Clinical oncologists continue to use sub-optimal dosing schedules for the most important solid tumor drug combination introduced during the past 15 years

The combination of gemcitabine + platinum (either cisplatin, carboplatin, or oxaliplatin) is the most important drug combination introduced for the treatment of solid tumors in the past 15 years. We have observed clinical responses with this regimen which are, to my knowledge, unprecedented. A complete remission and 6 year history of enduring remission in a patient with unresectable pancreatic adenocarcinoma metastatic to spleen, kidney, and omentum .  A complete remission and greater than 4 year survival in a patient with massive, non-cytoreducible ovarian cancer who had primary progression on platinum/Taxol, followed by progressive disease despite tandem high dose chemotherapy and tandem stem cell transplants at a cost of more than $200,000.  A clinical complete remission in a patient with colon cancer metastatic to liver and lungs (large "cannonball" lesions), following failure of adjuvant 5FU/levamisole, 5FU/leucovorin, 9-aminocamptothecin, and biotherapy.  A durable, complete remission (lasting years) in a patient with gastric cancer metastatic to nodes and liver. And many others.

We began Cell Culture Drug Resistance Testing (CCDRT) of the gemcitabine + cisplatin combination in the mid-90s at the specific suggestion of Dr. Robert Nagourney, Director of Rational Therapeutics,Inc. .  At the time, it was a virtually unexplored combination, and many patients received treatment with this regimen because of our CCDRT results long before any clinical trials in their particular disease types had ever been published.  Dr. Nagourney's contributions in terms of recognizing the profound synergy of this combination and promoting the use of this combination have been very important in getting clinical trials with this regimen started in a broad spectrum of cancers. In our experience, gemcitabine + platinum combinations are the most synergistic drug combinations in solid tumors which we have ever tested.

I believe that the most probable mechanism for the profound synergy between gemcitabine + platinum is gemcitabine inhibition of repair of platinum/DNA adducts. Basically, 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.  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.

As just one example of how clinical oncologists too often get this wrong, there is a study just published in the current issue of Gynecologic Oncology, by a team of French and Belgian investigators (Belpomme, et al. Gemcitabine combined with cisplatin as first-line treatment in patients with epithelial ovarian cancer: a phase II study. Gynecol. Oncol. 91:32-38, 2003).

In the above study, patients with previously-untreated ovarian cancer were treated with gemcitabine plus cisplatin.  Patients received cisplatin 75 mg/M2 on Day 1 and gemcitabine 1250 mg/M2 on Days 1 (after cisplatin) and Day 8 (by itself, without cisplatin) of a 21 day treatment cycle. The results were decidedly ordinary (about the same which would be expected with single agent platinum alone).  Overall response rate of 65%. Median survival of 24 months.

The above results were entirely predictable, as the investigators did not design their treatment schedule to take advantage of the profound gemcitabine/platinum synergy which does exist when platinum is administered in the presence of gemcitabine.

In cases where CCDRT identifies gemcitabine/platinum as the in vitro best regimen, I personally recommend to all of our referring oncologists the below-described treatment schedules of gemcitabine/cisplatin and gemcitabine/carboplatin, designed 7 years ago by Dr. Dwight McKee:

Dwight L. McKee, M.D.
Diplomate American Board of Internal Medicine, Oncology, and Hematology
Integrative Cancer Care
530 Sumner Avenue
Aptos, CA 95003

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Preliminary note regarding the use of amifostine:

Amifostine may reduce platinum toxicity, including the thrombocytopenia with
gemcitabine + carboplatin, but has the disadvantage of being emetogenic, if given
without anti-emetic premedication or if given after the anti-emetic effects of
premedications have dissipated. If amifostine is administered, care must be taken
regarding the timing of antiemetic premedication.
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Gemcitabine/Cisplatin/Amifostine Protocol

Day One:

Ondansetron hydrochloride 32 mg IV + dexamethasone 10 mg IV + cimetidine
300 mg IV + diphenhydramine 25 - 50 mg IV (these are medications to reduce
nausea and vomiting); then immediately give gemcitabine 1 gram/M2 IV over 45 -
60 minutes* and at the same time gemcitabine is started also start to give
hydration with one liter of 0.9% NaCl over one hour. Then administer amifostine
740 mg/M2 over 10 minutes, monitoring the blood pressure carefully and
interrupting the infusion for a drop of systolic blood pressure >> 25% from the
baseline, restarting if the systolic blood pressure recovers to the baseline after 5
minutes. Immediately after the amifostine, begin infusion with cisplatin 100
mg/M2, along with suitable hydration and according to an infusion schedule
compatible with the tolerance of the patient (determined according to the
judgement of the treating physician).

Days 2 through 21: rest. No treatment. Monitor patient for treatment-related
side effects and for evidence of tumor response.

Day 22: Begin next cycle of treatment, if tolerance of chemotherapy and results of
treatment with first cycle have been satisfactory.

*Longer infusion schedules for gemcitabine may be more active, but probably also
more toxic
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Gemcitabine/Carboplatin Protocol

Dr. McKee has  found that using chemoprotective doses of amifostine significantly protects against the (sometimes profound) thrombocytopenia which otherwise tends to occur when carboplatin is used with gemcitabine. Because carboplatin is so much better tolerated in terms of subjective side
effects, this is Dr. McKee's regimen of choice for gemcitabine/platinum combinations, switching to cisplatin only if profound thrombocytopenia develops, despite the use of amifostine and
Neumega. Dr. McKee reports that chemoprotective doses of amifostine are best tolerated when
taxane type premeds are utilized. Usually he uses 32 mg Zofran or 1-2 mg Kytril IV along with
10 mg Decadron, 300 mg cimetidine, and 25-50 mg Benadryl. Immediately after the premeds are
administered, he infuses gemcitabine 1 gm/m2 given over 30 minutes in 500 ml normal saline,
which also functions as prehydration for amifostine. 740mg/M2 amifostine is then
administered over 10 minutes, monitoring the BP carefully and holding the infusion for a drop
of systolic BP >25% from baseline, restarting it if the SBP recovers to baseline after 5 min.
Immediately after the amifostine, the carboplatin in an AUC of 5-6 is given over 30 minutes
for doses of 400 mg or less, over 1 hour for doses of more than 400 mg (more nausea with
rapid administration of higher doses). If the platelet count nadirs below 70,000, consider
repeating the amifostine (same dose) after the carboplatin is administered because of the long
half life of carboplatin. The second dose of amifostine is often transiently emetogenic, less so
if the short acting anti-emetic medications are repeated just prior.

This combination is given x2 cycles q 3 wks, followed by some type of restaging procedure.

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