is the first study to compare baseline V 0 2 m a x with V 0 2 m a x following a chemotherapy regime. Segal and colleagues (1996) followed V 0 2 m a x in women undergoing chemotherapy but also implemented an exercise program to see i f V 0 2 could be maintained. V 0 2 values were in fact maintained and, of course, were more favorable than the non-exercising control group that was selected for comparison nine and a half weeks into their adjuvant therapy. In a similar study (Earle et a l , 1996), aerobic capacity as measured by the Canadian Aerobic Fitness Test ( C A F T ) was maintained while exercising during chemotherapy. Although these two studies examine oxygen consumption in women before and after chemotherapy, they are providing V 0 2 values which are under the influence of training. Contrary to this, the present study has attempted to provide baseline measures and a pattern of aerobic capacity change during chemotherapy treatment to see if, in fact, chemotherapeutic drugs have an effect on the heart and lungs. The majority of studies performed investigating cardiac toxicity of anthracyclines have examined the late effects of these drugs (Weesner et al., 1991; Forbes, 1992; Dresdale et al., 1983). While many studies have examined cardiac damage up to ten years post-treatment, this study provides evidence for drug-24 induced acute changes in the heart occurring within weeks after completing chemotherapy. Doxorubicin is the most well-known chemotherapeutic drug that is associated with cardiac toxicity. Doxorubicin-associated toxicity, which is characterized by diffuse myocardial injury leading to irreversible cardiomyopathy, is related to the total dose administered (Dresdale et al., 1983). The exact temporal relationship between the administration of doxorubicin and the onset of detectable cardiomyopathy is unclear in the literature. Nonetheless, biopsies performed three to four weeks after the last dose of drug have shown myocyte damage (Bristow et al., 1978). These same authors believe that the doxorubicin-associated myocardial degenerative process begins before any functional abnormality of left ventricular dysfunction can be detected either by clinical examination, prolongation of the P E P / L V E T , or abnormal catheterization findings (Bristow et al., 1978). This supports the idea of acute onset of damage. There is a ten percent chance that congestive heart failure wi l l develop when cumulative doses rise above 450 mg/m 2 (Speyer et al., 1988), and it is recommended that the total dose of doxorubicin not exceed 550 mg/m 2 (Bristow et al., 1978). Bristow and colleagues found that the lowest dose of doxorubicin at which there was biopsy evidence of drug-effect was 45 mg/m 2 . Examining lower doses, doxorubicin administration was found to be associated with a dose-related increase in the degree of myocyte damage and degenerative cardiac changes as identified by cardiac biopsies in 27 of 33 adult patients receiving doses greater than 240 mg/m 2 of doxorubicin (Bristow et al., 1978). A t a total dose of 400 mg/m 2 , the pre-ejection period to left ventricular ejection time ratio began to increase. Patients in our study received on average 380 mg/m 2 of doxorubicin, with a peak cumulative dose of 420 mg/m 2 received by 25 subject B . Results from Bristow and colleagues support the idea that doses of doxorubicin received by patients in our study may be sufficient to induce V0 2 m ax-sensitive changes in heart function. It should be noted, however, that subject A , who was not administered doxorubicin, also exhibited decreased maximal oxygen consumption. It cannot be ignored that a psychological factor may play a part in determination of VC^ax- Of the criteria outlined to determine attainment of V02max, volitional fatigue is the most subjective. Women receiving chemotherapy have been shown to experience fatigue and depression (MacVicar, 1986). It cannot be overlooked that "volitional fatigue" becomes "perceived fatigue," which may occur at a lower threshold in these women following chemotherapy, resulting in early termination of the test. Peak power output and maximal heart rate values remained unchanged yet maximal oxygen consumption decreased; these results are difficult to reconcile. A s many of the subjects had not cycled regularly in the past, they may have become more familiar with the cycling protocol by the second and third tests, therefore being able to reach a consistent maximal power output with less oxygen consumption. Another explanation could be that subjects became peripherally fatigued throughout the test before they were centrally limited by their working heart and lungs. Anecdotally, subjects complained of soreness in their legs before being out of breath. Objectively, however, all subjects met the criteria for obtaining maximal V 0 2 by achieving a respiratory exchange ratio greater than 1.15, a heart rate greater than 90 percent of predicted maximum, and most importantly, a plateau in oxygen uptake with increasing workrate. 26 It has been suggested that women undergoing chemotherapy for breast cancer become entangled in a negative cycle of debilitation and reduced physical conditioning that fosters a further decrease in physical activity (MacVicar and Winningham, 1986). The patient's ability to exercise is likely to be influenced by progressive inactivity resulting from the side-effects of treatment. In order to assess the effects of chemotherapy alone on exercise capacity, activity levels were recorded during the treatment period as well as calculated one year prior to diagnosis in an attempt to control for the effect of activity or lack thereof. Seven of nine women were unable to maintain their pre-diagnosis exercise level and the activities they performed were reduced. It is possible that the discrepancy in activity level between pre- and post-diagnosis played a role in the observed decreases in oxygen consumption. However, despite a decreased VO2 from pre-surgery to post-chemotherapy (Test 1 to 3), activity levels during this period remained unchanged. Therefore although activity patterns during the study period were different from those prior to diagnosis, activity remained unchanged during testing while V 0 2 decreased. The function of the lung depends on the integrity of the airways, the pulmonary vascular system, the alveolar septa, the respiratory muscles, and the respiratory control mechanisms. It would be ideal i f pulmonary function tests could assess the functional status of each of these systems separately, however, they do not. In this study, the evaluation of pulmonary function was to determine the presence of potential drug-induced lung disease and the extent of any abnormalities. 27 Results from the pulmonary function testing did not support the original hypothesis. It was expected that the cytotoxicity of the chemotherapeutic drugs would create measurable changes in lung function. Instead, measures of FVC, FEV1, MVV, and the ratio FEV1/FVC were remarkably similar for all three tests, and were all equal to or greater than the calculated predicted values for each woman. Subjects' values at each test were considered "normal" under the guidelines for grading the severity of pulmonary function impairment provided by Morgan and Seaton (1984). Smoking activity did not appear to have an effect on spirometry measures. Ruppel (1986) suggests that FEV1 might be reduced in chronic obstructive diseases and that decreased values of both FEV1 and FVC are common in restrictive patterns. As a result of this, the ratio of the two values is expected to be low with obstruction, but remain the same or increased with restrictive disease; FVC and FEV1 would either be reduced in equal proportion or FVC alone would be decreased (Ruppel G., 1986; Morgan and Seaton, 1984). The pulmonary function tests in this study showed no evidence of restrictive or obstructive disease. The literature suggests that chemotherapeutic-induced lung damage can present as acute or chronic disease. Todd and colleagues (1992) suggest that acute pneumonitis is caused by an inflammatory cascade triggered by oxidant injury responsible for permanent epithelial and endothelial lung damage. McDonald et al. (1995) describes the early restrictive damage of pneumonitis as occurring one to three months after drug completion/but occasionally within days. Chronic fibrosis is described as occurring within months to years. Radiography, computed tomography, nuclear medicine ventilation/perfusion scanning and 28 pulmonary function tests are listed as possible means of determining such early changes. In the present study, it is likely that the spirometry tests performed were not sensitive enough to detect any early changes in inflammation that may be developing, and that other detection methods may be needed. Pulmonary function testing three to four months following completion of chemotherapy might reveal obstructive or restrictive patterns, perhaps due to the late effects of pulmonary fibrosis. Because the majority of cytotoxicity is thought to interfere with gas exchange at the alveolar-capillary membrane, a measure of diffusing capacity may have shown some impaired function. If portions of the lung become nonfunctional following chemotherapy, compensatory overexpansion of already ventilated non-damaged portions may increase lung volumes. McDonald suggests, however, that this overexpansion mainly increases the dead space and does not necessarily provide additional alveolar surface area for gas exchange; therefore diffusion capacity may be the more sensitive assessment of whole lung function. A recent unpublished study by Reid et al. (1997) showed a decrease in both F E V 1 and F V C / F E V 1 one week as well as two months following radiation therapy for stage I breast cancer. The authors attributed this change to an obstructive pattern. Moreover, decreases in diffusion capacity were found to occur at similar time periods, likely attributable to inflammation. Similar pathological changes in the lung are thought to occur from both chemotherapy and radiotherapy (McDonald et al., 1995), however, irradiation may produce more early measurable changes due to the direct nature of the therapy versus the systemic approach of chemotherapy. Despite this theory, McDonald et al. (1995) report that no gross 29 abnormalities in lung function occur before 4-8 weeks after completion of a course of radiotherapy. It is also possible that the cumulative doses of chemotherapy these patients received were not high enough to cause measurable lung damage. Eight of nine patients received A C therapy and one received C M F . O f these two regimes, the most common drugs known to produce lung damage are methotrexate and cyclophosphamide. Reference to exact doses known to cause toxicity are rare in the literature but some authors report doses found to produce toxicity in their particular studies. Eight subjects in a study by White et al. (1984) receiving C M F and vincristine sulfate developed pneumonitis as diagnosed by chest roentgenograms and abnormal pulmonary function tests with a decreased diffusing capacity. Cumulative cyclophosphamide doses ranged from 1800 to 11900 mg/m 2 , and total methotrexate doses ranged from 100 to 3,800 mg/m 2 with the lowest weekly dose of 15 mg that lead to a toxic reaction. Treatment regime in a study by Todd et al. (1993) consisted of four cycles of F A C to provide a total dose of 2400 mg/m 2 of cyclophosphamide. Following this treatment, high-dose consolidation chemotherapy consisted of an additional 1875 mg/m2/day of cyclophosphamide for three days. T h i s study by Todd and colleagues is one of few to measure baseline pulmonary function measures. Subjects in both studies showed evidence of obstructive and restrictive lung disease. Patients in our study received on average 3800 mg/m 2 of cyclophosphamide (for both A C and C M F regimes), not taking into account any reductions in doses due to low white blood cell or platelet counts. Although this dose falls within the range of potentially toxic doses mentioned above, it is still unclear as to the exact amount of cyclophosphamide 30 that w i l l induce lung damage. While acute changes in pulmonary function were not significant, late effects of pulmonary fibrosis may still pose a risk to this group. S U M M A R Y The results indicate that chemotherapy can affect the cardiorespiratory fitness of women, as evidenced by the significantly decreased V 0 2 m a x values following treatment. The reduced functional capacity was suspected to be due to decreased contractility of the heart as a result of acute cardiac myocyte necrosis. Respiratory function failed to show any deterioration, although more sensitive measures may be necessary to detect such acute changes. R E C O M M E N D A T I O N S The goal of this study was to identify where decreases in functional capacity, i f any, occur during a protocol of surgery and chemotherapy as treatment for breast cancer. Now that these baseline measures have been determined and it has been established that reduced exercise capacity occurs between the initiation and completion of chemotherapy, it is possible to design exercise programs appropriate for that time period which wi l l help prevent such decreases in exercise ability. Studies have already shown that exercise during chemotherapy is both possible as well as safe (Mac Vicar & Winningham, 1986; Mac Vicar & Winningham, 1989). Activity logs showed that the women were able to exercise during chemotherapy but not at the level they did one year prior to diagnosis. Normal physical activity during breast cancer treatment is therefore important for maintaining functional capacity and may help alleviate or prevent the decreased 31 exercise capacity caused by the chemotherapeutic drugs. Specific programs in regards to frequency, intensity and duration of exercise, as well as group interaction may make exercising easier for women. 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Godwin, and D .E . Stover. Chemotherapy-associated pulmonary toxic reactions during treatment for breast cancer. Archives of Internal Medicine. 144(5):953-956, 1984. Wingate, L . , L . Croghan, N . Natarajan, A . Michalek, and C . Jordan. Rehabilitation of the mastectomy patient: a randomized, blind, prospective study. Arch Phys Med Rehabil. 70:21-24, 1989. Winningham, M . L . Walking program for people with cancer. Cancer Nursing. 14(5):270-276, 1991. Winningham, M . L . and M . G . MacVicar. The effect of aerobic exercise on patient reports of nausea. Oncology Nursing Forum. 15(4):447-450, 1988. Winningham, M . L . , M . G . MacVicar , M . Bondoc, J. Anderson, and J. Minton. Effect of aerobic exercise on body weight and composition in patients with breast cancer on adjuvant chemotherapy. Oncology Nursing Forum. 16(5):683-689, 1989. Young-McCaughan, S. and D . Sexton. A retrospective investigation of the relationship between aerobic exercise and quality of life in women with breast cancer. Oncology Nursing Forum. 18(4):751-757, 1991. 40 APPENDIX A: L I T E R A T U R E REVIEW The staging of breast cancer consists of several systems, but all have the common goal of grouping patients with respect to prognosis and treatment. The most common are the stage I, II, UI, I V system, and the T N M system (Appendix B) . In the former, stage I represents early cancer with a small tumour and no spread to the lymph nodes. The tumour becomes progressively advanced in stage II and III with probable involvement of the lymph nodes, and stage I V refers to metastatic disease that has spread to other areas of the body (Olivotto et al., 1995). The T N M system describes the tumour in terms of: the size/extent of the tumour (T), lymph node involvement (N), and the presence or absence of metastases (M) (Olivotto et al., 1995). The final diagnosis of breast cancer is made by examining the pathology of the tumour and the lymph nodes. Features of the pathology report that affect the treatment strategy include: size of the tumour, type, extent of invasion, grade, necrosis, receptors for estrogen and/or progesterone, and the number of lymph nodes involved (Olivotto et al., 1995). Breast cancers are divided generally into two types: invasive cancers and non-invasive or in situ cancers, which in turn are both generally divided into lobular and ductal. Within these broad categories, however, there are over 30 different types as seen under the microscope (Dollinger et al., 1995). Specifically, ductal carcinoma in situ (DCIS) refers to cancer that is still within the milk ducts of the breast.. In situ cancer of the ducts comprise 10 to 20% of the cancers found by screening mammography and i f left untreated, may progress to form an invasive cancer (Olivotto et al., 1995; Page et a l , 1982). Confined to the milk lobules, lobular carcinoma in situ (LCIS) is also associated with an increased frequency of subsequent invasive carcinoma (Flutter, 1984; Olivotto et al., 1995). Cancer becomes invasive, or infiltrating, when the cancer cells grow through the 41 walls of the milk ducts and glands into the normal fatty tissue of the breast. A s with in situ cancers, infiltrating cancers involve the ducts and lobules (IFDC and I F L C ) of the breast. I F D C is the most common of the invasive cancers, representing 65 - 80% of breast tumours. There is often D C I S present with I F D C (Devita et al., 1989). A n important factor in determining prognosis and treatment is hormone receptor status. To determine this, estrogen receptor (ER) protein of the primary cancer and progesterone receptor (PR) levels are measured in fentimoles (fmol) per milligram of cytosol protein, and a tumour with a level above ten fmol is usually considered positive (Dollinger et al., 1995). In general, the higher the estrogen receptor level, the more responsive the tumour wi l l be to any anti-estrogen therapy, such as Tamoxifen (Olivotto et al., 1995). Fisher et al. (1988) evaluated the predictive power of E R and PR as to disease-free survival and overall survival in node negative patients. In ER-positive, node-negative patients, both disease-free survival and overall survival were significantly better than in those patients with ER-negative tumours. P R status made no independent prediction of prognosis. T R E A T M E N T OF S T A G E H B R E A S T C A N C E R After the presence of a malignancy is confirmed and histology is determined, treatment options are discussed. It is now more common for primary physicians, surgeons, medical oncologists, and the patient herself to work together to plan the patient's treatment. If the cancer is confined to the breast and axillary lymph nodes then the primary therapy is usually surgery. During the 1970's, the modified radical mastectomy replaced the radical mastectomy as the predominant surgical procedure for breast cancer (Stefanik et al., 1985). Today, conservative therapy in the management of early-stage carcinoma of the breast is becoming an established alternative to mastectomy, and several randomized studies involving an accumulated median of 42 ten or more years of follow-up confirm that breast-conserving local therapies and more radical surgical therapies yield similar rates of survival (van Dongen et al, 1992; Veronesi et al., 1990; Sarrazin et al., 1989; and Fisher et al., 1989). Stage II breast cancer is curable with a range of accepted surgical procedures as well as adjuvant therapy. Surgical options include mastectomy, mastectomy with reconstruction, or conservative surgery (i.e., lumpectomy). Survival has been shown to be equivalent with any of these options, as documented in randomized prospective trials (Fisher et al., 1995; Jacobson et al., 1995; van Dongen et al, 1992; Sarrazin et al;, 1989). Following surgery, adjuvant combination chemotherapy is given to reduce the rate of recurrence and improve survival, and in some cases, radiation follows in order to improve local control of the disease. Studies have confirmed that when both adjuvant radiotherapy and chemotherapy are necessary, it is preferable to give a course of chemotherapy followed by radiation therapy, rather than the reverse (Recht et al., 1996; and Wallgren et al., 1995). Chemotherapy is the obvious treatment of choice when dissected axillary nodes are positive for metastatic cancer. Some patients, however, usually pre-menopausal women, with no obvious metastases at the time of surgery but who are at high risk for such micrometastases may also be prescribed adjuvant chemotherapy (Dollinger et al., 1995). Numerous studies have shown that combination chemotherapy is superior to single-agent treatment (Jones et al., 1987; Bonadonna et al., 1976; Pearson et al., 1989). The following combinations are the most commonly used and have been shown to provide therapeutic benefit in conjunction with surgery, compared to surgery alone: cyclophosphamide + methotrexate + 5-fluorouracil ( C M F ) (Tancini et al., 1983; and Bonadonna et a l , 1976; Stefanik et al., 1985); 5-fluorouracil + doxorubicin + cyclophosphamide (FAC) (Buzdar et a l , 1989); and doxorubicin + cyclophosphamide (AC) (Jones et a l , 1982; Fisher et al. (a), 1990). 43 The literature clearly reinforces the need for adjuvant chemotherapy when treating breast cancer. In a trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP-B-16) , node-positive women 50-59 years of age had improved disease-free and overall survival when treated with tamoxifen and chemotherapy (AC) compared to those treated with tamoxifen alone (Fisher et al. (b), 1990). Because a significant number of patients with node-negative breast cancer can also have disease recurrence (Rosen et al., 1991), several prospective randomized trials have studied adjuvant chemotherapy in node-negative breast cancer. A small randomized trial comparing adjuvant chemotherapy with C M F versus no adjuvant therapy showed improved disease-free and overall survival for poor-prognosis node-negative patients treated with C M F (National Institutes of Health Consensus Development Conference statement: adjuvant chemotherapy for breast cancer, 1985). A C and C M F have been found to produce similar results in terms of disease-free survival in both pre- and postmenopausal patients, but there are differences in toxicity that may influence the choice of regime (Fisher et al. (a), 1990). E F F E C T S O F C H E M O T H E R A P Y Although chemotherapy has been proven to increase overall and disease-free survival in •f breast cancer patients, this adjuvant therapy can cause side-effects, some of which may be lethal (Forbes, 1992; Ginsburg and Comis, 1982; McDonald et al., 1995; Stefanik et al., 1985). Apart from the well-known effects such as fatigue, nausea, hair loss and mouth sores, both acute and chronic drug-induced damage has been known to occur in the heart and lungs. Doxorubicin (anthracycline antibiotic), cyclophosphamide (alkylating agent), methotrexate (antimetabolite), and 5-fluorouracil have all been shown to exhibit toxic effects (Billingham et al., 1978; Bristow et al., 1978; Cherniack et al., 1994; Dresdale et al., 1983; Forbes, 1992). 44 \ P U L M O N A R Y E F F E C T S Pulmonary toxicity has been associated with a variety of chemotherapeutic agents, two more remarkable ones being cyclophosphamide and methotrexate. Cases of pulmonary toxicity thought to be related to cyclophosphamide administration have been documented since 1967 (Patel et al., 1976; Mark et a l , 1978; Sostman et a l , 1977). Cyclophosphamide pulmonary toxicity does not appear to be schedule or dose dependent and has been seen as early as one month and as late as eight years after beginning therapy (Ginsberg and Comis, 1982). It has occurred after both intermittent intravenous administration and continuous oral administration of the drug. Total doses have ranged from 150 mg to 81 gm, however, in a study of 39 patients who received cyclophosphamide in a high dose of 50-120 mg/kg/day for one to four days, no interstitial pneumonias believed to be due to cyclophosphamide were seen (Slavin et al., 1975). W e l l described cases of pulmonary parenchymal disease attributed to methotrexate have been reported since the late 1960's (Clarysse et al., 1969; Ginsberg and Comis, 1982). While the pulmonary toxicity does not appear to be related to total dose, there may be a threshold effect since patients receiving weekly doses of less than 20 mg are not likely to develop the disease. Like the alkylating agent cyclophosphamide, the incidence of methotrexate induced pulmonary toxicity is difficult to determine. They are widely used to treat both malignant and certain nonmalignant disorders, and patients often receive other antineoplastic drugs in combination with these (Ginsberg and Comis, 1982). The mechanism behind drug-induced pulmonary toxicity is thought to occur due to direct cytotoxicity to the cells maintaining the alveolar capillary barrier, i.e., the alveolar epithelium and capillary endothelium. This direct cytotoxicity takes place among the anthracyclines, whereas methotrexate may cause a marked inflammatory or immune response in the lung, resulting in a 'hypersensitivity' reaction (Cherniack et al., 1994; VanHoutte, 1987). When drugs are used in 45 combination, such as in CMF therapy, the potential pathogenic mechanisms for such multiple agent exposure may include: a direct interaction between the two chemicals, leading to a third, more toxic compound; amplification of the original toxicity by a second agent when the two agents attack different target sites; and enhanced susceptibility to toxic insult by a pre-existing disease process (Cherniack et a l , 1994). It is also possible that irradiation for breast cancer following chemotherapy may enhance the existing toxicity (Cherniack et al., 1994). Typically, anticancer drugs are thought to produce type I cell injury in the lung resulting in acute pneumonitis or chronic pulmonary fibrosis. The pathogenesis appears to include formation of free radicals and lipid peroxidation of phospholipid membranes. Permeability therefore increases resulting in interstitial edema and swelling and necrosis of the type I pneumocytes. They become replaced by cuboidal cells and, later, proliferation of fibroblasts with resulting fibrosis (Cherniack et al., 1944; McDonald et al., 1995). Interstitial pneumonitis is also seen with alkylating agents and may lead to the development of pulmonary fibrosis, characterized by the enhanced production and deposition of collagen (McDonald et al., 1995). Subsequent compromise in gas exchange results. Atypical type I I cells and endothelial damage are also characteristic of lung injury due to chemotherapeutic agents. In a study by Todd etal. (1993), 23 of 59 patients who received high-dose combination alkylating agent chemotherapy were associated with a clinical syndrome of pulmonary drug toxicity, and ten of these in whom open-lung biopsies were obtained, exhibited features of Type I I cell and endothelial cell damage. In another study, chemotherapy-related pneumonitis developed in eight patients during treatment for breast cancer (White et al.., 1984). Six patients were receiving adjuvant chemotherapy and two were receiving therapy for metastatic disease. Although the study involved multi-drug therapy, the common drug received by all patients was methotrexate, and investigators believed that their pathologic and clinical findings 46 were consistent with methotrexate-induced pneumonitis. In a similar setting of multi-drug chemotherapy for breast cancer, Stutz et al. (1973) noted six cases (35% incidence) of pulmonary toxic reactions and proposed the joint action of methotrexate and cyclophosphamide as the causative agents. The clinical syndrome of pneumonitis has been said to occur one to three months after completion of drug therapy, but occasionally an accelerated phase of the syndrome has developed within a period of days (McDonald et al., 1995). In contrast to the acute reaction, chronic effects of pulmonary fibrosis have been observed from months to years following treatment. Aside from radiography and nuclear medicine tests, a wide range of less expensive and more accessible pulmonary function tests can be performed to measure the extent of the pulmonary damage. McDonald et al. (1995) suggests that the basic evaluation that would be. valuable in assessing patients would first consist of measurement of the forced vital capacity ( F V C ) , the forced expiratory volume in one second (FEV1) and the ratio of the two ( F E V 1 / F V C % ) . This measure indicates whether there is an obstructive or restrictive pattern of impairment. It is also stated that the most sensitive measure is a carbon monoxide diffusing test which measures the degree of alveolar capillary block. Preferably, these tests should be administered before the anticancer therapy is begun. In a study by White et al. (1984) where six patients developed chemotherapy-related pneumonitis, pulmonary function tests were abnormal and diffusing capacity for carbon monoxide was greatly decreased in all patients. Four of these patients also had evidence of mild to moderate restrictive lung disease based on decreased lung volumes. In this study and in others, procedures used to measure pulmonary toxicity have included: chest radiographs (White et al., 1984; Todd et al., 1993), gallium scans (McDonald et al., 1995), biochemical markers such as plasma T G F - B levels (Anscher et al., 1994), lung biopsies and C T scans (Todd et al., 1993). 47 C A R D I A C E F F E C T S The most popular chemotherapeutic drug known to cause cardiac damage is the anthracycline, doxorubicin (Forbes, 1992; Dresdale et al., 1983). It has been established in multiple reports (Gottlieb et al., 1973; Lefrak et al., 1973; Lenay and Page, 1976; Minow et al., 1977) that the clinical incidence of doxorubicin-induced deterioration of cardiac function is proportional to the total dose administered. Late cytotoxic effects of doxorubicin include: dysrhythmias, tachypnea, cardiac dilation, pulmonary edema, and cardiogenic shock (Forbes, 1992; Minow et al., 1975; Billingham et a l , 1978; Bristow et al., 1978). According to a review by Forbes (1992), anthracycline-induced cardiotoxicity is predominantly seen in advanced breast patients rather than in patients receiving adjuvant chemotherapy, and that in general, the cumulative dose used in adjuvant therapy (i.e., 200-240 mg/m2) should be safely below a cardiotoxic dose. There has, however, been very little long-term follow-up concerning this issue, or in regards to cardiotoxicity with the added use of radiotherapy. The pathology of cardiotoxicity caused by anthracyclines has been described by Billingham et al. (1978). An increasing cumulative dose is known to cause progressive damage. Initially, drug-induced myofibrillar loss and altered sarcoplasmic reticulum occurs, followed by more extensive changes including cytoplasmic vacuolization, loss of organelles and diffuse myocardial fibrosis. The mechanism may involve altered calcium handling, damaged sarcoplasmic reticulum, and the induction of toxic radicals by peroxidation (Billingham et al., 1978). As a result, anthracyclines are known to cause both acute (arrhythmias, pericarditis, and heart block) and chronic complications (cardiomyopathy and cardiac failure) (Forbes, 1992). The incidence of developing cardiomyopathy is 0.4-0.9% of all patients treated with a total dose of up to 550 4 8 mg/m 2 , and cardiac failure occurs in 0.1-1.2% of patients. It is also thought that 21-day cycles may be more cardiotoxic than weekly infusions (Forbes, 1992). To study possible late anthracycline-induced cardiotoxicity, Weesner et al. (1991) examined twenty long-term survivors of childhood cancer. Both patients who had received anthracyclines and those who had not demonstrated normal cardiac function at rest, but the latter group had a greater increase in M-mode shortening fraction, velocity of circumferential fibre shortening and Doppler aortic peak flow velocity. The authors suggested that abnormalities in myocardial function become apparent after exercise. Dresdale et al. (1983) prospectively investigated doxorubicin-induced cardiomyopathy resulting from postsurgical adjuvant treatment of patient with soft tissue sarcomas. 101 patients received a range of 430-600 mg/m 2 of doxorubicin, and 14 developed clinical congestive heart failure attributable to doxorubicin. Nine of the 14 were found to have abnormal mean ejection fraction both at rest and exercise. Of the 61 asymptomatic patients, 13 had abnormal resting left ventricular function, and overall incidence of cardiomyopathy was 46%. Doxorubicin appears to have a positive dose-response relationship (Jones et al., 1987), and compounds containing this drug are generally more toxic in that they guarantee alopecia and cause irreversible congestive heart failure in as many as one of 65 patients treated (Allen, 1979; VonHoff et al., 1979). As a protective effect, dexrazoxane may delay cardiac damage, however, its impact on efficacy remains unclear as it is not approved for use in the adjuvant setting (Hudis and Norton, 1996). Considering the cytotoxic effects on both the heart and lungs, it is important that oncologists understand the risks that many chemotherapeutic drugs pose on patients, and that they prescribe both the type of drug and the dose very carefully. When two regimes for adjuvant chemotherapy have been shown to be equally efficient in providing disease-free survival, such as 49 the case with A C and C M F (Fisher et al., 1990), the use of one combination over the other in order to reduce the potential toxicity should be considered. EFFECTS ON EXERCISE CAPACITY PHYSIOLOGY OF EXERCISE While deficient exercise performance of women treated for breast cancer can result from hypoactivity and detraining, it can also be caused by specific treatment-induced pathophysiological factors that limit exercise-related function (Frontera and Adams, 1986; Harvey and Beattie, 1996; Howley et al., 1995). To understand the effects of radiation and chemotherapy on the heart and lungs during exercise, it is necessary to consider the processes involved in the transport of oxygen to the tissues during exercise. The transport of oxygen involves ventilation, diffusion from alveoli to pulmonary capillaries, pumping of the heart to provide circulation, and delivery of oxygen to the mitochondria. To meet the metabolic demands of exercise each component of the oxygen transport system must make adjustments (Frontera and Adams, 1986). Respiratory contributions to oxygen transport involve an increased minute ventilation resulting from increases in both rate and tidal volume. Diffusion and the ratio of alveolar ventilation to lung perfusion also determine gas exchange, as do the length of the diffusion path, the number of red blood cells or their hemoglobin concentration, and the surface area available for diffusion (Fox et al., 1992; Frontera and Adams, 1986; Skinner, 1993). Ideal physiological conditions for diffusion at the alveolar-capillary membranes include a short diffusion path, both a large surface area and pressure gradient, and fully saturated hemoglobin. It is clear that the development of cytotoxic-induced pulmonary pneumonitis and pulmonary fibrosis would interfere with this ideal pathway for gas exchange. Reduced flexibility and elasticity of the pulmonary tissue (Marieb and Mallat, 1992) as well as alveolar septal thickening and intraalveolar edema 50 (Frontera and Adams, 1986) wi l l compromise lung function. This decrease in diffusion wi l l increase the ventilation required to transfer oxygen between the alveoli and the pulmonary capillaries. Cardiovascular adjustments for aerobic exercise include an increase in the volume of blood pumped, or cardiac output, which is a function of heart rate times stroke volume. There is a linear rise in cardiac output versus maximal oxygen uptake ( V 0 2 m a x ) , with heart rate contributing most to this rise because stroke volume increases minimally above 40 to 50% V 0 2 m a x (Skinner, 1993). The increase in stroke volume during exercise is due to an increase in myocardial contractility, or stronger ventricular contraction (Fox et al., 1993). A relatively slow heart rate coupled with a relatively large stroke volume indicates an efficient circulatory system. V 0 2 is also dependent on cardiac output and the extraction of oxygen from the blood, which is the arteriovenous oxygen difference. This difference reflects how much oxygen is extracted by the tissues and the redistribution of blood flow between inactive and active muscles. With exercise, blood flow is directed away from inactive organs to the active skeletal muscle. The V 0 2 of muscle then depends upon vascularity, diffusion, muscle fiber distribution, and the total oxidative potential of these muscle fibers (Skinner, 1993). Decreased contractility possibly due to myofibrillar loss or altered sarcoplasmic reticulum (Billingham, 19) may affect one's ability to increase stroke volume during exercise. In normal individuals, the limitation in oxygen transport probably lies in the delivery of oxygen to active muscle by the circulation. Intensive treatments for cancer, however, can affect one or more of the components of the oxygen transport system creating a subnormal exercise capacity (Frontera and Adams, 1986). 51 EFFECTS OF EXERCISE INTERVENTION A s in other populations of patients who experience debilitating diseases and treatments, exercise has been postulated as a form of rehabilitation in breast cancer patients. Winningham and Mac Vicar have performed various intervention studies examining the effects of exercise on body weight and body composition (Winningham et al., 1989), as well as nausea and other treatment-related symptoms (Winningham and Mac Vicar, 1988). Assuming a yet-to-be-established decline in functional capacity due to' treatment regimes, these researchers have also examined the effects of aerobic training on V 0 2 m a x measures in cancer-treated women (MacVicar and Winningham, 1989). Also studying the effects of exercise intervention in women treated for stage I and stage II breast cancer, Mock et al. (1994) examined exercise tolerance, and Young-McCaughan et al. (1991) retrospectively investigated quality of life. Each of these studies revealed positive effects of exercise programs on the parameters measured. CRITIQUE OF THE LITERATURE A s observed in the studies by Mock et al. (1994) and Greenberg et al. (1992), the authors have made a minor attempt at examining the functional capacity of women treated for breast cancer, however, this was never the main purpose of these studies. In fact, there are no studies which have set out to directly measure the baseline effects of a combined breast cancer treatment therapy on aerobic capacity parameters. Maximal aerobic power ( V 0 2 m a x ) is one of the most common measurements made in exercise physiology laboratories and is generally accepted as the best measure of the functional limit of the cardiovascular system (Howley et al., 1995). A s we have seen from the literature, intensive treatments for cancer can affect one or more of the components of the oxygen transport system, namely the heart and lungs, thus creating a subnormal exercise capacity. V 0 2 m a x tests accompanied by measures of pulmonary function 52 would surely provide an indication of aerobic capacity in these women. Nevertheless, there are no known studies in breast cancer research which have measured VC-2max before, during and after treatment therapies, and very few which have measured pulmonary function. Studies in children, however, have been performed which have evaluated exercise tolerance after cancer therapy. Most recently, McKenzie et al. (1995) determined the aerobic capacity of children and adolescents who were treated for malignant disease. Subjects had been treated with surgery, chemotherapy, and/or radiation and were asked to perform resting pulmonary function tests as well as a maximal V O 2 tests on a cycle ergometer. Compared to healthy controls, the female patients exhibited a significantly decreased maximal aerobic capacity whereas the male patients were also lower than the controls but the difference was not significant. Numerous studies have documented the effects of cancer therapy on pulmonary and cardiac function in children (Benoist et al., 1982; Hancock et al., 1993; Lipshultz et al., 1991; Pihkala et al., 1995; Sharkey et al., 1993). As in breast cancer research, however, no studies exist which examine the treatment effects on physiological variables such as VC-2max , with McKenzie et al's (1995) study being the exception in children.. There thus remains no information on the response to an exercise challenge in patients who have been successfully treated for stage II breast cancer. The only attempt to measure the effects of breast cancer therapy on the heart and lungs before and after treatment was by Strender et al. (1986). The study, however, examined only the effects of radiation on the heart, and although an exercise test was performed to measure working capacity of the patients, a measure of V 0 2 m a x was not included. Late cardiac complications were examined six months and ten years following treatment, but measures were neither performed during treatment nor weeks after to determine the early effects of therapy. 53 Some studies have jumped ahead and attempted to design exercise programs for cancer patients who have undergone various treatment regimes (Johnson and Kel ly , 1990; Mac Vicar and Winningham, 1986; Mac Vicar et al., 1989; Winningham, 1991). One of the first reported studies to determine the effect of exercise on breast cancer patients was by Mac Vicar and Winningham (1986), and evaluated the effect of a progressive, interval training exercise program on the physical responses of six cancer patients undergoing adjuvant chemotherapy. Patients exercising three times per week for ten weeks at an intensity of 60-85% of maximum were compared with four non-exercising patient controls and six exercising, healthy age-matched controls. They found breast cancer patients who exercised demonstrated a pre-to-post-test increase in oxygen uptake of 20.7 % (from 1.37 to 1.73 litres of oxygen) as compared to an increase of 17.4 % for healthy, age-matched controls who exercised. The non-exercising patients decreased 1.8 % during the experimental period. More recently, Mac Vicar and Winningham (1989) studied the effect of a ten week aerobic interval-training exercise program on functional capacity (V0 2 max) in 45 women receiving chemotherapy for treatment of stage II breast cancer. Exercise patients completed a program similar to their previous study and the placebo group participated in ten weeks of non-aerobic stretching exercises. A 40 % improvement of V02m ax was achieved by the exercise group from pre-to-post-test while V0 2 m ax of the placebo group did not significantly change. Although both studies show that the intervention protocol was effective in promoting adaptation of the aerobic physiological energy systems of the exercise patients, these studies can only be assuming that a decrease in functional capacity accompanies such treatment programs because no direct baseline measures of functional capacity (i.e. V02max) in relation to cancer therapy exist in the literature. If baseline, descriptive studies were to be performed and showed no decrease in functional capacity due to breast cancer treatment, then the previously mentioned intervention studies would simply 54 be showing a training effect which has been well documented in the past. It is unlikely that descriptive studies would fail to show a decrease in V 0 2 m a x with cancer therapy, however, it is unreasonable to think that such intervention studies can be performed without first obtaining baseline data. WHAT IS THE LITERATURE MISSING? There is currently no information on the descriptive changes in V 0 2 m a x that occur in patients who have been successfully treated for breast cancer. A s described earlier, a V 0 2 m „ test in combination with pulmonary function tests would be a good measure of the functional capacity of the heart and lungs in these patients. Although these measures would provide an excellent indication of the extent to which the various cancer treatment methods have affected the oxygen transport systems of these women, to date there have been no attempts to perform these measures. Measures that have been performed document the late effects of chemotherapy and radiation on the heart and lungs (Forbes, 1992; Strender et al., 1986; Wallgren, 1992), but few studies (Mock et al., 1994; Strender et al., 1986) examine early effects occurring one to two months following treatment. Furthermore, identification of exact treatment methods utilized in the studied women has not been thoroughly reported (Forbes, 1992; Mock et al., 1994; Wallgren, 1993; Wingate et al., 1989). It becomes difficult to compare the effects of various treatment schedules when both the magnitude of treatments studied is small, and similar schedules are not examined. Although it is difficult to find a group of subjects who are all diagnosed with the same stage of breast cancer and who are undergoing the same treatments, this type of study is necessary if conclusive results are to be made regarding treatment effects on functional capacity. 55 Most important is the lack of research that examines functional capacities in these women before they have undergone cancer therapy as well as during the treatment. A s mentioned earlier, all of the studies that document changes in the heart and lungs due to cancer therapy are retrospective, with the exception of Strender et al (Strender et al., 1986). This is a serious drawback because the researchers are naive to the patients' pre-treatment cardiovascular status. Thus even though cardiac and pulmonary problems are encountered after cancer treatments have been administered, there is no way of knowing if these cardio- and pulmonary- toxic effects were present before the treatment schedule. Additionally, many women who are treated for breast cancer are above 50 years of age, yet studies that do not consist of pre-treatment measures cannot control for age. This presents a problem because the patients could not be expected to be free from heart disease and other risk factors for heart and lung disorders which may interfere with study measures. 56 APPENDEX B: T N M STAGING S Y S T E M T N M staging system T U M O U R Stages: (T) T(x): primary tumour cannot be assessed T(0): no identifiable tumour in the breast T(is): in-situ, non-invasive cancer T ( l ) : invasive cancer 2 cm or less in diameter T(2): invasive cancer 2 cm to 5 cm in diameter T(3): invasive cancer larger than 5 cm without skin or chest wall involvement T(4): tumour of any size with direct extension to chest wall or skin N O D E Stages: (N) N(0): no evidence of palpable lymph nodes N ( l ) : palpable, mobile lymph nodes in the armpit only N(2): lymph nodes in the axilla are fixed to each other or to adjacent structures such as nerves, muscles, skin or bones N(3): involved lymph nodes beside the breast bone M E T A S T A S I S Stages: (M) M(0): no evidence of metastases M ( l ) : metastases present including spread to lymph nodes above the collarbone Olivotto etal, 1995; Harris, 1996. 57 APPENDIX C: FIVE STAGES OF BREAST CANCER Roman Numeral Staging T N M Staging S T A G E 0 Non-invasive cancers, including Tis, NO, MO ductal carcinoma in-situ lobular carcinoma in-situ S T A G E I Tumour less than 2 cm, no metastases, no T I , NO, MO cancer in lymph nodes S T A G E II H A TO, N l . M O Tumour 2-5 cm but not involving skin and T 1 . N 1 . M 0 chest wall. If lymph nodes are involved they IIB must be movable T2, NO, MO T 2 . N 1 . M 0 T3, NO, MO S T A G E III niA TO, N2 , MO Advanced local tumour, fixed to the skin or T I , N 2 , MO chest wall , or presence of lymph nodes T2, N2 , MO attached to structures in the axilla T 3 . N 1 . M 0 T3, N 2 , MO nm T4, any N , M A n y T, N 3 , MO S T A G E IV Cancer spread beyond the breast and axilla, Any T, any N , M l to lymph nodes above the collarbone, or to distant organs Olivotto et al., 1995 and Harris, 1996 58 APPENDIX D: RAW D A T A A N T H R O P O M E T R I C D A T A Table 10. Pre-surgery Age and Height, individual subject data Subject Age (yrs) Height (cm) A 48 162.0 B 38 165.2 C 54 161.0 D 49 167.5 E 40 172.7 F 39 161.2 G 58* 162.1 H 41 170.0 I 40* 174.9 Mean ± SD 45.2 ± 7 . 3 166.3 ± 5 . 3 * age and height post-surgery Table 11. Body Mass (kg), individual subject data Subject Test 1 Test 2 Test 3 A 56.1 56.3 59.6 B 68.1 68.5 69.9 C 60.2 57.5 54.6 D 55.9 55.0 58.1 E 62.5 63.1 64.6 F 51.2 51.2 47.7 G 72.6 76.4 • 76.7 H 52.7 52.5 50.2 I 67.8 71.3 67.6 Mean ± SD 60.8 ± 7 . 5 61.3 ± 9 . 0 61.0 ± 9 . 5 B o l d numbers have been estimated 59 Table 12. Sum of Skinfolds (mm), individual subject data Subject Test 1 Test 2 Test 3 A 47.0 43.4 51.0 B 122.1 124.0 133.0 C N / A N / A N / A D 63.0 62.3 81.4 E 68.3 72.9 73.0 F 48.7 45.0 44.4 G 113.1 137.4 141.2 H 26.0 27.6 24.5 I 78.7 95.6 70.2 Mean ± S D 70.9 ±33.0 63.5 ± 3 8 . 1 7 7 . 3 ± 4 1 . 1 B o l d numbers have been estimated N / A = no data available P U M L O N A R Y F U N C T I O N D A T A Table 13. Forced Vital Capacity (L), individual subject data Subject Test 1 Test 2 Test 3 A 4.28 4.47 4.44 B 3.35 3.41 3.48 C 3.01 2.83 2.80 D 3.19 3.25 3.12 E 5.00 5.1.4 5.33 F 3.54 3.49 3.45 G 2.81 2.78 2.78 H 3.46 3.41 3.32 I 3.98 3.94 4.03 Mean ± SD 3.62 ± 0 . 6 9 3.64 ± 0 . 7 7 • 3.64 ± 0 . 8 3 B o l d numbers have been estimated 60 Table 14. Forced Expiratory Volume in One Second (L), individual subject data Subject Test 1 Test 2 Test 3 A 3.45 3.47 3.26 B 2.72 2.80 2.89 C 2.40 2.25 2.24 D 2.58 2.51 2.35 E 3.84 3.92 4.14 F 3.04 3.00 3.00 G 2.39 2.37 2.32 H 2.92 2.83 2.95 I 3.54 3.51 3.56 Mean ± S D 2.99 ± 0 . 5 2 2.96 ± 0 . 5 7 2.97 ± 0.63 B o l d numbers have been estimated Table 15. Ratio of Forced Expiratory Volume in One Second / Forced Vita l Capacity (%), individual subject data Subject Test 1 Test 2 Test 3 A 80 78 73 B 81 82 83 C 80 80 81 D 81 77 75 E 77 76 78 F 86 86 87 G 84 85 83 H 84 83 89 I 88 89 88 Mean ± SD 82.33 ± 3 . 4 3 81.78 ± 4 . 4 1 81.89 ± 5 . 6 9 B o l d numbers have been estimated 61 Table 16. Maximal Voluntary Ventilation (L/min), individual subject data Subject Test 1 Test 2 Test 3 A 122 132 123 B 104 109 119 C 88 84 96 D 99 102 98 E 127 127 126 F 119 129 113 G 75 75 88 . H 90 92 94 I 117 117 133 Mean ± SD 104.56 ± 17.90 107.44 ± 2 0 . 6 6 110.00 ± 1 6 . 2 9 , B o l d numbers have been estimated E X E R C I S E C A P A C I T Y D A T A Table 17. Maximal Oxygen Consumption (ml/min), individual subject data Subject Test 1 Test 2 Test 3 A 1852 1688 1513 B 1809 1753 1543 C 1239 1135 1035 D 1258 1176 1051 E 1864 1838 1548 F 1469 1362 1270 G 1695 1678 1495 H 1989 1911 1916 I 2089 2068 1863 Mean + S D 1696.00 ± 3 0 7 . 7 8 1623.22 + 327.38 1470.44 + 310.65 B o l d numbers have been estimated 62 Table 18. Maximal Oxygen Consumption (ml/kg/min), individual subject data Subject Test 1 Test 2 Test 3 A 33.0 30.0 25.4 B 26.6 25.6 22.4 C 20.6 19.7 19.0 D 22.5 21.4 18.1 E 30.2 29.1 24.0 F 28.7 26.6 26.6 G 23.3 22.0 19.5 H 37.7 36.4 38.1 I 31.5 29.7 27.6 Mean + SD 28.23 ± 5 . 5 4 26.72 ± 5 . 2 5 24.52 ± 6 . 1 3 B o l d numbers have been estimated Table 19. Maximal Heart Rate (bpm), individual subject data Subject Test 1 Test 2 Test 3 A 170 161 151 B 163 170 168 C 155 160 155 D 148 147 155 E 163 160 145 F 184 185 179 G 154 153 150 H 156 157 161 I 157 156 168 Mean ± SD 161 ± 1 0 161 ± 11 159 + 11 B o l d numbers have been estimated 63 Table 20. Ventilation (L/min), individual subject data Subject Test 1 Test 2 Test 3 A 91.0 80.5 73.9 B 99.8 98.2 97.6 C 57.7 63.6 48.1 D 71.0 69.5 67.7 E 95.6 71.6 46.4 F 80.4 66.5 68.4 G 86.5 84.0 81.9 H 86.1 84.7 83.5 I 104.7 101.7 107.6 Mean ± S D 85.87 ± 14.64 80.03 ± 13.57 75.01 ± 2 0 . 4 1 B o l d numbers have been estimated Table 21. Peak Power Output (watts), individual subject data Subject Test 1 Test 2 Test 3 A 162 153 148 B 199 200 185 C 121 117 100 D 126 165 126 E 183 173 177 F 170 160 150 G 171 171 160 H 164 162 216 I 151 151 201 Mean ± S D 160.78 + 25.11 161.33 + 22.03 162.56 + 36.52 B o l d numbers have been estimated 64 Table 22. Saturation of Oxygen (%), individual data Subject Test 1 Test 2 Test 3 A 97 96 93 B 96 88 88 C 97 93 96 D 96 97 95 E 97 96 97 F 93 93 96 G 98 97 98 H 97 96 94 I 98 ,97 93 Mean + SD 96.56 ± 1.51 94.78 ± 2.99 94.44 ± 2.96 B o l d numbers have been estimated A C T I V I T Y D A T A Table 23. Daily Activity (Kcal/day) During Study Period, individual subject data Subject Test 1. - 2 Test 2 - 3 Mean For Subject A 123 69 96 B 94 230 162 C 61 30 46 D 74 109 92 E 264 73 169 F 164 94 129 G - 219 219 H 294 228 261 I - 220 220 Mean ± S D 153 ± 9 2 141 ± 8 1 154 ± 7 0 Mean for Test 1-2 does not include subjects G and I 65 Table 24. Pre-Diagnostic Activity Levels (Kcal and Kcal/day), individual subject data Subject 1 - Y r . Pre-Diag (Kcal) Pre-Diag/Day (Kcal/day) A 50 960 139 B 114 036 312 C 24 570 67 D 120 848 331 E 148 304 406 F 28 101 77 G 131 898 361 H 58 936 161 I 167 418 459 Mean ± SD 93 896 ± 5 3 785 257 ± 1 4 7 1-Yr. Pre-Diag = activity the year preceding diagnosis; Pre-Diag/Day = activity the year preceding diagnosis + 365 days/year T I M E L I N E D A T A Table 25. Number of Days Between Treatments and Testing, individual subject data Subject D - T l T l - S S-T2 T 2 - B C T B C T - E C T E C T - T 3 Total Days A 20 3 7 16 133 73 252 B 22 7 18 10 66 11 134 C 8 11 50 1 60 37 167 D 41 2 13 2 62 27 147 E 16 8 45 9 61 25 164 F 20 16 8 3 64 16 127 G - - 28 1 78 38 145 H 24 1 20 1 64 9 119 I - - 37 2 74 29 142 Mean±SD 21 ± 10 7 ± 5 25 ± 15 5 ± 5 73 ± 2 3 29 ± 19 D = diagnosis; T# = test number; S = surgery; B C T = begin chemotherapy; E C T = end chemotherapy 66 S M O K I N G D A T A Table 26. Smoking History, individual data Subject Smoke at Smoke- Packs/wk Packs/yr Total Packs Smoke-free Diagnosis? #years Smoked years A N o 10 2 104 1040 14 B No - - - - -C N o 6 7 364 2184 23 D N o - - - - -E N o - - - - -F N o - - - - -G N o 8 3.5 182 1456 21 H N o - - - - -I N o 2 2 104 208 17 Mean + - 6 ± 4 ± 188 ± 1222 ± 1 9 ± S D 3 2 122 825 4 67 


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