Killing Lung Cancer

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                                                                               Vol. 19, No. 2      March/April 2004

                                                                                      Association of Community Cancer Centers

  Oncology Economics & Program Management

  Issues in
  and Cancer:
  UPDATE 2004

                                    2       An Overview for Clinicians
                                            by Faith D. Ottery

                                    5       New Approaches in Reversing Cancer-related
                                            Weight Loss
                                            by Vickie E. Baracos

                                 11         Multimodality Approaches to Optimize
                                            Survivorship Outcomes: Body Composition,
                                            Exercise, and Nutrition
                                            by Faith D. Ottery, Suzanne R. Kasenic, and
                                            Regina S. Cunningham

                                 Sponsored by Savient Pharmaceuticals, Inc.
                                 ©Copyright 2004. Association of Community Cancer Centers. All rights reserved. No
                                 part of this publication may be reproduced or transmitted in any form or by any means
                                 without written permission. Articles and other contributed materials represent the opin-
                                 ions of the authors and do not represent the opinions of the Association of Community
                                 Cancer Centers or the institution with which the author is affiliated unless the contrary
                                 is specified. Cover Image/
Issues in Nutrition and Cancer:
An Overview for Clinicians
by Faith D. Ottery, MD, PhD

…an increasing number of cancer survivors are living with         prediagnosis periods for the family members who want
long-term effects of disease and treatment that impair their      and need to address aspects of lifestyle as they affect risks
functioning and quality of life. While diagnosis, treatment,      for developing cancer, as well as the prognosis of that
and even cure-oriented research continues, it is imperative       cancer should it develop.
that there be a parallel commitment to the improvement                 For many people, quality of survivorship is as
of the status of everyday living for cancer survivors.            important as the duration of survivorship, whether one is
Development of research-based clinical interventions in           addressing acute (e.g., having enough energy to go out and
these areas holds promise for significant improvement in          get the morning paper), intermediate (e.g., getting back to
functioning and quality of life for cancer survivors and          work or usual activity) or chronic time frames (e.g., chron-
may constitute valuable rehabilitation techniques that            ic sequelae of body composition loss and fatigue years
can be adjunctive to standard therapies.1                         after completion of therapy as in lymphoma4 or lung can-
                                                                  cer5). In addition, it can be postulated that those patients
                           —Maryl Winningham, RN, PhD             who maintain better nutritional status and body composi-
                                                                  tion during and after primary therapy are better and more
                                                                  willing candidates for therapy should the cancer recur.

                       hen I was asked to coordinate this
                       supplement to address the inclusion        PREVENTION, PHYSICAL ACTIVITY, AND
                       of the principles and practice of nutri-   HEALTH
                       tional oncology into an integrated         Cancer is a disease process that affects not only the indi-
                       approach to cancer care, I was partic-     vidual patient but also his or her family members and sig-
                       ularly honored since the supplement        nificant others. Often when a parent is diagnosed with a
                       is to be published on the celebration      cancer, the question is asked, “What can we do so that my
of the 30th anniversary of the Association of Community           daughter/son doesn’t have to go through this?” Any
Cancer Centers (ACCC). Dr. Winningham’s comments                  answer to questions about what one can do to prevent
echo components of ACCC’s Mission: to preserve and                cancer or improve prognosis must include a discussion
protect the entire continuum of quality cancer care.2             about the components of nutrition and physical activity,
      Standardization of assessment and evidence-based            with the goal of optimizing body composition and metab-
clinical interventions are imperative to optimize patient         olism. While we do not specifically address the issues of
functionality and quality of life across the cancer experi-       nutrition and exercise in cancer prevention in any of the
ence. In the following articles, we applied a framework,          following articles, the discussion of this quality of sur-
defined by Courneya and colleagues,3 for physical exercise        vivorship would be incomplete without a brief summary
across the cancer experience to the broader concepts of           of what is known about nutrition, exercise, and body
functionality and quality of life (Figure 1). Known as the        composition in terms of cancer risk and prognosis.
“Framework PEACE” (Physical Exercise Across the                        The proposed Health Determinants and Health
Cancer Experience), this proposed framework divides the           Outcomes Set of the Healthy People 20106 program
cancer experience into six time periods: two prediagnosis         includes eight indicators representative of health determi-
(prescreening and screening/diagnosis), and four postdiag-        nants: physical environment, poverty, high school gradua-
nosis (pretreatment, treatment, posttreatment, and                tion, tobacco use, weight, physical activity, health insur-
resumption).3 As with the original concept, it is hoped that      ance, and cancer detection. These indicators have been
this framework will stimulate a more comprehensive and            chosen because they represent some of the most powerful
in-depth inquiry into the role of functionality and quality       determinants of health for which meaningful action can be
of life in cancer control.                                        taken at multiple jurisdictional levels, ranging from the
                                                                  national and state levels to individuals and families in
QUALITY OF SURVIVORSHIP AND NUTRITION                             neighborhoods and communities.
With the successes in cancer diagnosis and treatment                   Two indicators address health outcomes. The first
accomplished over the past 70-plus years, we have a               focuses on prevention of mortality associated with inten-
growing population of cancer survivors. Quality of sur-           tional and unintentional injuries, while the second address-
vivorship is important, whether we are talking about the          es the extent to which illness, injury, or disability prevents
four postdiagnosis periods for a given survivor or the two        people from performing important social roles. The

2                                                                  I  N  C: U  March/April 2004
  Figure 1. An organizational
  model for examining
  Physical Exercise Across                    Diagnosis
  the Cancer Experience
  (Framework PEACE)

                                                                                Rehabilitation ➝ Health Promotion

  Control          Prevention     ➝ Detection ➝ Buffering ➝ Coping                                                    Survival
  Outcomes                                                        ➝


                   Prescreening       Screening          Pretreatment       Treatment       Post-treatment       Resumption

                        Prediagnosis                            Postdiagnosis

                                        Cancer-related Time Period

indicator set, therefore, recognizes that just as society has   vivors—from those undergoing current therapy to those
an effect on health, so too the health of the population has    for whom chemotherapy or radiation are somewhat dis-
an effect on the functioning and productivity of society.       tant memories. The topics discussed in the following arti-
     Since the 1940s body weight, body fat distribution,        cles are part of the “food for thought” as ACCC celebrates
and adult weight gain have been linked to the development       its 30th Anniversary and clearly support the mission state-
of endometrial, postmenopausal breast, colon, esophageal,       ment and the vision that form the foundation of the
and renal carcinoma incidence and breast carcinoma prog-        Association. OI
nosis.7-9 Studies also point to a possible role for physical
activity in cancer incidence, because of the interrelation-     Faith D. Ottery, MD, PhD, is the founding president
ship between weight and physical activity. Considerable         of the Society for Nutritional Oncology Adjuvant
data indicate a 40 to 50 percent reduction in colon carcino-    Therapy (NOAT) and current chair of the Rehabilitation
ma incidence in active compared to sedentary individuals        Committee of the Multinational Association of Supportive
and a 30 to 40 percent reduction in breast carcinoma inci-      Care in Cancer (MASCC). Her research focuses on the
dence among women engaging in three or more hours per           complex interplay of nutrition and exercise that forms the
week of regular vigorous activity. Somewhat more limited        basis of many of the seminal publications in the field of
and less consistent data associate prostate and lung            nutritional oncology. She trained in medical oncology
carcinoma with inactivity.7, 10,11                              and was a practicing surgical oncologist at Fox Chase
     In the context of the growing interest in “metabolic       Cancer Center from 1987-1994. She is director of medical
syndrome” or hyperinsulinemia as a determinant of com-          affairs in oncology, HIV, and geriatrics for Savient
promised health in terms of obesity, type II diabetes melli-    Pharmaceuticals, Inc.
tus, and cardiovascular risk, data now suggest a role for
this syndrome in risk for breast, colorectal, and prostate      REFERENCES
                                                                1Winningham M. Strategies for managing cancer-related fatigue
cancer and for their prognosis.12-18 Current evidence sug-
gests that obesity, lack of physical activity, alcohol con-     syndrome: A rehabilitation approach. Cancer. 2001;92:988-997.
                                                                2Association of Community Cancer Centers. http://www.accc-
sumption, and a typical high-energy Western diet are all
associated with the development of insulin resistance and Accessed January 2004.
                                                                3Courneya KS and Friedenreich CM. Framework PEACE: An
hyperinsulinemia and may stimulate the growth of
tumors, particularly breast and colorectal tumors.12,14-16,19   organizational model for examining physical exercise across the
Hyperinsulinemia has also been associated with mortality        cancer experience. Ann Behav Med. 2001;23:263-272.
                                                                4Oldervoll LM, Kaasa S, Knobel H, Loge JH. Exercise reduces
in breast cancer patients.20 Elevated waist-to-hip ratio,
representing a higher abdominal fat distribution, is a mark-    fatigue in chronic fatigued Hodgkin’s disease survivors – results
er of insulin resistance and hyperinsulinemia22,23 and has      from a pilot study. Eur J Cancer. 2003;39:57-63.
                                                                5Langendijk JA, et al. Quality of life after curative radiothera-
been associated with both incidence of and mortality
of several chronic diseases, including heart disease,           py in Stage I non-small-cell lung cancer. Int J Radiat Oncol
                                                                Biol Phys. 2002;53(4):847-53.
hypertension, diabetes mellitus, and cancer.24-26               6Institute of Medicine. Available at:
     The articles that compose this supplement address
                                                                healthy3. Accessed January 2004.
areas of clinical importance in caring for cancer sur-

I  N  C: U  March/April 2004                                                                     3
7Scientific Program Committee. Physical activity across the can-    17Barnard RJ, Aronson WJ, Tymchuk CN, et al. Prostate cancer:

cer continuum: Report of a workshop. Review of existing knowl-      Another aspect of the insulin-resistance syndrome? Obes Rev.
edge and innovative designs for future research. Cancer. 2002;      2002;3(4):303-8.
95:1134-43.                                                         18Hsing AW, Gao YT, Chua S Jr, et al. Insulin resistance and
8Ballard-Barbash R. Energy balance, anthropometrics, and can-       prostate cancer risk. J Natl Cancer Inst. 2003;95(1):67-71.
cer. In: Heber D, Blackburn GL, Go VLM, editors. Nutritional        (Comment: J Natl Cancer Inst. 2003;95(14):1086-7; author reply
Oncology. San Diego. Academic Press, Inc. 1999:137-153.             1087.)
9National Center for Health Statistics, Center for Disease          19Reaven GM. Banting Lecture 1988. Role of insulin resistance in

Control. Cardiovascular fitness In: National Health and             human disease. Nutrition. 1997;13(1):65;discussion 64, 66.
Nutrition Examination Survey. Survey questionnaires, examina-       20Goodwin PJ, Ennis M, Pritchard KI, et al. Fasting insulin and
tion components, and laboratory components. Available at:           outcome in early-stage breast cancer: Results of a prospective 39-43. Accessed           cohort study. J Clin Oncol 2002;20:42-51.
January 2004                                                        21Nilsen TI, Vatten LJ. Prospective study of colorectal cancer
10Colditz GA, Cannuscio CC, Frazier AL. Physical activity and
                                                                    risk and physical activity, diabetes, blood glucose, and BMI:
reduced risk of colon cancer: Implications for prevention. Cancer   exploring the hyperinsulinemia hypothesis. Br J Cancer.
Causes Control. 1997;8:649-667.                                     2001;84;417-422.
11McTiernan A, Ulrich CM, Yancey D, et al. The physical             22Stoll BA. Obesity and breast cancer. Int J Obes Relat Metab
activity for total health (PATH) study: Rationale and design.       Disord. 1996;20:389-92.
Med Sci Sports Exerc. 1999;31(9):1307-12.                           23Hollmann M, Runnebaum B, Gerhard I. Impact of waist-to-
12Borugian MJ, Sheps SB, Kim-Sing C, et al. Waist-to-hip ratio
                                                                    hip ratio and body-mass—index on hormonal and metabolic
and breast cancer mortality. Am J Epidemiology. 2003;158:963-       parameters in young, obese women. Int J Obes Relat Metab
968.                                                                Disord. 1997;21:476-83.
13Bruning PF, Bonfrer JM, van Noord PA et al. Insulin resistance    24Folsom AR, Kaye SA, Seller TA, et al. Body fat distribution
and breast-cancer risk. Int J Cancer. 1992;52:511-16.               and 5-year risk of death in older women. JAMA. 1993;269: 483-7.
14Del Giudice ME, Fantus IG, Ezzat S, et al. Insulin and related    25Folsom AR, Kushi LH, Anderson KE, et al. Associations of
factors in premenopausal breast cancer risk. Breast Cancer Res      general and abdominal obesity with multiple health outcomes in
Treat. 1998;47:111-20.                                              older women: The Iowa Women’s Health Study. Arch Intern
15Borugian MJ, Sheps SB, Whittemore AS, et al. Carbohydrates        Med. 2000;160:2117-28.
and colorectal cancer risk among Chinese in North America.          26Friedenreich CM, Courneya KS, Bryant HE. Case-control
Cancer Epidemiol Biomarkers Prev. 2002;11:187-93.                   study of anthropometric measures and breast cancer. Int J
16Giovannucci E. Insulin and colon cancer. Cancer Causes            Cancer. 2002;99:445-52.
Control. 1995;6:164-79.

4                                                                    I  N  C: U  March/April 2004
New Approaches in Reversing
Cancer-related Weight Loss
by Vickie E. Baracos, PhD

                                                                 three categories of influences combine to define muscle
                                                                 mass. A fourth category of stimuli exists: a series of cata-
  IN BRIEF                                                       bolic factors that mainly occur during disease or injury,
  Should those of us involved in anticancer therapy              including tumor-derived factors.1
  of patients adopt the mindset of our sports medicine
  colleagues? The few available trials suggest that in           FACTORS INFLUENCING MUSCLE LOSS AND
  cancer patients, resistance training, adequate protein,        GAIN
  and amino acid or amino acid derivative supplemen-             The plasticity of skeletal muscle—its ability to adapt—
  tation can each individually promote net gain of lean          covers a broad range.
  body mass and associated function. If these observa-               Muscle mass falls to a minimum when:
  tions are borne out, it seems possible to conjecture           s Contractile work is limited or absent
  that a combination therapy involving several or all of         s Nutrients (especially amino acids for building muscle
  these may hold the promise of much more important                protein and necessary co-factors) are unavailable
  gains—as seen in healthy people.                               s Anabolic hormones, such as insulin and testosterone,
                                                                   are at low levels or when muscle is resistant to their

                ancer cachexia is a profound metabolic           s Catabolic factors related to stress (i.e., cortisol) or
                process characterized by the breakdown of          disease (i.e., proinflammatory cytokines) are present.
                skeletal muscle, as well as abnormalities in
                fat and carbohydrate metabolism. The diag-             Muscle mass rises to its maximum when:
                nosis of cachexia is made by a history of        s   Contractile work is frequent, especially resistance-type
                substantial weight loss in the context of            activity (i.e., weight-lifting)
advanced disease and a physical examination demonstrat-          s   Nutrients (especially amino acids for building muscle
ing muscle wasting. The prognostic significance of weight            protein and necessary co-factors) are not limiting
loss in cancer patients is well established, with weight loss    s   Anabolic hormones, such as insulin and testosterone,
strongly associated with shortened survival and poor                 are at optimal levels and muscle is sensitized to their
response to therapy from the earliest disease stages                 action
through to advanced cancer. The negative nitrogen balance        s   Catabolic factors related to stress (i.e., cortisol) or
underlying cancer cachexia leads to a significant wasting of         disease (i.e., proinflammatory cytokines) are absent.
skeletal muscle and other lean tissues. This lean tissue loss
reduces patient mobility, jeopardizes respiratory function,      ANABOLIC COMPETENCE—THE SPORTS
is related to reduced immunity, and is associated with           MEDICINE APPROACH
poor performance status and outcome. Stabilizing muscle          The commonly used approach in sports for building
loss or regaining lean tissue mass must, therefore, be           maximal muscle mass is well known: resistance training
considered primary targets of cachexia therapy.                  (weight-lifting); nutritional supplements, especially pro-
     Research on the biology of skeletal muscle and its          tein; and a variety of natural and synthetic hormones to
regulatory anabolic and catabolic factors is many decades        provide the three strong anabolic signals to which muscles
old. Skeletal muscle is terminally differentiated. Thus, it is   can respond. These signals are synergistic, not just addi-
not cell division and cell death that contribute to muscle       tive in their action, which can lead to spectacular gains of
mass, but mainly synthesis and degradation of proteins           muscle in some individuals. While some of the interven-
within existing cells. These metabolic processes have been       tions have been controversial, the model does demon-
described in considerable biochemical detail and are             strate the importance of integrating the approaches.
known to be precisely controlled.                                     The approach used in sports training is highly devel-
     A host of factors stimulating muscle protein synthesis      oped. Detailed progressive weight-training programs,
and degradation has been characterized. These fall into          addressing specific muscle groups are available in any
three major categories: muscular work/mechanical activi-         sports training manual, as well as in physical therapy
ty, endocrine factors, and nutrients. Muscle mass and            texts. The amino acid requirements for maximal muscle
function are dependent on this simple triad. In any given        growth are at least partially understood, and these are
person and within any given physiological state, these           commercially available as amino acid and protein supple-

I  N  C: U  March/April 2004                                                                    5
    Integrated Interventions in Nutritional Oncology

            he goal of nutritional intervention in patients       cancer cachexia has recently been published by
            with cancer is to prevent or reverse the progres-     Baracos and her colleagues in Canada.2
            sive weight loss and inanition that is seen in up
    to 80 percent of patients at some point in their disease      REFERENCES
                                                                  1Langer  CJ, Hoffman JP, Ottery FD. Clinical significance of
    or treatment. Unfortunately, even this simple goal
    is rarely achieved, and there has been little or no           weight loss in cancer patients: Rationale for the use of ana-
    progress in impacting the gold standard of survival by        bolic agents in the treatment of cancer-related cachexia.
    simply addressing nutritional interventions. Clinicians       Nutrition. 2001;17(suppl 1):S1-S20.
                                                                  2MacDonald N, Easson AM, Mazurak VC, et al.
    who use nutritional therapies alone to combat weight
    loss in cancer patients experience three common frus-         Understanding and managing cancer cachexia. J Am Coll
                                                                  Surg. 2003;197:143-161.
    trations: 1) lack of consistent reversal of weight loss
    with intervention, 2) lack of repletion of lean tissue or
    muscle, and 3) lack of translation of any change in
    weight or nutritional parameters into improved
    oncology outcomes.
         This relative lack of success can be presumed to be      Figure 1. The Three Primary Components
    because of a one-dimensional approach that does not           of Nutritional Intervention
    integrate nutrition into a program of comprehensive
    cancer care. A paradigm of integrated intervention has
    been developed that supports anabolism or anabolic
    competence, defined as that state which optimally
    supports protein synthesis and lean body mass.1 This
    paradigm also addresses the more global problems of
    muscle and organ function, immune competence,
    functionality, and quality of life. This approach is illus-      Nutritional                            Exercise
    trated in Figure 1 and demonstrates the importance of              Milieu
    addressing the three primary components of interven-
    tion: nutrition, the hormonal milieu (including both                               Optimal
    classic hormones and cytokines), and exercise.                                    Composition
         Until recently, treatment of cancer cachexia has                                 &
    focused on the provision of macro- and micronutrients                             Physiologic
    to reverse weight loss, with little clinical attention                             Function
    to the composition of body tissues lost or repleted.
    During the past decade, the level of understanding of
    the etiology of muscle catabolism in cancer cachexia,
    as well as intermediary markers of muscle breakdown
    and lipid mobilization, have served to re-focus                                     Hormonal
    research into interventional options for cancer cachex-                               Milieu
    ia that target the functional aspects of body composi-
    tion (lean tissue)—instead of simply focusing on ener-
    gy reserves (adipose tissue). This appreciation is
    addressed by Vicki Baracos, PhD. A more comprehen-
    sive review of the understanding and management of

ments in various combinations and forms. While these              supplementation in the diet is used as an adjunct in this
were initially used based on anecdotal evidence, there is         recipe, as creatine phosphate serves as an essential phos-
an increased research database supporting the use of some         phate donor for the synthesis of ATP, a critical energy
and refuting others. Elegant work has been done on the            source for initiating muscle activity. 5-17
appropriate timing of protein feeding, relative to the                 Evidence of the success of this integrated muscle-
timing and type of exercise bouts.2 Synthetic anabolic            building program can be seen in gymnasiums, bodybuild-
steroids derived and developed from the basic structure of        ing competitions, and football fields. The sports model is
testosterone have been intensified in their anabolic action       simple, and—insofar as it involves diet and activity—can
on skeletal muscle, while minimizing other effects, such as       be generally inexpensive and can be used by patients
liver damage and male pattern hair growth.3,4 Creatine            directly or coordinated by the clinician. Use of pharmaco-

6                                                                  I  N  C: U  March/April 2004
logic intervention, such as anabolic agents, is to be regard-   relatively long history and has been the focus of activity
ed as a medical intervention, with appropriate dosing and       in large research centers. AIDS and COPD cachexia
monitoring in the context of the underlying disease.            research has been enhanced by targeted funding and is
                                                                also quite active at this time.
Fatigue is the most distressing phenomenon experienced          MUSCLE MASS AND STRENGTH
by cancer patients.18 Vogelzang and colleagues used a sur-      Currently literature on exercise training and muscle
vey designed to characterize the epidemiology of cancer-        anabolism is very extensive, and a review of this literature
related fatigue from the perspectives of the patient (n =       is outside the scope of this article. (See page 11.) However,
419, median age 65), primary caregiver (n = 200), and           exercise training is shown clearly to stimulate muscle pro-
oncologist (n = 197).18 The principal cancer diagnoses          tein synthesis and to develop muscle mass and functional
were breast in females and genitourinary in males. Cancer       status. A key point emerging from the research is that our
treatment included chemotherapy (59 percent), radiation
therapy (63 percent), or both (24 percent); 20 percent of
patients received their last treatment within 6 weeks, 31
percent within 7 to 52 weeks, and 49 percent more than
                                                                    Clinical researchers in cancer
one year ago.
      More than three-fourths of patients (78 percent)              cachexia and anorexia can learn
experienced fatigue, defined as a general feeling of debili-
tating tiredness or loss of energy, during the course of            from the related research work
their disease and treatment, 32 percent daily, and 32 per-
cent reported fatigue significantly affecting their daily
routines. Caregivers reported observing fatigue in 86 per-
                                                                    of their colleagues in other
cent of the index patients, and oncologists perceived that
76 percent of their patients experienced fatigue. Patients          disciplines. Some results from
felt that fatigue adversely affected their daily lives more
than pain (61 percent vs. 19 percent). Most oncologists             clinical trials looking at reversal
(80 percent) believed fatigue is overlooked or undertreat-
ed, and most patients (74 percent) considered fatigue a             of muscle wasting in noncancer
symptom to be endured. Fifty percent of patients did not
discuss treatment options with their oncologists, and only
27 percent reported that their oncologists recommended
                                                                    disease may be immediately
any treatment for fatigue.
      Given this background, it is important to consider            translatable to cancer
that fatigue is multifactorial in etiology. However, the sig-
nificant catabolic loss of muscle is an important target for        populations.
interventional consideration. It is possible to argue that we
already have the knowledge necessary to improve muscle
mass and consequently patient function and mobility—
that is, we know the sports-training approach that results
in increased muscle mass. What seems to be lacking is the       concept of who can exercise should be revisited. Various
translation of this knowledge into practice. Are the “new”      patients considered too frail and ill to exercise have been
integrated approaches to supporting anabolism to wasting        shown to benefit from exercise. Schulte and Yarasheski19
syndromes simply the application of well-established con-       provide a pertinent example in frail elderly (76 to 92 years
cepts? Should those of us involved in anticancer therapy        of age) who participated in up to three months of
of patients adopt the mindset of our sports medicine col-       weightlifting. Study participants showed increased
leagues? This integrated approach of nutrition, resistance      biosynthesis of myosin heavy chain and mixed muscle
and aerobic exercise, and appropriate hormonal support          proteins, as do younger people. This finding suggests that
has already been adopted by researchers in muscle wasting       the protein synthetic machinery adapts rapidly to
in the elderly,19-21 in patients with wasting syndromes         increased contractile activity and that the adaptive
associated with AIDS,22,23 and chronic obstructive              responses are maintained, even in frail elders.
pulmonary disease.24-26                                              In addition, evidence from recent publications indi-
      Clinical researchers in cancer cachexia and anorexia      cates that repeated exercise may enhance the fitness,
can learn from the related research work of their col-          strength, and quality of life of cancer patients. The stud-
leagues in other disciplines. Some results from clinical        ies have addressed patients with a variety of different
trials looking at reversal of muscle wasting in noncancer       cancers. In one study, men with prostate cancer who
disease may be immediately translatable to cancer popula-       were scheduled to receive androgen deprivation therapy
tions. Research in the sports medicine area has led the         were randomly assigned to an intervention group that
way with interventions, including creatine, amino acids,        participated in a resistance exercise program three times
and anabolic agents, in combination with exercise pro-          per week for 12 weeks or to a waiting list control
grams tailored to develop muscle mass and optimize per-         group.27 Men in the resistance intervention group
formance. Clinical research on wasting in the elderly has a     demonstrated fewer fatigue-related problems with

I  N  C: U  March/April 2004                                                                 7
activities of daily living and had a higher quality of life     adverse effects have been reported. Mild abnormalities in
and higher levels of upper-body and lower-body muscu-           renal function may occur.12 Creatine has not been tested
lar fitness than men in the control group.                      in cancer patients, and if considered, should be used with
     Dimeo and coworkers 28 have produced a surprising          with caution in individuals with renal impairment or with
series of reports on exercise in patients undergoing            fragile electrolyte balance.
chemotherapy, including high-dose chemotherapy with                  Anabolic Agents. Testosterone was identified and
stem cell rescue. These patients are generally very sick in     characterized more than 70 years ago and recognized
the aftermath of chemotherapy, yet they are able and will-      shortly thereafter as a hormone that stimulated muscle
ing to exercise. These daily physical training programs         growth. Many clinical studies report that testosterone and
reduce the treatment-related loss of physical performance       its analogs support muscle growth,30-36 yet anabolic
in patients with hematological malignancies undergoing          steroids have only achieved a tentative hold in medical
chemotherapy. The lack of reported negative effects and         practice aside from their use in clearly demonstrated
the consistency of the observed benefits lead to the con-       hypogonadal states. Physicians have been slow to act on
clusion that physical exercise may
provide a low-risk therapy that can
improve patients’ capacity to perform
activities of daily living and improve         If the sports medicine data on creatine are
their quality of life.29
                                               applicable without intense exercise programs,
In addition to the exercise interven-
                                               perhaps creatine may also be used adjunctively
tions that have been studied in
patients with cancer, the use of other         to rebuild the muscles of cancer patients.
interventions that may be used by
patients needs to be addressed by cli-
nicians caring for patients with can-
cer. Clinicians should question
patients with an open mind regarding any aspect of com-         the possible applications of anabolic steroids in patients
plementary medicine. If the issue is not raised by the          with catabolic losses of muscle mass. In part, this lack of
clinician, the patient or family may fail to include the        use stems from the tainted association with illicit use of
information in any medical review.                              these compounds, as well as lack of clinical studies until
     Creatine. Creatine is a very commonly-used supple-         the past decade. In addition, the long-term effects of
ment among athletes who believe creatine builds muscle          androgens, which may include virilizing in women, liver
and increases muscle energy, enabling them to train longer      damage in both sexes, and adverse changes in serum
and perform at a higher level. The sports medicine litera-      lipids, have discouraged their use. More recent studies
ture is replete with trials that demonstrate that healthy       with attenuated androgens, also known as anabolic agents,
individuals taking creatine achieve a significant increase in   have limited some of these concerns. In view of the pro-
lean body mass in comparison with placebo and may also          found suffering associated with wasting and chronic ill-
improve muscle function. 5-17 Increase in muscle mass may       ness, and in view of the very substantial improvements in
be secondary to the athlete’s ability to maintain a program     the efficacy and side-effect profile of these compounds, a
of physical activity, although it remains possible that crea-   re-evaluation of the role of anabolic steroids in these
tine may have a direct effect on muscle protein synthesis.      conditions is currently underway.
     A creatine trial including normally active older men            Testosterone levels are commonly reduced in patients
(59 to 72 years of age) used a double-blind, placebo-con-       with severe illness. For example, a hypogonadal state is
trolled design with repeated measures and showed                often present in patients with advanced lung cancer.31,35
improved muscle performance with seven days of admin-           Testosterone replacement is simply accomplished, but the
istration trial.20 These data indicate that seven days of       androgen status of cancer patients has been assessed only
creatine supplementation was effective at increasing sever-     on a few highly selected patients. Studies on healthy males
al indices of muscle performance, including functional          indicate that supraphysiologic injections of testosterone
tests in older men without adverse side effects. Creatine       or its analogs induce muscle synthesis with short-term
supplementation may be a useful therapeutic strategy for        use. Testosterone replacement in elderly men, men under-
older adults to attenuate loss in muscle strength and           going knee replacement, and AIDS patients is associated
performance of functional living tasks.                         with improved muscle size and function. 33,37,38
     If the sports medicine data on creatine are applicable          A few studies of testosterone or anabolic agents in
without intense exercise programs, perhaps creatine may         treatment of weight loss and inanition in patients with
also be used adjunctively to rebuild the muscles of cancer      cancer have been carried out. A recently reported trial of
patients. Currently, evidence on this straightforward           oxandrolone (an oral synthetic derivative of testos-
proposition is not available, as there are few crossover        terone) concluded that weight-losing cancer patients on
studies from sports medicine to wasting disorders and           this agent not only gained weight, but their weight gain
additional research is clearly needed. Creatine is regarded     was also associated with improvement in lean body
as a safe supplement for healthy people and is available        mass, improved ECOG performance status, and quality
over the counter in health food stores, as only minor           of life scores, including the functional component.34,39,40

8                                                                I  N  C: U  March/April 2004
This work is particularly interesting because it also          more important gains—as seen in healthy people. In the
demonstrated that men showed greater gains in lean             age of high technology and super-drugs, this potential
body mass. Preliminary data demonstrated that when             solution to cancer-associated wasting may simply be too
patients were stratified into those who lost weight,           obvious or not sufficiently glamorous to have merited
stayed weight stable, and gained weight during oxan-           attention. On the other hand, if it were possible that these
drolone treatment, the most responsive group of men            effectors were additive or even synergistic in their actions
gained up to 13.9 pounds over a four-month period and          on muscle of cancer patients, then 10 or 20 pounds of tis-
the majority of this (10.9 pounds) was lean body mass.39       sue gain may be realizable in the context of a multimodal-
This result—net gain of lean body mass—is in striking          ity strategy for promoting anabolism in individuals with
contrast to the often-expressed belief that cancer cachex-     cachexia.
ia is inevitable and that its progression is unstoppable.           This approach, which stems from basic muscle
      A subsequent placebo-controlled study of oxan-           physiology, does not necessarily address the question of
drolone confirmed the results of the open label study          tumor-derived catabolic factors. Recent work of Tisdale
referenced above, with significant increases in weight         and colleagues suggest that tumors secrete novel lipolysis-
and lean tissue weight at month two of a four-month            inducing factors as well as potent catabolic factors specific
study.34,40 These studies extend some of the earlier results   for skeletal muscle.1 The nature and mechanisms of action
noted with the injectable anabolic androgenic steroid,         of these factors are beginning to be elucidated, and these
nandrolone.41-43 These data address the potential effec-       will form the basis of targeted therapies, including aspects
tiveness and safety of anabolic agents in cancer-related       that may have an anticatabolic effect. OI
weight loss. 41-44 While many believe it is not possible to
maintain weight in patients with advanced malignancy,          Vickie E. Baracos, PhD, is professor of protein metabo-
others have established that important gains of weight         lism in the Department of Nutrition Science and
and lean tissue are possible.                                  Oncology at the University of Alberta in Alberta,
      In addition, in view of the evidence of hypogonadism     Canada.
in patients with advanced cancer, it may be possible to ask
if there is any reason not to offer testosterone replacement   REFERENCES
                                                               1Tisdale  MJ. Cachexia in cancer patients. Nat Rev Cancer.
to patients with clinical evidence of androgen deficiency,
if the patient so desires.                                     2002;2(11):862-871.
      Amino Acids. While anabolic therapy directed at the      2Baracos VE. Management of muscle wasting in cancer-associ-

lean tissues seems unlikely to be entirely successful with-    ated cachexia: Understanding gained from experimental stud-
out provision of the amino acids required for protein          ies. Cancer. 2001; 92(suppl):1669-1677.
anabolism, this area of research is relatively neglected.      3Meyers FH, Jawetz E, Goldfien A. The gonadal hormones &

Only a small number of studies look at amino acid supple-      inhibitors. Review of Medical Pharmacology. 7th ed. Los Altos,
mentation in cancer patients, and the specific amino acids     Calif.: Lange; 1980:393-416.
supplemented are suggested by a relatively sparse literature   4Matsumoto AM. Clinical use and abuse of androgens and

on amino acid utilization in tumor-bearing animals.            antiandrogens. In: Becker KL (ed.) Principles and Practice of
      Supplemental oral N-acetyl-cysteine was reported to      Endrocinology and Metabolism. 3rd ed. Philadelphia:
improve quality of life and increase plasma albumin levels     Lippincott Williams & Wilkins; 2001:1181-1187.
                                                               5Huso ME, Hampl JS, Johnston CS, et al. Creatine supplemen-
and body cell mass in patients with various forms of inop-
erable cancer, suggesting that cysteine becomes a condi-       tation influences substrate utilization at rest. J Appl Physiol.
tionally dietary essential amino acid in cancer.45 The lack    2002; 93:2018-2022.
                                                               6Kreider RB, Ferreira M, Wilson M, et al. Effects of creatine
of a difference in survival between treated and control
groups indirectly suggests that supplemental cysteine did      supplementation on body composition, strength, and sprint
not enhance tumor growth.                                      performance. Med Sci Sports Exerc. 1998;30:73-82.
                                                               7Volek JS. Strength nutrition. Curr Sports Med Rep. 2003;2:189-93.
      An amino acid mixture containing glutamine, argi-
nine, and β-hydroxy β-methyl butyrate (a metabolite of         8Willoughby DS, Rosene JM. Effects of oral creatine and resist-
leucine) promoted deposition of lean body mass in non-         ance training on myogenic regulatory factor expression. Med Sci
small cell lung cancer patients without any reported side-     Sports Exerc. 2003;35:923-9.
effects.46 This proprietary product originated as a sports     9Kreider RB, Melton C, Rasmussen CJ, et al. Long-term crea-
supplement and is currently being assessed in a number         tine supplementation does not significantly affect clinical mark-
of larger, ongoing randomized trials. To formulate amino       ers of health in athletes. Mol Cell Biochem. 2003;244:95-104.
acid mixtures optimized to support anabolism and func-         10Juhn MS, Tarnopolsky M. Oral creatine supplementation and
tion in cancer patients, formal assessments of amino acid      athletic performance: A critical review. Clin J Sport Med.
requirements using current methods are much needed.            1998;8:286-297.
                                                               11Izquierdo M, Ibanez J, Gonzalez-Badillo JJ, et al. Effects of
CONCLUSION                                                     creatine supplementation on muscle power, endurance, and
The few available trials suggest that in cancer patients,      sprint performance. Med Sci Sports Exerc. 2002;34:332-343.
resistance training, adequate protein, and amino acid or       12Juhn MS, Tarnopolsky M. Potential side effects of oral creatine
amino acid derivative supplementation can each individu-       supplementation: A critical review. Clin J Sport Med.
ally promote net gain of lean body mass and associated         1998;8(4):298-304.
function. If these observations are borne out, it seems        13Kreider RB. Effects of creatine supplementation on perform-
possible to conjecture that a combination therapy involv-      ance and training adaptations. Mol Cell Biochem. 2003;244:89-94.
ing several or all of these may hold the promise of much       14van Loon LJ, Oosterlaar AM, Hartgens F, et al. Effects of cre-

I  N  C: U  March/April 2004                                                                   9
atine loading and prolonged creatine supplementation on body          32Langer  CJ, Hoffman JP, Ottery FD. Clinical significance of
composition, fuel selection, sprint and endurance performance         weight loss in cancer patients: rationale for the use of anabolic
in humans. Clin Sci (Lond). 2003;104:153-62.                          agents in the treatment of cancer-related cachexia. Nutr.
15Rawson ES, Volek JS. Effects of creatine supplementation and        2001;17(suppl 1):S1-20.
resistance training on muscle strength and weightlifting per-         33Ferrando AA, Sheffield-Moore M, Yeckel CW, et al.
formance. J Strength Cond Res. 2003;17:822-31.                        Testosterone administration to older men improves muscle func-
16Branch JD. Effect of creatine supplementation on body com-          tion: Molecular and physiological mechanisms. Am J Physiol
position and performance: A meta-analysis. Int J Sport Nutr           Endocrinol Metab. 2002;282:E601-E607.
Exerc Metab. 2003;13:198-226.                                         34Von Roenn JH, Tchekmedyian S, Ottery F. Oxandrolone
17Chwalbinska-Moneta J. Effect of creatine supplementation on         increases weight, lean tissue, performance status and quality of
aerobic performance and anaerobic capacity in elite rowers in         life (QOL) scores in cancer-related weight loss (Poster 114).
the course of endurance training. Int J Sport Nutr Exerc Metab.       14th International Symposium: Supportive Care In Cancer at
2003;13:173-83.                                                       the combined meeting of The Multinational Association of
18Vogelzang NJ, Breitbart W, Cella D, et al. Patient, caregiver,      Supportive Care in Cancer and The International Society of
                                                                      Oral Oncology. Boston, MA, June 23-26, 2002.
and oncologist perceptions of cancer-related fatigue: Results of      35Tchekmedyian S, Thropay J, Von Roenn J, Ottery F. Patients
a tripart assessment survey. The Fatigue Coalition. Semin
Hematol. 1997;34(3 suppl 2):4-12.                                     with aerodigestive tract cancer and pre-exiting weight loss:
19 Schulte JN, Yarasheski KE. Effects of resistance training on       Performance status, quality of life, and laboratory parameters
                                                                      with oxandrolone use (Poster 2176). Annual Meeting of the
the rate of muscle protein synthesis in frail elderly people. Int J   American Society of Therapeutic Radiology and Oncology.
Sport Nutr Exerc Metab. 2001;11(suppl):S111-8.                        New Orleans, LA, October 6-10, 2002.
20Gotshalk LA, Volek JS, Staron RS, et al. Creatine supplemen-
                                                                      36Sheffield-Moore M, Urban RJ, Wolf SE, et al. Short-term oxan-
tation improves muscular performance in older men. Med Sci            drolone administration stimulates net muscle protein synthesis in
Sports Exerc. 2002;34:537-543.                                        young men. J Clin Endocrinol Metab. 1999;84:2705-2711.
21Lambert CP, Sullivan DH, Freeling SA, et al. Effects of testos-
                                                                      37Amory JK, Chansky HA, Chansky KL, et al. Preoperative
terone replacement and/or resistance exercise on the composi-         supraphysiological testosterone in older men undergoing knee
tion of megestrol acetate stimulated weight gain in elderly men:      replacement surgery. J Am Geriatr Soc. 2002;50:1698-1701.
A randomized controlled trial. J Clin Endocrinol Metab.               38Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replace-
22Fairfield WP, Treat M, Rosenthal DI, et al. Effects of testos-      ment and resistance exercise in HIV-infected men with weight
                                                                      loss and low testosterone levels. JAMA. 2000;283:763-770.
terone and exercise on muscle leanness in eugonadal men with          39Tchekmedyian S, Fesen M, Price LM, et al. On-going placebo-
AIDS wasting. J Appl Physiol. 2001; 90:2166-2171.
23Strawford A, Barbieri T, Van Loan M, et al. Resistance exercise     controlled study of oxandrolone in cancer-related weight loss
                                                                      (Abstract 1039, Discussed Poster Presentation). 45th Annual
and supraphysiologic androgen therapy in eugonadal men with           Meeting of the American Society of Therapeutic Radiology and
HIV-related weight loss: A randomized controlled trial. JAMA.         Oncology. Salt Lake City, UT, October 19-23, 2003. In: Int J
1999;281:1282-90.                                                     Radiat Oncol Biol Phys. 2003;57(2 Suppl):S283-4.
24 Creutzberg EC, Wouters EF, Mostert R, et al. A role for ana-
                                                                      40Von Roenn JH, Tchekmedyian S, Cleary S, et al. State of the
bolic steroids in the rehabilitation of patients with COPD? A         art in cachexia therapy: Anabolic ateroids. Oral Presentation.
double-blind, placebo-controlled, randomized trial. Chest.            2nd International Cachexia Conference. Berlin, Germany,
2003;124(5):1733-42.                                                  December 4-6, 2003.
25Jagoe RT, Engelen MP. Muscle wasting and changes in muscle
                                                                      41Chlebowski RT, Herrold J, Ali I, et al. Influence of nan-
protein metabolism in chronic obstructive pulmonary disease.          drolone decanoate on weight loss in advanced non-small cell
Eur Respir J. (suppl.) 2003;46:52s-63s.                               lung cancer. Cancer. 1986;58:183-6
 26 Debigare R, Marquis K, Cote CH, et al. Catabolic/anabolic
                                                                      42Darnton SJ, Zgainski B, Grenier I, et al. The use of an anabolic
balance and muscle wasting in patients with COPD. Chest.              steroid (nandrolone decanoate) to improve nutritional status
2003;124(1):83-9.                                                     after esophageal resection for carcinoma. Dis Esophagus.
27Segal RJ, Reid RD, Courneya KS, et al. Resistance exercise in
men receiving androgen deprivation therapy for prostate cancer.       43Spiers AS, DeVita SF, Allar MJ, et al. Beneficial effects of an
J Clin Oncol. 2003;21:1653-9.                                         anabolic steroid during cytotoxic chemotherapy for metastatic
28Dimeo F, Schwartz S, Fietz T, et al. Effects of endurance train-
                                                                      cancer. J Med. 1981;12:433-45.
ing on the physical performance of patients with hematological        44Von Roenn JH, Tchekmedyian S, Hoffman R, et al. Safety of
malignancies during chemotherapy. Support Care Cancer.                oxandrolone in cancer-related weight loss (Poster N2 3013).
2003;11:623-8                                                         39th Annual Meeting of the American Society of Clinical
29Ardies CM. Exercise, cachexia, and cancer therapy: A molecu-
                                                                      Oncology. Chicago, IL, May 31-June 3, 2003.
lar rationale. Nutr Cancer. 2002;42:143-57.                           45Hack V, Breitkreutz R, Kinscherf R, et al. The redox state as a
30Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138:
                                                                      correlate of senescence and wasting and as a target for therapeu-
Anabolic-androgenic steroid therapy in the treatment of chronic       tic intervention. Blood. 1998;92:59-67.
diseases. J Clin Endocrinol Metab. 2001; 86:5108-5117.                46May PE, Barber A, D’Olimpio JT, et al. Reversal of cancer-
31Simons JP, Schols AM, Buurman WA, et al. Weight loss and
                                                                      related wasting using oral supplementation with a combination
low body cell mass in males with lung cancer: Relationship with       of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine.
systemic inflammation, acute-phase response, resting energy           Am J Surg. 2002;183:471-9.
expenditure, and catabolic and anabolic hormones. Clin Sci
(Lond). 1999; 97:215-223.

10                                                                     I  N  C: U  March/April 2004
Multimodality Approaches to
Optimize Survivorship Outcomes:
Body Composition, Exercise,
and Nutrition
by Faith D. Ottery, MD, PhD, Suzanne R. Kasenic, RD, and Regina S. Cunningham, PhD, RN, AOCN®
                                                                 ment.1 Interestingly, these recommendations may exacer-
  IN BRIEF                                                       bate the fatigue that plagues the survivor. In fact, living
  Our perceptions of the effects of deterioration in             alone may actually contribute to improved functionality as
  nutritional status and body composition must                   well as supporting continued independence. Physical inac-
  expand beyond the realm of acute toxicity to one of            tivity can contribute to disuse muscle atrophy, contribut-
  long-term and quality survivorship. The cornerstone            ing to loss of cardiorespiratory fitness and to fatigue.
  for addressing appropriate body composition and                Catabolic losses of weight that occur as the result of
  metabolic balance in patients with cancer is a multi-          cytokine-mediated changes in metabolism or chronic use
  modality approach that combines nutrition, physical            of corticosteroids can also contribute significantly to loss
  activity (aerobic and resistance exercises), and phar-         of muscle mass during cancer treatment. The combined
  macologic intervention as necessary. This integrated           losses of weight and lean tissue may be synergistic and if
  approach is important from time of diagnosis                   not reversed with cancer rehabilitation may progress
  through treatment and in long-term survival.                   further over time due to impaired physical activity.
                                                                      Structure and function of muscle and bone are
                                                                 dependent on physical activity combined with appropriate

                  nce, in giving a nutritional presentation to   nutrition and hormonal milieu supporting anabolism. In
                  the National Surgical Adjuvant Breast and      healthy volunteers, complete bed rest for as short as a
                  Bowel Project, I made the comment that         week has been associated with a 1-4 percent loss of muscle
                  the initials NSABP actually referred to        mass and a number of metabolic changes including insulin
                  the phrase “Nutritional Stability Always       resistance and increase in extremity fat.2-4 These changes
                  Brings Pleasure.”                              can be exacerbated in the setting of fever, corticosteroids,
     In other words, significant changes—increases or            and the proinflammatory cytokines associated with malig-
decreases—in a patient’s weight or body composition are          nancy. Each of these settings is also associated with mobi-
undesirable for anyone going through cancer treatment.           lization of bone calcium, again with implications for the
This perspective allows a consistent and integrated philo-       long-term survivor.
sophic approach to cancer care, whether one is addressing             Accelerated loss of bone mineral density, with its
a postmenopausal woman with breast cancer who is at risk         ensuing complications of pain and risk for compression
for significant weight gain and potential adverse oncologic      and other pathological or traumatic fractures, becomes
outcomes or the patients with cancers in which progressive       increasingly important with increased survivorship—in
weight loss and cachexia may be the rule, also associated        terms of both numbers of survivors and duration of sur-
with adverse outcomes.                                           vivorship. Inactivity, combined with direct complications
     The cornerstone for addressing appropriate body             of chemotherapy and changes in the survivor’s hormonal
composition and metabolic balance in patients with cancer        milieu (orchiectomy, contraindications to hormone
is a multimodality approach that combines nutrition,             replacement therapy or HRT, and corticosteroid use) all
physical activity (aerobic and resistance exercises), and        contribute to increased risk of progressive bone deminer-
pharmacologic intervention as necessary. This integrated         alization and osteoporosis. Resistance exercise is increas-
approach is important from time of diagnosis through             ingly recognized as an important therapeutic intervention
treatment and in long-term survival.                             for preventing or reversing bone loss and its complica-
PHYSICAL ACTIVITY AND SURVIVORSHIP                                    Studies of physical exercise in cancer initially focused
“Life is a metabolic dance between anabolic and catabolic        on aerobic exercise in women with breast cancer.12 More
processes.”1 Optimal cancer rehabilitation techniques            recently, resistance exercise has been added to the regimens
should focus both on the reduction of unnecessary cata-          with impact on cardiorespiratory fitness, improved body
bolic processes (such as unnecessary activity restrictions or    composition with increased lean tissue and decrease in fat
anemia) as well as building on anabolic processes to opti-       mass, as well as improved strength and functionality. There
mize daily functioning and quality of survivorship (QOS).        is an increasing body of literature supporting the impor-
    Family members and clinicians frequently advise peo-         tance of physical exercise in cancer survivors with a variety
ple with cancer to rest and to reduce the amount and             of different cancer types with demonstrated improvement
intensity of their activities—both during and after treat-       in 1) functional capacity, 2) perception and measured

I  N  C: U  March/April 2004                                                               11
fatigue, 3) lessening requirements for medications for                Lack of awareness regarding the impact of nutrition
nausea or pain, 4) psychological or emotional aspects of         and body compositional changes on acute and chronic
improved self-esteem, mood, sense of control, overall            aspects of survivorship as well as a lack of awareness of
sense of well-being, reduced depression and anxiety, and         cost-effective interventional options are the two greatest
5) immunologic function as assessed by increased natural         impediments to success in addressing acute and chronic
killer cell activity.13-19                                       sequelae of cancer therapy. Table 1 addresses the specifics
     The specific physical aspects of cancer rehabilitation      of this approach. Components as simple as the intake of
can include one or more of the following: deficit-related        adequate protein in chemotherapy toxicity and loss of
physical and occupational therapy; individual or group           muscle mass and function in individuals on bed rest to the
exercise programs; institutional, gym, home-based, or            chronic sequelae of malnutrition and body compositional
nature-based programs; aerobic (walking, cycling, swim-          change have long been underappreciated in the armamen-
ming, dancing), stretching, and resistance exercise (elasti-     tarium of the oncologist and are now beginning to play a
cized resistance bands, light-to-moderate weight lifting).       role as we address issues of survivorship.
                                                                      Since the inception of the Association of Community
CORTICOSTEROIDS: CHRONIC                                         Cancer Centers (ACCC) 30 years ago, the Association
MUSCULOSKELETAL SEQUELAE                                         has set standards of integrated quality oncology care.
Corticosteroids have a number of physiologic effects that        Evolution of standardized assessment, as well as recent
contribute to broad use in patients receiving cancer thera-      research in multimodality intervention, offer new insight
py as well as in treatment of survivor co-morbidities.           that is immediately applicable to the oncology team.
Antiemetic, anti-inflammatory, and antineoplastic roles          Today the role of exercise, specialty nutriceutricals
are common as well as used in terminal palliative care for       containing omega-3 fatty acids23 (ProSure®, Resource
its central effects to improve sense of well-being and           Support®) or β-hydroxy β-methylbutyrate (HMB) with
short-term improvements in affect and appetite.                  glutamine and arginine24 (Juven®), anticatabolic agents
     In the context of the current discussion, it is important   such thalidomide25 (Thalomide®), and now anabolic
to consider the effects of glucocorticosteroids on lean tis-     agents such as oxandrolone 26-28 (Oxandrin®) demonstrate
sue and the skeleton. The development of muscle weak-            increases in total weight or slowing of weight loss, increase
ness and atrophy is a well-known complication of therapy         in lean tissue weight, all of which are with associated func-
with exogenous glucocorticosteroids, and is probably the         tional and quality of life improvements. A newly launched
most common form of drug-induced myopathy encoun-                NCI-sponsored study addressing an integrated approach
tered in clinical practice.20-22 The clinical presentation of    of nutrition, exercise and pharmacologic intervention
steroid-induced muscle weakness is characterized by an           (oxandrolone vs. megestrol acetate) characterizes the new
insidious onset and is usually painless. The proximal mus-       model of multimodality approaches for improving quality
cles of the arms and legs are affected first with the lower      of cancer survivorship. OI
extremities demonstrating the earliest signs of weakness.
There is a relative sparing of distal musculature, and           Faith D. Ottery, MD, PhD, is current chair of the
smooth muscle does not appear to be involved. The                Rehabilitation Committee of the Multinational Association
patient first notes difficulty climbing stairs and rising from   of Supportive Care in Cancer and director of medical affairs
low chairs because hip girdle and thigh weakness, but by         in oncology, HIV, and geriatrics for Savient Pharma-
the time this occurs marked muscle atrophy is evident. In        ceuticals, Inc. Suzanne R. Kasenic, RD, is oncology nutri-
addition to effects on muscle, glucocorticoids also con-         tionist at Fox Chase Temple Cancer Center in Philadelphia,
tribute significantly to bone demineralization and risk          Pa. Regina S. Cunningham, PhD, RN, AOCN® is chief
for progressive osteoporosis.                                    nursing officer and director of Ambulatory Services at the
     In review of the published literature, exercise is          Cancer Institute of New Jersey in New Brunswick, N.J.
increasingly included as integral to any intervention
addressing prevention or treatment of musculoskeletal            REFERENCES
                                                                 1Winningham ML. Strategies for managing cancer-related fatigue
complications of corticosteroids, regardless of the
underlying disease state utilizing chronic corticosteroids.      syndrome: A rehabilitation approach. Cancer. 2001;92(4 Suppl):
     Prevention and treatment of corticosteroid-induced          2Shangraw RE, Stuart CA, Prince MJ, et al. Insulin responsiveness of
osteoporosis is based upon general measures such as calci-       protein metabolism in vivo following bedrest in humans. Am J
um and vitamin D supplementation, adequate protein               Physiol. 1988; 255(4 pt 1):E548-58.
intake, regular physical exercise, hormonal replacement          3Stuart CA, Shangraw RE, Prince MJ, et al. Bed-rest-induced insulin
therapy and upon specific means like therapies used in           resistance occurs primarily in muscle. Metab. 1988;37(8):802-6.
primary osteoporosis. Bisphosphonates, which are potent          4Stuart CA, Shangraw RE, Peters EJ, et al. Effect of dietary protein

bone resorption inhibitors, have been shown to increase          on bed-rest-related changes in whole-body-protein synthesis. Am J
bone mineral density and to decrease fracture rate.              Clin Nutr. 1990;52(3):509-14.
                                                                 5Braith RW, Magyari PM, Fulton MN, et al. Resistance exercise
                                                                 training and alendronate reverse glucocorticoid-induced osteoporosis
                                                                 in heart transplant recipients. J Heart Lung Transplant. 2003;22(10):
SURVIVORSHIP                                                     1082-90.
Support of whole-body anabolism is based on an integrated        6Fiechtner JJ. Hip fracture prevention. Drug therapies and lifestyle
approach of nutrition, exercise, and support of an appropri-     modifications that can reduce risk. Postgrad Med. 2003;114(3):22-28.
ate hormonal milieu. Probably the most important aspects         7Mitchell MJ, Baz MA, Fulton MN, et al. Resistance training

of a synergistic multimodality approach are 1) awareness,        prevents vertebral osteoporosis in lung transplant recipients.
2) assessment, and 3) appropriate intervention.                                                             continued on page 14

12                                                                I  N  C: U  March/April 2004
  Table 1. Practical Assessments in Prevention and Treatment of
  Chronic Sequelae of Cancer Therapy
  Variable                           Assessment                Intervention

  Nutritional Status
       Weight, weight history        Scale, PG-SGA*
       Nutritional intake            Patient history, PG-SGA, Nutritional intervention
                                     protein/calorie counts     s Define macronutrient goals
                                                                     Protein 0.7 g/lb of ideal weight (1.5 g/kg)/day
                                                                     Calories 16-18+ kcal/lb current weight
                                                                s Micronutrient—multivitamin and vitamin,
                                                                  mineral as indicated
                                                                s Consideration of commercial nutritional
                                                                s Consideration of specialty nutriceuticals:
                                                                  HMB or omega-3
                                                              Pharmacologic intervention
                                                                s Antiemetics, analgesics, antidepressants;
                                                                  orexigenic, anticatabolic/antimetabolic or
                                                                  anabolic agents; others

        Nutrition impact             Patient history, PG-SGA   Behavioral intervention
        symptoms                                                 s Address taste and smell sensory changes
                                                                 s CAM: ginger, ice, behavioral

                                                               Pharmacologic intervention
                                                                 s Antiemetics, analgesics, antidepressants;
                                                                   orexigenic, anticatabolic/antimetabolic or
                                                                   anabolic agents; others

        Catabolic/metabolic          Vitals, concommitant      Pharmacologic intervention
        stresses                     meds, PG-SGA                s Anticatabolic/antimetabolic or anabolic agents,

        Physical examination:        Focused physical exam,    Behavioral intervention
        muscle, fat, fluid           PG-SGA                      s Mixed modality exercise (aerobic,
                                                               Pharmacological intervention
                                                                 s Orexigenic, anticatabolic/antimetabolic or
                                                                   anabolic agents; diuretics

  Body Composition/Bone                                        Behavioral intervention
  Mineral Density                                                s Mixed modality exercise (aerobic,
                                                               Pharmacological intervention
                                                                 s Orexigenic, anticatabolic/antimetabolic or
                                                                   anabolic agents; diuretics; vitamins A and D,
                                                                   calcium, magnesium; bisphosphonates,
                                                                   parathyroid hormone, other

        Physical examination:        PG-SGA,
        muscle, fat, fluid           anthropometrics

        Body composition             Bioelectrical impedance analysis (BIA)
        assessment                   Dual energy X-ray absorptiometry (DEXA)

  Functionality                                                Behavioral intervention
                                                                 s Mixed modality exercise (aerobic, strength-
                                                                   resistance bands, weight lifting)
                                                                                                  continued on page 14

I  N  C: U  March/April 2004                                                           13
     Variable                              Assessment                       Intervention

  Functionality continued                                                   Pharmacological intervention
                                                                              s Antiemetics, analgesics, antidepressants; or
                                                                                exigenic, anticatabolic/antimetabolic or anabolic
                                                                                agents; diuretics; vitamins A and D, calcium,
                                                                                magnesium, bisphosphonates, parathyroid
                                                                                hormone, other

         Assessment of activities           ECOG/Zubrod, Karnofsky,
         of daily living                    PG-SGA

         Assessment of change               How fast? How often?
         from individual’s norm             How long to recover?

                                            Borg scale of perceived

         Endurance                          6-minute walk

         Strength                           Rise from chair, other,
                                            handgrip strength

  *The Patient-Generated Subjective Global Assessment (PG-SGA) tool and worksheets are for patient or clinician use. They can be
  found on ACCC’s web site at, and
  The PG-SGA addresses the global status of the patient from this integrated perspective—weight loss and weight loss history, nutritional
  intake, nutrition impact symptoms, ECOG performance status in patient terms, metabolic/catabolic stresses, and physical examination
  focused on body composition. From the standpoint of functionality, ECOG or Karnofsky performance status assessments are impor-
  tant prognostic indicators, but greater insight may be obtained in terms of functionality and QOS with questions addressing change in
  functioning as it impacts that survivor.

Transplantation. 2003;76(3):557-62.                                        plantation. Bone Marrow Transplantation. 1996;18:1157-1160.
8Winett RA, Carpinelli RN. Potential health-related benefits of            19Na YM, Kim MY, Kim YK, et al. Exercise therapy effect on natural

resistance training. Prev Med. 2001;33(5):503-13.                          killer cell cytotoxic activity in stomach cancer patients after curative
9NIH Consensus Development Panel on Osteoporosis Prevention,               surgery. Arch Phys Med Rehab. 2000;81:777-779.
                                                                           20Mastaglia FL. Adverse effect of drugs on muscle. Drugs.
Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and
therapy. JAMA. 2001;285(6):785-95.                                         1982;24:304-321.
10Kerr D, Ackland T, Maslen B, et al. Resistance training over 2 years     21Braith RW, Welsch MA, Mills RM, et al. Resistance exercise pre-

increases bone mass in calcium-replete postmenopausal women.               vents glucocorticoid-induced myopathy in heart transplant recipi-
J Bone Miner Res. 2001;16(1):175-81.                                       ents. Med Sci Sports Exerc. 1998;30:483-489.
11Hurley BF, Roth SM. Strength training in the elderly: Effects on         22Horber FF, Hoppeler H, Scheidegger JR, et al. Impact of physical

risk factors for age-related diseases. Sports Med. 2000;30(4):249-68.      training on the ultrastructure of midthigh muscle in normal subjects
12Winningham ML. Effects of a bicycle ergometry program on func-           and in patients treated with glucocorticoids. J Clin Invest.
tional capacity and feelings of control with breast cancer.                1987;79:1181-119
                                                                           23Fearon KC, Von Meyenfeldt MF, Moses AG, et al. Effect of a
Unpublished doctoral dissertation. The Ohio State University,
Columbus, Ohio. 1983.                                                      protein and energy dense N-3 fatty acid enriched oral supplement
13Courneya KS, Friedenriech CM. Relationship between exercise              on loss of weight and lean tissue in cancer cachexia: A randomised
during treatment and current quality of life among survivors of            double blind trial. Gut. 2003;52(10):1479-86.
                                                                           24May PE, Barber A, D’Olimpio JT, et al. Reversal of cancer-related
breast cancer. J Psychosoc Oncol. 1997;15:35-57.
14Nelson JP. Perceived health, self-esteem, health habits, and per-        wasting using oral supplementation with a combination of beta-
ceived benefits and barriers to exercise in women who have and who         hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg.
have not experienced stage I breast cancer. Oncol Nurs Forum.              2002;183:471-9.
                                                                           25Khan ZH, Simpson EJ, Cole AT, et al. Oesophageal cancer and
15Schwartz AL, Mori M, Gao R, et al. Exercise reduces daily fatigue        cachexia: the effect of short-term treatment with thalidomide on
in women with breast cancer receiving chemotherapy. Med Sci Sports         weight loss and lean body mass. Aliment Pharmacol Ther.
Exerc. 2001;33:718-723.                                                    2003;17:677-82.
16Kolden GG, Strauman TJ, Ward A, et al. A pilot study of group            26Von Roenn JH, Tchekmedyian S, Hoffman R, et al. Safety of

exercise training (GET) for women with primary breast cancer:              Oxandrolone in Cancer-related Weight Loss (Poster N2 #3013) 39th
Feasibility and health benefits. Psychooncol. 2002;11:447-456.             ASCO meeting, Chicago, Ill. May 31-June 3, 2003.
17Fairey AS, Courneya KS, Field CJ, et al. Effects of exercise training    27Tchekmedyian S, Fesen M, Price LM, et al. On-going placebo-con-

on fasting insulin, insulin resistance, insulin-like growth factors, and   trolled study of oxandrolone in cancer-related weight loss (Abstract
insulin-like growth factor binding proteins in postmenopausal breast       1039, Discussed Poster Presentation). 45th ASTRO meeting, Salt
cancer survivors: A randomized controlled trial. Cancer Epidemiol          Lake City, Utah. October 19-23, 2003. In: Int J Radiat Oncol Biol
Biomarker Prev. 2003;12:721-727.                                           Phys. 2003;57(2 suppl):S283-4.
18Dimeo F, Bertz H, Finke J, et al. An aerobic exercise program for        28Von Roenn JH, Tchekmedyian S, Cleary S, et al. State of the Art in

patients with haematological malignancies after bone marrow trans-         Cachexia Therapy: Anabolic Steroids. Oral Presentation. 2nd Interna-
                                                                           tional Cachexia Conference, December 4-6, 2003, Berlin, Germany.

14                                                                          I  N  C: U  March/April 2004