Combination Chemotherapy Richard Lam, MD

Combination Chemotherapy

By Richard Lam, MD

Prostate Oncology Specialists Marina del Rey, CA.

Dr. Lam, like the majority of the preceding speakers, was presenting a review of chemo regimens that have been tried in PCa. No original research was presented.

He identified three “goals” of chemotherapy: firstly, it is used with other therapies in an “adjuvant”, that is supplemental not primary, secondly it is used in an attempt to cause the cancer to go into “remission” when other treatments have failed, and thirdly, chemo is used to slow or stop progression and to reduce symptoms from the cancer.

It’s important to note that no report of “cure” by chemotherapy was claimed by Dr. Lam.

If, for a given treatment, no evidence of progress has been measured in 60 days, he suggested that then would be the time to switch to a different regimen. Evidence for benefit, he reported, is “almost always” reflected by a decline in such markers as PSA, PAP, LDH, ALP, CEA, CGA or NSE.

[Ed Note: Most commonly, change in PSA is followed and used as a surrogate for effectiveness of the chemo.]

He also reported that baseline measurements including physical exam with DRE, CT scan, bone scan, color Doppler ultrasound, MRI and/or PET scans should be taken to allow for determination of protocol effectiveness.

Lam then went into a review of several chemo protocols that have been tried with varying degrees of success. Adriamycin in combination with radioactive Strontium showed an increase in survival of 11 months (from 16 with adria alone to 27 with the combo).

Strontium-89 is used in treatment of bone mets in men who have metastatic disease. Combining it with adriamycin did reduce blood counts and cause GI upset. This work was reported in 2001 in the journal Lancet.

A similar regimen using Taxotere with Samarium (another radioactive element for bone mets) was reported in 2003 at ASCO. This was a small study (n=6) that started treatment with the TAX for six weeks and then introduced injection of the Samarium at the fourth week. It was reported that 5/6 men had a >50% decline in PSA “that was maintained for 6 mos.”

However, the side effects of the Samarium on blood counts were such that great care was required in monitoring the subjects. They experienced low red blood cell counts (anemia) and also low white BC that increased risk of infection. Low platelet counts raised the risk of bleeding and reportedly, might limit the man’s ability“to withstand future chemotherapy treatments”.

He then discussed some more current chemo combinations regimens such as Taxotere and Thalidomide. In 2005 a study involving 75 men was reported that showed an improvement in overall survival of 26 months for the combination vs 15 months for the TAX alone arm.

Without seeing the statistical confidence limits around this difference it’s not possible to evaluate the significance. The major side effect reported by Dr. Lam was an increase in the number of blood clots for the combination arm of the study.

Lam also referred to trials of Taxotere and high dose Calcitriol. A study of 250 men showed an increase in overall survival in the combination arm of 23.5 months vs 16 months for the Tax alone group. No increase in SEs was reported for the Calcitriol arm.

Avastin® is a new drug intended to act as an anti-angiogenesis agent for cancer control. When used with Taxotere, he reported that 6/12 men who had become resistant to further treatment with TAX alone, “experienced a further response or disease stabilization with the combo of TAX and AVASTIN®.

He showed some slides that illustrated how the tumor vasculature was affected by anti-angiogenic substances.

Another very recent test involving the combination of Taxotere(TAX), Avastin®(AVA), and Thalomid®(THAL) was discussed. The study population was 22 men with baseline PSA of 111. Nineteen of them had bone mets, PSA doubling time was 1.7 months, and their Gleasons were 8.

The protocol included prednisone and Lovenox also. He reported that all 22 pts experienced at least “some” decline in PSA with 19/22 showing a > 50% decline. He also reported that 11/22 of the men had “GREATER THAN 90% DECLINE IN PSA”. He did not report on the duration of this dramatic PSA response. Some 10% of the study group (2.2 men?) developed fevers as a result of low white blood cell counts.

10% had fainting episodes and one pt experienced a “colon perforation”.

[Ed Note: More results from this trial are needed before one should get too excited about the promising results to-date.]

Yet another chemo-cocktail Lam discussed was the combination of TAX, Carboplatin, and Emcyt (this is an “old” chemo drug whose technical name is Estramustine and which derives from Mustard gas combined with estrogen.).

Lam reported that with a combination of these three drugs, they got a 73% response rate in men who had shown resistance to testosterone inhibiting drugs and who had not been treated with TAX before. He further reported that about 50% of men they have treated with TAX resistant disease, responded with a greater than 50% PSA decline when treated with the combination cocktail of TAX, CARBO, and EMCYT.

Dr. Lam also briefly discussed Alimta® with and w/o Pemetrexed. The results he described were not impressive and until more results are published that have some more “meat” in them, one should reserve judgement.

He listed about a dozen more chemo drugs that he didn’t discuss: Novantrone, Velban, Cytoxan, Gemcitabine, Fluoracil, Navelbine, Abraxane, Doxil, Vincristine, Epithilones, and Xeloda.

[Ed Note: If one looks at the simplest possible combinations of these drugs along with ones mentioned earlier that have shown some decent results, it becomes obvious that many, many papers are yet to be published with less than overwhelming results. It seems that medical oncology (at least in prostate cancer) clings to the paradigm that combining two only-partially-successful drugs can produce a synergism that has a dramatically better result than either drug individually.

So a drug that is cytotoxic, the thinking goes, can be combined with a drug that is anti-angiogenic to produce a “double whammy” against the cancer. This is why we have the broad range of chemo drugs from which doctors can formulate their own pet cocktails. Sadly, the history of cancer cure rates does not support this idea very strongly. Improved response rates do not equate to improved cure rates.]

Dr. Lam concluded his lecture with a slide that made these three points:

Modern Chemotherapy is built on a foundation of taxane chemo

Chemotherapy drug combinations can significantly improve response rates

Combinations,( i.e., cocktails) are associated with more side effects than single agents



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