From the Phase I Clinical Study of Fish Oil Fatty Acid Capsules for Patients with Cancer Cachexia: Cancer and Leukemia paper, Discussion section

To highlight some additional points:

This study establishes the MTD (Maximum Tolerable Dose) of 0.3 g/kg/day for v-3 fatty acids given in capsule form to patients with advanced cancer. The dose determined in this study is now being used in a Phase II CALGB study to determine whether these unsaturated fatty acids can ameliorate cancer cachexia and/or tumor growth. It is generally thought for cytotoxic agents that it is necessary to use the highest possible dose at or near the MTD in oncological studies to identify the maximum effect. We believe that this may apply as well to the use of fish oil fatty acids in cancer cachexia.

In animal studies, high doses of fish oils were required to ameliorate weight loss of animals bearing experimental tumors. For example, weight loss was reduced by 25% in mice with transplantable murine colon adenocarcinoma on a 5% fish oil diet, but a 50% fish oil diet was required to show statistical significance (3). In another study of the same tumor, 5 g/kg of EPA were required to obtain complete reversal of weight loss (15). However, the requirements in humans may be quite different and to properly test the ability of these fatty acids to ameliorate tumor cachexia in humans, we thought it necessary to use maximum doses possible. We were unable to find published Phase I data that could be applied to cachexic cancer patients.

There have been only limited previous studies of v-3 fatty acids in terminal cancer patients. Wigmore et al. (7) performed a dose escalation study on 18 patients with unresectable pancreatic cancer who received 2–16 capsules per day. They found that patients tolerated a median number of 12 Max-EPA fish oil capsules/day (2.2 g of EPA 1 1.4 g of DHA per day) and had no serious toxicity. However, 25% had steatorrhea, and some patients received pancreatic enzyme supplements. A number of patients had taste aberrations or transient diarrhea. Gogos et al. (16) studied immune response and survival in patients with advanced solid tumors who were randomized to Max-EPA capsules or placebo. They found no toxicity of the fish oil except for mild abdominal discomfort and transient diarrhea, but they gave a dose of 3.06 g of EPA and 2.07 g of DHA per day, which is less than half of the dose for a 70-kg person using the MTD of our study. In a study of the fish oil antitumor response of 12 patients with metastatic breast cancer reported in abstract form, the investigators found no untoward side effects except unpleasant taste (17). That study used a dose of fatty acids (3.6 g of EPA and 2.4 g of DHA daily), also well below our MTD. All three studies used Max-EPA capsules, which contain less than half the v-3 fatty acids (17% EPA and 12% DHA) as in the capsules used in our study. In this regard, to properly compare the doses of fish oil fatty acids given in various studies, it is necessary to compare the amount of actual EPA, DPA, and other v-3 fatty acids taken. It is misleading to compare based on number of “1 gram” fish oil capsules taken because the capsules contain widely varying amounts of v-3 fatty acids.

Most previous therapeutic studies of v-3 fatty acids in other diseases such as rheumatoid arthritis, coronary artery disease, kidney disease, hypertriglyceridemia, and hypertension have used a dose of v-3 fatty acids below what we found to be the MTD for patients with advanced cancer. This low dose may have been chosen in part because of a low amount of v-3 fatty acids in the capsules available. Max-EPA capsules or similar capsules used in many other studies contain about half as much v-3 fatty acid per capsule compared with the capsules we used, which were 38% EPA and 25% DHA. However, some previous studies used doses equivalent to ours. Krokan et al. (18) gave fish oil capsules for a total dose of almost 12 g of EPA 1 DHA to a few normal subjects for 14 days, and there were no adverse effects. Many other studies that gave total v-3 fatty acid doses equivalent to those of this study administered the fatty acids as an oil or emulsion rather than a capsule. For example, the reported studies which used similarly high doses (.10 g of EPA 1 DHA, the major v-3 fatty acids in the preparations) given as oils found no adverse effects (19 –21), which suggests that the v-3 fatty acids might be better tolerated as oils as compared with capsules.

Most other published studies of capsules used less total v-3 fatty acids, usually considerably less. It is possible that a greater therapeutic effect would have been found in those studies if higher doses had been administered. The MTD of natural fatty acid capsules may be influenced by several factors such as pancreatic function and the types and amounts of other fats taken in the concurrent diet. We have no evidence of pancreatic insufficiency in any of the study subjects; however, differences in the diet of the patients were likely. This may explain the difference of tolerability of some patients who could tolerate doses above the MTD, and those who had symptoms at doses considerably below the MTD. It is known that the fatty acid composition of experimental animal tumors can be modified by supplementing the diets of tumor-bearing animals with various fatty acids (9, 10). Neutrophils of normal human subjects can be modified by ingesting capsules containing v-3 fatty acids (14). Therefore, it seemed likely that human tumors can be modified if the patients take fish oil. However, there is limited information on the dietary modification of human tumors.

We could not determine the fatty acid composition of the tumors of most patients on this Phase I study because multiple biopsies of often difficult-to-access solid tumors would be required at times that there were no other clinical indications for the procedure. The multi-institutional nature of the study and cost involved in utilization of operating rooms (needle biopsy provides inadequate amounts of tissue) further precluded such a study. However, one patient with chronic lymphocytic leukemia offered a singular opportunity for obtaining malignant cells during and after the period of fish oil ingestion. In our biochemical case study, there was a considerable increase in the EPA of malignant lymphocytes obtained during the ingestion of fish oil capsules. Enrichment of the malignant cells with EPA, which is a highly polyunsaturated fatty acid, enhances susceptibility to oxidation, physical properties, membrane transport, and eicosanoid production (10, 22). Therefore, EPA enrichment has the potential to ameliorate cachexia in several ways, including decreased production of a possible mediator of cachexia. This also provides a biochemical rationale for a possible direct effect of fish oil ingestion on tumor growth kinetics. Taken together, the modification of tumor, serum, and whole blood provides a rational basis for a Phase II study of the effect of fish oil fatty acids on the cachexia of patients with advanced cancer.

In summary, we found that patients with advanced cancer can tolerate a large dose of the encapsulated fish oil with only minor side effects. Our data indicate that ingestion of the capsules is feasible for periods of time appropriate for the expected life span of cachectic cancer patients and sufficient to test the hypothesis of reversal of cachexia in a Phase II study. We identified a MTD that was higher than the doses used in previous studies of patients with cancer or other diseases in which fish oil capsules were used. This MTD of encapsulated fish oil is now being used in an ongoing Phase II CALGB cooperative group study of the effect of fish oil on cachexia and tumor growth. This dose may also be useful in the design of studies of patients with cardiac, renal, and rheumatic diseases to deliver a maximum fish oil dose to test therapeutic efficacy.

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