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Current Management of Cancer-Associated Anorexia and Weight Loss

Current Management of Cancer-Associated Anorexia and Weight Loss

ABSTRACT: Loss of appetite and weight predict a poor prognosis for cancer patients. Although caloric supplementation might benefit subgroups of patients—specifically, perioperative, severely malnourished cancer patients, stem cell and bone marrow transplant patients, and head and neck cancer patients—its use remains controversial and is not recommended for the majority of patients with cancer-associated weight loss. Most patients with advanced cancer, anorexia, and/or weight loss do not appear to benefit from nutritional supplementation. Instead, discussions with patients and families about realistic eating goals and, at times, pharmacologic interventions with progestational agents or corticosteroids—both of which are aimed at palliating anorexia—provide clinical benefit. Other pharmacologic interventions such as eicosapentaenoic acid, thalidomide (Thalomid), adenosine triphosphate, and nonsteroidal anti-inflammatory agents focus on the fact that cancer-associated weight loss is an entity distinct from simple starvation. These interventions promise to replenish lean tissue but require further investigation before they can be recommended as standard clinical practice. [ONCOLOGY 15(4):497-510, 2001]

Introduction

Loss of weight and appetite predict a poor prognosis for cancer
patients. In an 1811 treatise, John Abernathy described a patient with a tumor,
"which made him look very sickly and grow very thin, and caused some
persons to deem the disease cancerous."[1] Abernathy went on to say that
"the derangement of the constitution was as violent as the local disease,
and in about a week, the patient died."

Spurred by such early observations, DeWys and others formally
analyzed the impact of weight loss on cancer prognosis.[2] In a
multi-institutional, retrospective, Eastern Cooperative Oncology Group
evaluation of 3,047 patients from 12 different clinical trials, these
investigators found that loss of more than 5% of premorbid weight predicted a
poor prognosis for cancer patients. Independent of tumor stage, tumor histology,
and patient performance status, this weight loss not only predicted a poor
outcome but was associated with a trend toward lower chemotherapy response
rates.

Along similar lines, Chang recently reviewed the prognostic
effect of various cancer symptoms.[3] He summarized studies showing that loss of
appetite also predicts a poor outcome for cancer patients. Taken together, these
three publications demonstrate a strong association between cancer-associated
anorexia/weight loss and an early demise.

Couple these prognostic data with the observation that
cancer-associated anorexia and weight loss are highly prevalent, and the
magnitude of the problem enlarges. Tchekmedyian and others examined the
prevalence of cancer-associated weight loss and anorexia in an ambulatory
oncology setting.[4] Among 644 consecutive patients, evidence of diminished
appetite, compromised oral intake, or weight loss greater than 5% of premorbid
weight occurred in more than half of patients. Additionally, 54% of patients
were underweight in direct comparisons between patients’ actual weight and
calculated ideal weight. These prevalence rates are likely to be even higher
among nonambulatory cancer patients in the late stages of advanced disease. In
short, cancer-associated anorexia and weight loss are common and carry a notable
adverse prognostic impact.

Treatment Options

Almost 200 years after Abernathy’s description of his patient
with a "derangement of the constitution," weight loss continues to
plague cancer patients. Yet, treatment has yielded only modest success. Clinical
efforts have primarily focused on energy repletion by means of either a direct
increase in caloric intake or mitigation of anorexia. Only more recently have
treatment efforts targeted maintenance of lean tissue. Below, we summarize
treatment approaches for cancer-associated weight loss and anorexia and the
rationale for their use, as they pertain to (1) caloric supplementation,
(2) orexigenic agents, and (3) agents targeted at maintenance of lean
tissue.

Role of Caloric Supplementation

At first glance, caloric repletion seems the optimal approach to
the treatment of cancer-associated weight loss. After all, since weight loss is
the result of an energy deficit, an increase in caloric intake would appear to
tilt the scales in favor of weight stability and, thereby, generate clinical
benefit for cancer patients. Studies have suggested, however, that increased
caloric intake might help cancer patients in only a few specific circumstances:
(1) perioperatively, (2) in the setting of stem cell or bone marrow
transplantation, and (3) during treatment for head and neck cancer.

The data to support these indications are discussed below (Table
1
). Otherwise, caloric supplementation either has not been tested or has proven
to be detrimental.

Perioperative Nutritional Support: First, two studies
suggest perioperative nutritional support benefits patients prior to major
surgery, counterbalanced by one recent meta-analysis on total parenteral
nutrition in general. The Veterans Affairs Total Parenteral Nutrition
Cooperative Study Group trial examined 395 malnourished patients who were
randomized to receive no fewer than 7 days of standard preoperative total
parenteral nutrition vs no nutritional supplementation.[5] All patients were
considered surgical candidates prior to study enrollment, and 65% had cancer.

Within this study, the 24 patients who were considered severely
malnourished, as suggested by low scores on the Nutrition Risk Index, appeared
to benefit from perioperative nutritional support. These patients manifested
fewer noninfectious complications—such as anastomotic leak, bronchopleural
fistula, and others—when compared to severely malnourished patients who did
not receive nutritional support. Such benefits were not observed among patients
with mild or moderate malnutrition.

Similarly, in the second trial, Fan et al evaluated 124
malnourished patients with hepatocellular carcinoma prior to surgery.[6] Many of
these patients were only mildly malnourished, with only 20% having sustained a
loss of > 10% of their premorbid weight. In this placebo-controlled,
randomized trial, patients who received total parenteral nutrition sustained an
overall reduction in postoperative morbidity. There was also a reduction in the
use of diuretics in the postoperative setting. Although neither of these studies
showed a survival advantage with total parenteral nutrition, they did
demonstrate a decrease in morbidity.

In contrast to these two studies, a recent meta-analysis, which
included 26 randomized trials and a total of 2,211 patients, concluded that the
use of total parenteral nutrition in surgical or critically ill patients did not
improve mortality or complication rates.[7] Although not all studies in this
meta-analysis included cancer patients, the comprehensiveness of the analysis
and the fact that some cancer patients were included suggest that the use of
total parenteral nutrition for cancer patients perioperatively should be weighed
carefully prior to implementation.

Taken together, these data support caloric supplementation in
the perioperative setting among cancer patients with severe malnutrition or in
patients with a potentially resectable hepatocellular carcinoma, although such
recommendations remain controversial.

Enteral and Parenteral Nutrition: Secondly, nutritional
supplementation potentially helps patients in the setting of stem cell rescue
after high-dose chemotherapy. Both enteral and parenteral nutrition appear to be
beneficial.

In one of the earliest and largest studies examining total
parenteral nutrition in the transplant setting, Weisdorf et al evaluated 137
patients who were well nourished at the initiation of their transplant
procedure.[8] The majority of these patients (93%) had been diagnosed with
cancer, predominantly leukemia. After stratification on the basis of age and
type of transplant (autologous vs allogeneic), patients were randomized to
receive either total parenteral nutrition or intravenous fluids with 5%
dextrose, electrolytes, minerals, trace elements, vitamins, and no lipids. Both
treatment arms were initiated prophylactically—ie, prior to patients showing
evidence of malnutrition. Because a decline in nutritional status became evident
during the clinical course of these patients, 61% in the control arm crossed
over to the total parenteral nutrition arm.

In a direct comparison of the two study arms, overall survival,
time to cancer relapse, and disease-free survival were significantly improved in
the total parenteral nutrition arm. In contrast, the incidence of graft-vs-host
disease, time to engraftment, and time to bacteremia were not significantly
different between the two arms. In effect, this study suggests that total
parenteral nutrition confers some benefit in this setting when administered
prophylactically.

Head and Neck Cancer: Thirdly, studies in patients with head
and neck cancer also suggest a role for nutritional supplementation, although
these studies are far less compelling than the studies cited above. In one
preliminary trial, 40 patients with inoperable nasopharyngeal or oropharyngeal
squamous cell carcinoma were randomized to receive either oral nutrition or
intensive nasogastric tube feedings during radiation treatment.[9] The latter
provided more calories.

Although no statistical differences were observed between the
two groups with respect to tumor response rates or survival, a slightly greater
percentage of patients who received the tube feedings—8 of 13 tube-fed
patients vs 5 of 11 orally fed patients—returned to their regular activities
after a 6-month follow up period. These data might be viewed as exploratory in
nature, but they nevertheless suggest that aggressive oral nutrition might
confer clinical benefit to head and neck cancer patients during aggressive
therapy.

Similarly, another randomized trial by Nayel and others found
that aggressive oral feeding resulted in completion of radiation without
interruption in 11 of 11 patients who received it. In contrast, radiation
therapy was interrupted in 5 of 12 patients who did not receive aggressive oral
feeding.[10] These data suggest that aggressive feeding might provide short- and
long-term benefits to head and neck cancer patients.

Advanced Cancer: In contrast to the specific clinical
indications sited above, trials in chemotherapy patients with advanced cancer
have not demonstrated favorable outcomes with aggressive caloric
supplementation. In one such study, Ovesen et al evaluated 105 cancer patients
who were receiving chemotherapy.[11] Patients were randomized to either
nutritional counseling or no nutritional counseling. Although the former group
consumed significantly more calories than the latter group, tumor response
rates, patient survival, and quality of life did not differ significantly
between the two groups.

Several clinical trials in which patients with advanced cancer
received total parenteral nutrition also failed to demonstrate a favorable
impact of nutritional supplementation. Some of these studies actually noted
increased rates of infection or other detrimental effects with the use of total
parenteral nutrition.

Recommendations: In 1989, a review of these studies led to a
consensus statement from the American College of Physicians (ACP) on total
parenteral nutrition in cancer patients receiving chemotherapy.[12] More than 10
years later, the ACP has not revised their original statement:

The routine use of parenteral nutrition for patients undergoing
chemotherapy should be strongly discouraged, and, in deciding to use such
therapy in individual patients whose malnutrition is judged to be life
threatening, physicians should take into account the possible exposure to
increased risk.

How do we reconcile the results of the foregoing studies, some
of which suggest clinical benefits with nutritional supplementation in cancer
patients, and others of which do not? Moreover, since not all groups of cancer
patients have been formally studied with respect to implementation of adjunctive
nutritional therapy, how do we decide when to use such supportive measures and
when not to?

Two empiric guidelines, derived from the studies cited above,
might help answer these questions. Cancer patients who seem to benefit from
caloric supplementation fall into both of the following categories: (1) patients
who are either notably malnourished or at risk of becoming so during cancer
treatment; and (2) patients who have potentially curable disease or look forward
to the promise of a long disease-free period after cancer treatment.

In summary, reasonable justification can be found for
administering adjunctive nutritional therapy to cancer patients prior to an
attempt at resecting the primary tumor, prophylactically during stem cell or
bone marrow transplantation, and during radiation treatment for head and neck
cancer. With malignancies such as potentially curative locally advanced
esophageal cancer treated with concomitant chemotherapy and radiation, the use
of adjunctive nutritional therapy remains of speculative value and must be
decided on a case-by-case basis. In contrast, little justification exists for
the use of adjunctive nutritional treatment, such as total parenteral nutrition,
in patients receiving chemotherapy for advanced cancer.

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