1. Individualized treatment of cancer patients have found out years ago that the combination of gemcitabine + platinum (either cisplatin, carboplatin or oxaliplatin) was the most important drug combination introduced for the treatment of solid tumors in the past 18 years. Clinical responses with this regimen were unprecedented.

Individualized testing of the gemcitabine + platinum combination began in the mid-1990s by Dr. Robert Nagourney, Director of Rational Therapeutics, Inc. Many patients received treatment with this regimen because of individualized testing long before any clinical trials in their particular disease types had ever been published.

The contribution of Dr. Nagourney in terms of recognizing the synergistic effects of this combination had been very important in getting clinical trials with this regimen started in a broad spectrum of cancers. Think of all the many cancer patients that were helped by this, long before these clinical trials ever started?

Posted at 12:42PM on Jul 17th 2006 by Gregory D. Pawelski

2. According to a study published in Gynecologic Oncology, the most probable mechanism for the synergy between gemcitabine + platinum is gemcitabine inhibition of repair of platinum/DNA adducts. What this means is that platinum-resistant tumor cells "cut out" the damaged DNA (to which the platinum is attached) in the same way that the railroad company repairs damaged sections of rail track. Then the railroad company lays down new track. Platinum-resistant tumor cells do the same thing, and gemcitabine interferes with this process. (Belpomme, et al. Gynecol. Oncol. 91:32-38, 2003)

Thus, you want to administer first gemcitabine (to have gemcitabine on board to inhibit the repair process). Then, you want to administer platinum shortly thereafter. In addition, you don't want to give either gemcitabine or platinum by itself on any days of the cycle; this doesn't take advantage of the synergy between the drugs and, in many cases, will just increase toxicity.

It is possible that clinical investigators did not design their treatment schedule to take advantage of the gemcitabine + platinum synergy which exists when platinum is administered in the presence of gemcitabine. An example in the Belpomme, et al study: patients received a platin on Day 1 and gemcitabine on Days 1 (after a platin) and Day 8 (without the platin) of a 21 day treatment cycle. The results were about the same that would be expected with a single agent platinum alone. Overall response rate of 65% and median survival of 24 months.

So it may have been more a problem with synergistic scheduling of the drugs rather than the drugs themselves. It may be one example of how clinical oncologists may get it wrong.

Posted at 5:02PM on Aug 3rd 2006 by Gregory D. Pawelski

3. Gregory P. said, "Thus, you want to administer first gemcitabine (to have gemcitabine on board to inhibit the repair process). Then, you want to administer platinum shortly thereafter. In addition, you don't want to give either gemcitabine or platinum by itself on any days of the cycle; this doesn't take advantage of the synergy between the drugs and, in many cases, will just increase toxicity."

Where is the study that shows that this method of administration is better than that recommended in the manufacturer's literature? I think that this is merely conjecture. Could you point me to the study that compares the two regimens?

Thank you,
Michele

Posted at 10:58PM on Aug 3rd 2006 by Michelle

4. For those that are not astute readers (Belpomme, et al. Gynecol. Oncol. 91:32-38, 2003)

Posted at 11:38AM on Aug 4th 2006 by Gregory D. Pawelski

5. G.P. said:
"For those that are not astute readers (Belpomme, et al. Gynecol. Oncol. 91:32-38, 2003)"

In fact, this study in no way compared methods of administration. Therefore, Wiesenthal's hypothesis, directly quoted from his URL, about the railroad and the synergy, etc. is not tested in this study.

Your, and/or Wiesenthal's statement, "It may be one example of how clinical oncologists may get it wrong" has not been tested or proven in the study you refer me to.

So, for now, patients undergoing the current recommended treatment regimen as recommended by their oncologists, should know this new Wiesenthal hypothesis is merely a theory until proven otherwise.

Michele

Posted at 1:23PM on Aug 4th 2006 by Michelle

6. This "hang-up" on Weisenthal seems to be an aberration. If Michelle wants to win arguments by attacking others, I'm not sure exactly what her underlying point is? What is wrong with wanting to improve the scheduling of an important drug combination (gemcitabine/platinum)?

It reminds me that in a way to determine whether helmuts are effective in preventing major trauma related to blunt force challenge, advocates of evidence-based medicine would criticize the adoption of interventions evaluated by using only observational data.

As with many interventions intended to prevent ill health, the effeciveness of helmuts has not been subjected to rigorous evaluation by using randomized controlled trials. The most radical protagonists of evidence-based medicine would think that everyone might benefit if they organize and participate in a double blind, randomized, placebo controlled, crossover trial of helmut use by skiers, snowboarders, and motorcycle drivers..

Posted at 5:14PM on Aug 4th 2006 by Gregory D. Pawelski

7. G.P. states:
"Thus, you want to administer first gemcitabine (to have gemcitabine on board to inhibit the repair process). Then, you want to administer platinum shortly thereafter. In addition, you don't want to give either gemcitabine or platinum by itself on any days of the cycle; this doesn't take advantage of the synergy between the drugs and, in many cases, will just increase toxicity."

How do we know that?

You then say oncologists "get it wrong."

If I was a cancer patient and I was offered this drug combination and you told me that my oncologist is giving it incorrectly, I would want to know how you have proven that. My argument is not ad hominem at all.

There is nothing wrong with "wanting to improve the scheduling of an important drug combination." But, you have pointed the readers here to a study that did not examine a different schedule at all, yet you continue to post that the current dosing schedule means the oncologists may "get it wrong." A cancer patient, and I work with them daily, wants to feel confindece in his or her prescribed regimen. Yet, you state that there is an article that indicates the regimen is no more effective than platinum alone, so it must be given incorrectly. That article says no such thing.

Your defensiveness may be telling. Merely point me to research that says a better dosing regimen is available. Then, perhaps cancer patients can inform their physicians of this.

Helmuts in a controlled trial? That would be like saying a parachute vs. no parachute: let's test it. The comparison to medicine is, well, you know....

Michele

Posted at 6:21PM on Aug 4th 2006 by Michelle

8. I gave an example of how clinical oncologists may get it wrong by citing the Belpomme, et al study published in Gynecologic Oncology. The study gave patients a platin on Day 1 and gemcitabine on Days 1 (after a platin) and Day 8 (without the platin) of a 21 day treatment cycle which resulted in about the same as would be expected with a single agent platinum alone (virtually no difference). Overall response rate of 65%. Median survival of 24 months.

And I cited Wiesenthal's analogy of the "railroad track repair" as an example of the most probable mechanism for the synergy between gemcitabine + platinum. I then stated that it may have been more a problem with synergistic scheduling of the drugs rather than the drugs themselves.

I may have mistaken your conjecture that this study somehow showed this method of administration is better than recommended in the manufacturer's literature, but I made no assumption that Wiesenthal's so-called hypothesis (or theory as you like to call it) was tested or proven in this study.

I also pointed out that the contribution of Dr. Robert Nagourney in terms of recognizing the synergistc effects of this combination had been very important in getting clinical trials with this regimen started in a broad spectrum of cancers (not just ovarian).

http://biz.yahoo.com/bw/060728/20060728005151.html?.v=1

Posted at 3:00AM on Aug 14th 2006 by Gregory D. Pawelski