Chemotherapy for HRPC - Part 3

Summary--I began weekly Taxotere @ 25 mg/m2 in June 2000 and completed 17 infusions but suffered extreme toxicities in the form of onycholis (deep nail neuropathy resulting in discoloration, pain, swelling, weeping, bleeding and deteriorating/loss of finger/toe nails). My PSA reached a nadir of 1.2 and I was relatively pain-free while on Taxotere. I was forced to stop chemo on 8 November 2000. During that time off, my PSA increased to 25, pain returned, and my bone scan revealed 37 new mets in my upper torso. On 21 March 2001 I returned to weekly (3/4 weeks) Taxotere and my PSA responded modestly to 17 after 2 cycles.

I fear that I have reached a point of exhaustion of effectiveness for weekly Taxotere and I am frantically searching for the next chemo protocol that will contain my monster. Therefore, my search of the recently published two volumes of the American Society of Clinical Oncology (ASCO) was selfish and intense.

Action Requested-- I am not a doctor or medical researcher; I hope some patient(s) will likewise devote the hours necessary to reviewing ASCO 2001 abstracts and correct my interpretations and/or discover pertinent abstracts that I have missed.

When compared to the past four ASCO meetings/abstracts, I find this edition to be without much content and certainly not much new is revealed in the way of treatments for HRPC. I suggest that some of us are caught between chemo protocols for HRPC that are ‘essentially equivalent’ and ‘matured’ (as stated in Soul H letter of 21 Oct 2000 summarizing the Cap CURE annual retreat at Lake Tahoe)-- and medical science statements again present annual promises that within three to five years any one of many conflicting theories will reveal the magic bullet that will render this monster into a chronic treatable disease. But, I assure you that none of the ASCO 2001 trials/reports reveal any suggestion of such magic bullets.

I have categorized the abstracts as follows:

Taxotere(Docetaxel)
Taxol (paclitaxel)
Gemzar(Gemcitabine) with a taxane (Taxotere or Taxol)
Doxil(liposomally encapsulated Adriamycin -- called ‘stealth’ Adrimycin)
Biological Response Modifiers (BRM) -- Vaccines and MoAbs
Bone integrity
Miscellaneous--a bit off topic, but interesting.

Acronyms -- necessary to read abstracts 
RR = response rate; in PCa abstracts-- the % of patients with > 50 % PSA reduction.
MDR = Median Duration of Response (usually in months)
MDS = Median Duration of Survival (usually in months)
p.o. = orally, by mouth
b.i.d. = twice/day
t.i.d. = three times/day
Q = frequency of cycle (usually in days)

Discussion/Review

NOTE: unless otherwise delineated, all references are to abstract numbers in ASCO 2001 Volumes 1 and 2.

Taxotere (docetaxel)

473---(Ishmael)--Gemzar @ 800-2500 mg/m2 on weeks 1, 3, 5 and Taxotere @ 30-55 mg/m2 on weeks 2, 4, 6, and no TX in week 7---at ten tranches of dosing; overall (multiple cancer types) RR 51%; with the 2 PCa patients ‘responding’; ‘minimal toxicity’ but, the stats look worse than ‘minimal’. What were the 2 PCa patients ‘response’ and were they Taxotere (chemo) naive? If the PCa patients were Taxotere (chemo) naive, the RR must be comapred to Taxotere alone to determine whether adding Gemzar contributed to the response. (Also see Gemzar below.)

2441---(Scholtz/Strum/Leibowitz) Low-dose Emcyt single-agent Taxotere: Q21, @ 70 mg/m2 + Emcyt @ 140 mg tid D 1-7; RR 60%, MDR 6.8 mos. vs. weekly Taxotere only @ 25 mg/m2; RR 61%, MDR 5.6 mos.---it does not appear that adding Emcyt is worth the risk of DVTs?

2443---concludes that following conventional Q21 Taxotere + Emcyt exhaustion, weekly Taxotere @ 36 mg/m2 +/- Emcyt has significant activity.

2442---(Petrylak-multiple cancer types)- concludes that weekly Emcyt IV @ 1000-1500 mg/m2 + Taxotere @ 20-30 mg/m2 (2/3 week cycles) is safe and active in HRPC with RR of 75%. No DVTs?

2360---Weekly Taxotere @ 43 mg/m2 on D2 (3/4 week cycle) + Emcyt 140 mg/day po D 1-5 + Decadron; RR 71.4%--38% had >75% PSA reduction; 1/21 had a DVT---this lower dose of Emcyt looks promising?

Interesting to compare with the above #2360 with--J Clin Oncol, Vol 19, Issue 9(May),2001:2509-2516 (Saverese)--Q21-- Taxotere @ 70 mg/m2 D2 + Emcyt @ 10 mg/kg/d, divided t.i.d. on D 1-5; Decadron 8 mg p.o bid D1-3; RR 68%--57% had >75% PSA reduction; DVTs 9%, MDR 8-10 mos., MDS 20 months---good results (better than Petrylak’s).

2410---Q21? Taxotere @ 60 mg/m2 D 1 + Navelbine @ 15 mg/m2 D 1,8 + G-CSF QD for 5 days after D 1 and 8; RR 63%---4/5 pts responded after being resistant to prior chemo---more details might be interesting.

2398---Q21 Taxotere @ 55 mg/m2 D 2 + Emcyt @ 280 mg po X 2, D 1-10 + Decadron @ 8 mg/12 hrs D 1-3 + Prednisone @ 5 mg/day D 7 and 10; RR 75%---Italian, ‘no significant toxicity’--DVTs?; = lots of steroids for The Sopranos.

2369---(Beer) weekly (6/8) Taxotere @ 36 mg/m2 + Calcitrol @ 0.5 mcg/kg po D 1 + Decadron @ 8 mg po 12 hr and 1 hr before Taxotere and 12 hr after = 24 mg. RR 46 %; Calcitrol, the active form of vitamin D, enhances the activity of Taxotere in tissue culture and animal models of prostate cancer.---worth adding to weekly Taxotere?---it seems harmless, and possibly additive to the action of Taxotere.

744---(Oh)---neoadjuvant Taxotere (36 mg/m2) before RP for high-risk at dx; ‘feasible’.

Taxol (paclitaxel)

Are the patents running on Taxol? There are 5 reports re modifying Taxol:

419---a novel potent taxane derivative able to cross the blood brain barrier, but with very unimpressive results of minor responses in PCa.

420---novel Taxol in vitro potent against Taxol-resistant tumors and lacking significant P/N; anti-tumor activity was observed.

421---the same novel Taxol derivative reported by another institution; greater potency and broader anti-tumor activity than Taxol.

423---a modification of the above 2 derivatives; lower neurotoxicity and higher anti-tumor activity than Taxol; this trial combined it with Adriamycin.

422---still another Bristol-Myers novel derivative of Taxol; superior activity; ‘very encouraging’; will test with carboplatin.

J Clin Oncol, Vol 19, Issue 9(May), 2001:2493-2503; PH 1 study of BMS-184476, an improved Taxol with advantages in toxicity, pharmacokinetics, pharmaceutics, and administration.

721--(Kelly/Slovin--MSKCC)-- re markers for their Taxol/Emcyt/Carbo protocol.

2388---(Pienta) --Q 21---Taxol @ 135 mg/m2 D 2 + Emcyt @ 280 mg tid + VP-16 @ 50 mg bid X 14 days; RR 13/15 (?), MDR 14 months (10-24.5). Reputable med onc with good results.

2396---weekly 6/8--single agent Taxol @ 100 mg/m2 (lowered to 80 mg if P/N)--RR 61%, MDR 5.3 months (3-8); 83%> alive at 1 year.

2435---Q21--Taxol @ 135 mg/m2 + Carbo @ ACU=5 + VP-16 @ 50 mg/m2 QD for 7 days + Emcyt 280 mg tid (WOW!)--RR 64%, MDR 1.5 months, MDS 9 months---not worth the suffering?

1857---(MBC)--protracted, long term Taxol @ 80 mg/m2 is associated with prolonged time to progression--MDS 27.9 months.

But, # 498---(ACC)--those on continuous chemo show serious events, toxicity, and worse QOL; there is no evidence of benefits from continuing chemo without any TX breaks.

1982---(MBC) --weekly Taxol @ 80 mg/m2; RR 96%.

Cytokines & antibodies that can be produced in the laboratory:

..interferons (IFN)--alpha, beta, and gamma--may stimulate NK cells, T cells, and macrophages--may be used with other BRMs or chemo--may cause flu-like symptoms (fever, chills, nausea, vomiting, appetite loss, fatigue).

..interleukins (IL)--stimulates the growth and activity of many immune cells-- may cause the symptoms of IFNs + bone pain and symptoms may be more severe than with IFNs.

..colony-stimulating factors (CSF)--does not directly affect cancer cells--they encourage bone marrow cells to divide and develop white/red blood cells and platelets, allowing increased doses of anticancer drugs.

..monoclonal antibodies (moab)--produced by a single type of cell and specific for a particular antigen--produced by injecting human cancer cells into mice; the mouse immune system produces an antibody against these specific cancer cells; these antibodies are harvested, fused with lab-grown cells (= hybridomas)--and these can be cloned into large quantities of pure antibodies (moabs)

--these moabs can: 1.) attach to particular cancer cells and enhance the immune response 2.) act against cell growth factors 3.) be linked to other anticancer agents (radiation, chemo, other BRMs)

and, when moabs attach to cancer cells, they deliver these linked agents directly to the tumor, and not to healthy cells.

but, moabs can have can cause serious allergic reactions, as well as all of the symptoms of IFNs, ILs, and CSFs--patients must be carefully monitored during TX.

..vaccines--vaccines for infectious diseases are given as preventative measures and expose the immune system to weakened versions of the disease; it responds by producing antibodies to that disease and those antibodies ‘remember’ the exposure and respond and destroy the next exposure to the intruder. Some cancer vaccines are being developed tolikewise recognize cancer before it is diagnosed and attack it-- but existing cancer vaccine trials are designed to be injected after the disease is diagnosed and to stimulate the immune system response to the intruder.

ASCO 2001 abstracts re BRMs:

2641---PSMA pulsed dendritic cell vaccine with 60% AIPC showing decreasing PSA slopes, ‘suggesting’ therapeutic potential.

1003---PSA transfected dendritic cell vaccine---3 vaccinations--significant decrease in PSA slope (5/7) and rapid clearance of circulating tumor cells from peripheral blood. Not a magic bullet yet.

1073---GM-CSF gene-transduced prostate cancer cell line vaccine --GVAX--one (of 34) PCa pts had a complete response---there is a trend toward longer median time to disease progression and it induces novel antibody responses against the vaccine.

1088--a vaccine trial of escalating doses of rV PSA = no tumor response; MDR of 106 days--(how can you have a MDR if there was no response?) But, the trial continues + GM-CSF and IL-2.

743----a 5-A-RI agent with confusing minor responses; MDR 4 months.

1106--another vaccine utilizing PSA; minimal responses in 5 men who had very low beginning PSAs--some alternated tx with IL-2.

750---(Small/Reese-UCSF) trial with PAP loaded dendritic cells---very questionable results. Many of us had followed this as the possibility of a magic bullet----but, no way, based on this abstract.

777---chronic low dose IL-2 and INF-a; it has therapeutic effects, but MDS of only 16 months, with considerable toxicities.

774---INF-a-2b + Liposome Encapsulated RA = prolonged effect of INF, but no survival benefits--lots of toxicity---what’s the point?

724---GM-CSF; RR of 24%; 79% had a decrease in PSA slope; ‘may have biological activity’----not a magic bullet yet, eh?

685---randomized HD IL-2 vs. SC Il-2 + INF; conclusion: HD IL-2 ‘shows a trend toward improved quality responses’. No magic bullet here.

1013--moabs improved survival and improved the health of MICE--maybe this is a magic bullet for mice, but a long way away from helping us people.

722---This is the long awaited (by some of my friends and me) Bander huJ591 moab and all the iterations thereof. Report re 4 doses of the naked huJ591--no HAHA problems; ‘no toxicity or side effects’ (?). Bander introduces his new trials of 3 weeks of IL-2 + naked huJ591; and PH I huJ591 taggeded with 90Yittrium. Very questionable interim results.

10---re Angiostatin---very inconclusive after all the hupula of 2 years ago.