July 24 2008 post: A few days ago Prof. Aggarwal’s senior administrative assistant sent me a message with an unexpected and very welcome attachment: the full report (yippee!) on the pancreatic cancer-curcumin clinical trial that has been taking place at MD Anderson in Texas. The report was published in the July 15 issue of “Clinical Cancer Research” (see abstract: http://tinyurl.com/6fjk59).

 

This was a Phase II study to determine whether oral curcumin has biological activity in patients with pancreatic cancer. Let’s skip all the introductory parts describing pancreatic cancer and then curcumin and go have a look at the “Results.”

 

The average age of the 25 patients enrolled in the study was 65. No treatment-related toxic effects were observed. To date, one patient remains stable for >18 months and another patient had a dramatic but brief tumor response. The former patient had previously undergone a failed Whipple’s surgery followed by gemcitabine and radiation for locally advanced disease. Curcumin decreased this particular patient’s CA125 level (CA125 is the abbreviation for Cancer Antigen 125, which is elevated in many types of cancer, but apparently and surprisingly not that common in myeloma), the size of his lesions remained stable, and indeed there has been a decrease in the standardized uptake value in those lesions from a baseline level of 10.6 to a level of 5.7 after 12 months of therapy.

 

The report continues: One patient had a brief but marked response (73% reduction in tumor size by Response Evaluation Criteria in Solid Tumors) that lasted 1 month […]. Interestingly, at the time of progression, the lesions that had regressed remained small, but other lesions grew larger. This patient also had a rapid and dramatic increase in cytokine levels (IL-6, IL-8, IL-1RA, and IL-10). When I read this last sentence, I confess to having felt slightly alarmed…Then I read the following: Conceivably, this occurred because of release of cytokines from the tumor associated with shrinkage. Oh, phew! Relief!

  

The discussion regarding this particular patient continues later on: Also, of potential importance in this patient is the observation that the tumors that originally regressed continued to show regression during the follow-up period on curcumin, whereas the tumors that grew were the ones that had been small originally. This observation suggests that there was a malignant clone responsive to curcumin, whereas another resistant clone emerged.

 

In contrast, the patient who has appeared to have benefited most from treatment with curcumin (patient 14) has had slow improvement over 1 year and a gradual decrease in cytokine levels […]. Of interest, patient 14 had the highest baseline levels of IL-1RA of any of the study patients. IL-1RA stands for “Interleukin 1 receptor antagonist” and is the natural antagonist of the pro-inflammatory cytokines interleukin-1alpha and interleukin-1beta (from Wikipedia).

  

Okay, in sum, this means that two patients appeared to have biological activity of curcumin after treatment. That sounds even less encouraging than the myeloma-curcumin study at first glance…BUT, after treatment with curcumin, a decline in NF-kB, STAT3 and COX-2 was observed, and that is important, methinks.

 

I was particularly interested in the test results of the patients taking 8 grams of curcumin/day: Although we found little, if any, free or unconjugated curcumin in these patients’ plasma, we easily detected levels of curcumin following digestion of plasma with combined glucuronidase and sulfatase enzymes. This is consistent with data suggesting that curcumin is present in plasma in conjugated (glucuronide and sulfate) forms. […] Plasma levels of drug released from conjugated derivatives of curcumin on day 1 of dosing decreased on average to 22 to 41 ng/mL from 2 to 6 h after the first dose of curcumin […]. This simply means that the curcumin that enters our body is transformed into conjugate forms, whose levels continue to decrease as time passes.

 

There is a lot of detail in this 9-page study. I couldn’t possibly summarize it or quote it all. But I think many of us are chiefly interested in the issue of bioavailability, which is dealt with on pages 7-8: only low levels of curcumin are detectable in plasma (steady-state level at day 3 is ~22-41 ng/mL). Nevertheless, some of the patients had biological activity of curcumin as evidenced by the antitumor effects noted above in two patients and by effects on cytokine levels and on NF-kB, COX-2, and pSTAT3 […]. Conceivably, the limited bioavailability of curcumin attenuated the response rate, because exposure to microgram amounts of curcumin is required to show antiproliferative effects in vitro. It is also possible that circulating curcumin levels do not reflect tumor tissue curcumin levels.

 

Ah, now this is what I have suspected (or hoped!) for quite some time: curcumin may be barely detectable in the bloodstream, but that doesn’t mean that it isn’t working on some different level…This thought seems to be confirmed by the following: It has been suggested previously that systemic levels of drug may not reflect drug levels actually present in tissues of interest. Although at least one study has examined curcumin levels in colon tissue of mice after oral administration, few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues. This is important: few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues.

 

The study continues with an unwelcome bit of news: However, the researchers add that even though the levels of NF-kB and COX-2 were decreased by curcumin, this did not translate into a clinical response. Bummer…

 

Conclusion: as we know, oral curcumin is well tolerated at doses for of 8 grams for up to 18 months (in my case, much longer than that!). And, even though our body doesn’t absorb it very well, biological activity is evident. This is an important statement.

 

The problem as far as pancreatic cancer is concerned is that higher levels of exposure need to be achieved. Curcumin is hydrophobic and therefore cannot be given i.v. However, because it is lypophilic, it can be encapsulated in a liposome, and such a preparation would allow i.v. administration, leading presumably to higher circulating levels of curcumin. Lipophilic…meaning that it dissolves in fats and oils. Okay, we already knew that, but read the following:

 

The researchers suggest that liposomal curcumin or other better formulations of curcumin may provide more consistent blood levels with better pharmacologic effect. And, (drum roll) they are developing liposomal curcumin for clinical trials.