Nutritional factors, ignored by the cancer community for many years, are now the focus of several mainstream studies. Recent findings highlighting the importance of nutritional factors include interim results of a long-awaited, well-designed study showing that dietary fat reduction reduces breast cancer recurrence. Other studies validate the use of vitamin supplementation as a strategy for ameliorating the toxicity of pemetrexed therapy for lung cancer.
These studies provide intriguing leads suggesting that vitamin supplementation may also reduce the harmful effects of other agents used to treat cancer.
A third area of current interest is the use of anabolic steroids and other supplements used by athletes and body builders to treat weight loss and muscle wasting in cancer patients. It may be possible to use these supplements earlier in the course of illness to boost energy and improve quality of life, rather than at the end of life.
Dietary Fat Reduction in Breast Cancer
The long-awaited preliminary results of the Women's Intervention Nutrition Study (WINS) demonstrated that reducing dietary fat intake lowered the risk of recurrence of breast cancer at 60 months of follow-up. The final results will be reported after 80 months of follow-up.
“Dietary fat reduction is a sustainable but not a trivial intervention,” said Rowan Chlebowski, MD, PhD, Professor of Medicine at UCLA's Jonsson Comprehensive Cancer Center and Chief of the Division of Medical Oncology at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.
“We hope that additional follow-up will provide definitive evidence to support a role for dietary fat reduction in patients with breast cancer.
“This is a strong signal that breast cancer patients can reduce the risk of recurrence by lowering the amount of dietary fat that they consume. This is an inexpensive strategy.”
The randomized, controlled, multicenter study, reported at a plenary session at this year's ASCO Annual Meeting (Abstract 10; OT 6/25/05), included 2,437 women aged 48 to 78 at entry with Stages I-IIIA breast cancer.
Patients received standard treatment of primary surgery followed by radiation, chemotherapy, and hormone therapy if needed. About 50% received anthracyclines, and 6% received a taxane.
All women in the study received general nutritional counseling every three months. A total of 975 women were also entered into a previously validated, intensive nutritional counseling program that entailed eight one-on-one sessions with a dietitian every other week, followed by quarterly visits; these women also attended monthly support groups.
“The goal of the intervention was not weight loss or caloric restriction, but rather to reduce intake of dietary fat to 20% or less of daily calories,” Dr. Chlebowski explained.
Self-reports by participants suggested that the dietary intervention was delivered as planned. A 40% reduction in fat gram intake (from 51 grams a day to about 33 grams a day) was achieved in the intervention group at study endpoint, and this was associated with weight loss of about 6 pounds. No change in fat intake or weight was observed in patients who had standard nutritional counseling.
At five years, less than 10% in the intervention group had a recurrence compared with more than 12% of those on their usual diet, reflecting an increase in disease-free survival of 24% for those on the low-fat diet.
A more robust effect was observed in patients with estrogen receptor (ER)-negative cancer, who had a 42% reduction in recurrence. However, women with ER-positive tumors had a 15% risk reduction, which was not significant.
Dr. Chlebowski said that the subgroup analyses are hypothesis-generating, but that the data are not sufficient to prove that the only effect is in ER-negative disease.
It is not clear whether dietary fat reduction or the associated modest weight loss potentially mediated the clinical effects, he said.
“This study shows that when you implement lifestyle changes such as dietary fat reduction, other things change, including weight and intake of other nutrients. Some oncologists mistakenly think that losing weight is easier than reducing dietary fat, but it is really the other way around. Reducing dietary fat can be achieved while eating the same amount of food as previously but eating different foods,” he stated.
He commented that oncologists may reasonably be reluctant to suggest reduced dietary fat intake, because they don't want to make their patients feel guilty until the data strongly indicate that a low-fat diet will change outcome.
But if more definitive evidence emerges after 80 months of follow-up of this study, he said he believes that a reduction in dietary fat should become part of standard management of patients with breast cancer.
Folic Acid & Vitamin B12 Supplementation
The addition of folic acid and vitamin B12 supplementation has been found to ameliorate the toxicity of pemetrexed, a multitargeted antifolate agent. This simple measure enables patients with non-small lung cancer (NSCLC) to benefit from this otherwise toxic treatment, said Nasser Hanna, MD, Assistant Professor of Oncology at Indiana University School of Medicine.
Single-agent pemetrexed, an effective second-line treatment for patients with NSCLC, was originally dosed at 600 mg/m2 based on Phase I studies, Dr. Hanna explained. Phase II trials, however, showed that this dose was too high, leading to an unacceptable rate of side effects such as myelosuppression, mucositis, and diarrhea—a combination that can lead to serious life-threatening infections.
Subsequent preliminary studies used a dose of 500 mg/m2, but a small percentage of patients still developed serious side effects.
Studies conducted by the drug's manufacturer, Eli Lilly, showed that patients with elevated homocysteine levels were at risk of developing complications with pemetrexed. Since homocystinemia reflects insufficient levels of vitamin B12 and folic acid, supplemental use of these vitamins was integrated into the clinical trial development program for pemetrexed, Dr. Hanna said.
“A strategy of folic acid and vitamin B12 supplementation, initiated one week prior to treatment and continued throughout treatment until three weeks beyond the last dose, led to a significant decrease in gastrointestinal and hematologic complications, and the incidence of treatment-related deaths plummeted. But we were concerned that the decrease in side effects could also result in reduced efficacy.”
Efficacy Not Compromised
These concerns were laid to rest by the international Phase III EMPHACIS (Evaluation of Multitargeted Antimetabolite in Mesothelioma in a Phase III Study with Cisplatin) trial in 448 patients with mesothelioma.
Patients with unresectable mesothelioma were randomized to receive either pemetrexed plus cisplatin or cisplatin alone. Seventy patients were entered in the trial prior to the discovery that vitamin supplementation could alleviate pemetrexed's side effects.
The protocol was then changed to include vitamin supplementation with folic acid and B12 injections for patients subsequently enrolled.
Results showed that the addition of vitamin supplementation achieved significant reductions in adverse events in both arms of the study, with no decrement in effectiveness.
Moreover, it appeared that the addition of vitamin supplementation improved the ability to give pemetrexed, resulting in fewer dose reductions, fewer dose delays, and more cycles of chemotherapy.
“In theory, vitamin supplementation may improve the ability to give the drug as well as its effectiveness,” Dr. Hanna said.
An intriguing finding of EMPHACIS was that patients in both treatment arms had improved response rates and survival once vitamin supplementation was added. Also, the incidence of Grade 3 and 4 adverse events was reduced in both arms when vitamin supplementation was added.
This suggests, Dr. Hanna said, that vitamin supplementation, as used in the study, might be of benefit with other anti-cancer drugs, but so far this has not been studied.
At present, the maximally tolerated dose of pemetrexed has not been defined. This question is being studied in a trial conducted by the Hoosier Oncology Group at Indiana University in which patients are treated with fixed-dose cetuximab and escalating doses of pemetrexed plus vitamin supplementation.
More information about the optimal dose of pemetrexed should be forthcoming from this and other trials, Dr. Hanna said.
The pivotal Phase III trial for approval of pemetrexed in NSCLC compared docetaxel versus pemetrexed plus vitamin supplementation. The study enrolled 571 patients. No patient died from pemetrexed-related toxicity, and there were no cases of neutropenic fever infections. A total of 5% of patients developed neutropenia, and 2% developed neutropenic fever.
“Vitamin supplementation led to a dramatic difference in the side-effects profile of pemetrexed,” Dr. Hanna said.
“The question remains whether these vitamins could make a similar difference with other cancer drugs in reducing hematologic and gastrointestinal toxicity and neuropathy without a decrement in the effectiveness of these agents. Although this is intriguing, I doubt whether it will be studied with older drugs.”
Oxandrolone for Cancer-Related Cachexia
Oxandrolone, an oral anabolic steroid used for treatment of unexplained weight loss in patients with a variety of conditions that include burns, extensive surgery, and trauma is now being studied in cancer-related cachexia, noted Jamie Von Roenn, MD, Professor of Medicine at the Feinberg School of Medicine of Northwestern University and the Robert H. Lurie Comprehensive Cancer Center.
“Oxandrolone has been used for many years to treat weight loss for a catchall of conditions, but until recently it hadn't been studied in cancer patients. Now several manuscripts of studies in cancer patients are under preparation.”
A Phase II study, with Dr. Von Roenn as lead investigator, found that oxandrolone at 10 mg bid achieved weight gain and improved energy in patients with advanced cancer and weight loss of at least 5%. Moreover, a correlation was observed between improvement in lean body mass and improved quality of life, she said.
“What I found fascinating is that patients who gained weight on oxandrolone gained lean mass preferentially over fat, and those who remained weight stable [±2% of their baseline weight] gained lean mass and lost fat, while those who lost weight lost fat disproportionately.”
In contrast, cancer patients treated with megestrol acetate—“the most potent appetite stimulator studied,” she said—gain fat mass preferentially, not muscle mass.
“Patients with cachexia lose muscle disproportionately, and we assume that is why they become so frail and have a cluster of symptoms that includes fatigue, weakness, and loss of appetite,” Dr. Von Roenn said.
“If a drug can maintain muscle mass, it should help patients have more energy. Megestrol acetate may be a good drug for palliative care, but for patients who are treated [for weight loss] early, a drug that preserves muscle mass would be more desirable. I am excited that people who took oxandrolone preserved lean body mass.”
Based on the encouraging results of the Phase II trial, a Phase III placebo-controlled study enrolled cancer patients with significant weight loss (i.e., more than 3% in one month or at least 5% in six months) and a life expectancy of more than six months. The results are not yet available, but Dr. Von Roenn said she and her colleagues are hopeful that the Phase II findings will be confirmed.
“If that is the case, it would make sense to study oxandrolone in an earlier population,” Dr. Von Roenn commented.
“If changing weight is going to have an impact on survival, we have to be able to change the underlying metabolic abnormalities. Some of these effects are clearly related to lean tissue, so it would be advisable to study this drug upstream—as soon as patients lose 5% of their body weight.”
Another question is whether oxandrolone will improve fatigue, weakness, and other symptoms associated with weight loss. The Eastern Cooperative Oncology Group is currently planning a Phase II study to look at the effect of oxandrolone on fatigue.
“Improvement in muscle mass should correlate with improved energy and less fatigue,” Dr. Von Roenn noted.
Another supplement that may hold promise for improving muscle mass in cancer patients with cachexia, she said, is called Juven—the brand name of a combination of arginine, glutamine, and HMB (beta-hydroxy-beta-methylbutyrate).
Juven is used by body builders, and some intriguing early leads suggest that it may be useful in cancer patients as well, Dr. Von Roenn said, adding that although as far as she knows there have not yet been any studies of the product in cancer patients, presumably there will be studies in the future.
Creatine for Weight Loss in Cancer Patients
Preliminary studies in a variety of metastatic cancers suggest that creatine, an amino acid derivative used by body builders and athletes, may be able to stem muscle wasting in patents with cancer-related weight loss, said one of the investigators, Aminah Jatoi, MD, Associate Professor of Oncology at the Mayo Clinic.
The studies are being done by the North Central Cancer Treatment Group (NCCTG). Clinically significant weight loss is a predictor of poor survival, she noted, explaining that it takes only a 5% drop in weight to put patients at greater risk for a poorer outcome. In addition, patients who suffer weight loss have a reduced quality of life.
The decision to study creatine in cancer patients was based on two lines of evidence, Dr. Jatoi said. First, athletes use it to “bulk up” on muscle and improve athletic performance. Second, in certain non-cancer disease states, such as neurologic disease with muscle atrophy, some very preliminary studies suggest an improvement in function with creatine treatment.
Currently, a large, placebo-controlled, NCCTG study is recruiting patients to study creatine. Endpoints will be weight gain, quality of life, and survival. “We are enthusiastic about this study,” she said. It may take a few years to fully recruit patients, but our hope is that we'll gain some evidence as to whether this approach might also help cancer patients.”
Creatine appears to be safe, but the side effects have not been well characterized, she added. “Kidney function may be affected, so one needs to be vigilant when using this agent.”