A Patient’s Personal Perspective

Part 2

January, 2001

Update

In August 1997, at age 62, I was diagnosed with prostate cancer-- bPSA 323, D2 (multiple lumbar/pelvis mets), Gleason 9, CT unremarkable. Casodex/Lupron relieved some discomfort and lowered my PSA to a nadir of 5.8 in June 1998, when it began increasing and I changed my care from a local urologist to a medical oncologist at MSKCC. My PSA continued to increase to 33.02 by November 1998 and I stopped Casodex, hoping for a withdrawal response. None resulted and in January 1999 my PSA was 59.53, my BS/MRI showed disease progression, and pain escalated to 8/9 (10 being unbearable). I began HDK + HC and had a SR 89 infusion. Pain greatly decreased within 12 hours and PSA decreased to a nadir of 2.59 and a BS/CT reflected no disease progression in October 1999. By May 2000 my PSA had increased to 13.5 and Level 6/7 pain returned, notwithstanding four months of PC SPES; a BS showed ‘unfavorable change’ and an MRI concluded ‘broad encroachment at L4-5’.

On 20 May 2000 I left MSKCC for care at a smaller medical oncology practice, had my first Aredia infusion that day, and was fitted with a template for RT. I had 15 sessions of a total of 37.5 Gy radiation (13 cm X 14 cm X 5 cm) and my lower back pain improved.

In July 2000 I began the first of 17 weekly Taxotere infusions consisting of 6 treatments (in 8 weeks) of Decadron pre-med @ 20 mg IV, followed by Taxotere @ 35 mg/m2=73 mg/week; followed by 11 consecutive treatments of Decadron @ 10 mg + Taxotere @ 25 mg/m2=51 mg + Celebrex @ 100 mg X 2/day, while continuing Aredia @ 90 mg/month. My pain was acceptable and my PSA decreased to a nadir of 1.55 on 18 October 2000, but increased to 1.70 (different lab) one month later. My last Taxotere treatment was 8 November, but a follow-up PSA was 1.2 on 12 December, one month after stopping chemotherapy; and 2.2 on 8 January 2001, two months after my last chemotherapy treatment. The velocity trend is not good, but perhaps my peripheral neuropathy will subside sufficiently for continued weekly Taxotere when my PSA reaches 10.0.

I was forced to stop chemotherapy because I was experiencing peripheral neuropathy from the Taxotere. Eight hours after infusion, my legs felt as if bugs were crawling on them and this progressed to tingling/numbness/burning in my feet and hands. The reaction lasted about 3 hours and slowly returned to near-normal. But the neuropathy was more severe and lasted longer with each consecutive infusion. In September/October my finger nails began to ache and discolor; they subsequently swelled grotesquely and a purulent foul-smelling fluid began seeping from underneath the nails. This developed into a major problem as my nails and some flesh began to disintegrate leaving painful and unsightly sores and my fingers were numb (no sensation), but they still ached. Wearing bandages and gloves was mandatory. This reaction to chemo is not common, but is possible. I have since met two people who found this condition to be treatment-limiting for Taxotere therapy.

A dermatologist suggested that I bore holes in the nails to allow the fluid and pressure to be relieved, and to soak them in Donboro. After I did this, the pain subsided and since I had stopped the chemo, the nails began to heal. But, I am now left with only one-third of a nail on each finger and the remaining finger end is very sensitive. I do not dig in my pocket for keys or loose change and, while the nail appearance would deny any TV hand commercials, I no longer wear gloves.

My intention is to wait without treatment (except Lupron) until my PSA is 10 (or symptoms return) and then begin the weekly Taxotere again, assuming my nails heal sufficiently. I will continue with the treatment until my PSA is less than 4.0, stop until it returns to 10, and do it again. Thus, I hope that this intermittent, or ‘stutter’, therapy will continue a quality life until a magic bullet arrives. I have no other choice.

Is chemotherapy an effective treatment for prostate cancer?

Enthusiasm for chemotherapy for PCa in the 70s gave way to disappointment in the 80s, when analysis of the data reflected poor response rates. In 1985 a review of 17 trials with 1,464 patients reported a response rate (PSA reduction of =>50%) of only 4.5%. (1) Later, a review of trials between 1987 and 1991 reported a response rate of 8.7%.(1,3) Therefore, the widely held view was that chemotherapy was ineffective for HRPC.

However, it is now well recognized that androgen-independent PCa is not as resistant to chemotherapy as previously believed.(4) This is due in part to improvements in measuring responses by PSA and better imaging techniques, as well as combinations of older drugs thought to be inactive and development of newer drugs like the Taxanes.(5) In the past three years, hundreds of trials report up to 70% response rates.(6) Unfortunately many doctors and patients continue to believe that chemo for HRPC is still not a viable option, or that it is a ‘last ditch’ therapy after all hormonal ablation therapies are exhausted. Although chemotherapy has clearly demonstrated improved palliation with the new combination of agents and the development of Taxanes, not much impact on survival has been demonstrated until recently. The concept of prostate cancer as being chemorefactory is simply no longer valid (7), and the development of new agents and combinations with specific cellular targets and definitions of end points challenge the earlier skepticism of chemotherapy for HRPC.(8)

Though great strides have been made since the 70s and 80s toward agents and combinations for treating HRPC, a recent Cap CURE gathering of many of the world’s leading PCa doctors and scientists reached a consensus that most of the clinical results of such new agents and combinations thereof are essentially equivalent, with response rates approaching 60%, and median duration of survival approaching one year. They concluded that chemotherapy for the treatment of advanced PCa has ‘matured’.(9)

At the end of my three month search for my next best therapy after exhausting all hormonal blockades, I came to the conclusion that all we could expect from chemotherapy treatment for HRPC was a protocol that had up to 60-70% response rates (RR), up to nine months median duration of response (MDR), and up to one year median duration survival (MDS). (6) It is one thing for me, a layman-patient not trained in medicine, chemistry, biology, or research to reach this conclusion after studying the trials of the last three years---but it is another thing and very discouraging to now read that a consensus of the Cap CURE conference attendees have likewise concluded that chemotherapy has ‘matured’ at this expectation.

The Cap CURE letter (9) continues with great hope for the future of MoAbs, vaccines, genetic engineering, angiogenetic inhibitors, etc. which will transform HRPC from an acute life-threatening disease into a treatable chronic disorder. Meanwhile, many of us are literally between a rock and a hard place having exhausted hormonal manipulations, with progressing disease, and having only limited chemotherapy protocols for palliation and hopefully, one more year of survival---while waiting for these infant theories to develop.

It seems to this farm boy that the last two decades have seen a lot promises, significant money spent, and many men subjected to bizarre experiments with limited success and no survival benefits--- and now we must wait for yet another tranche of promised experiments to develop. But, again, many of us are caught in a ‘goose chase’ between second and third base---between a ‘matured’ series of chemotherapy choices with no identifiable ‘best’ protocol and more promises of a smorgasbord of conflicting new theories to be developed and tested in the future.

But perhaps a new paradigm is emerging from current chemotherapy protocols that will prolong a quality survival for those of us struggling with HRPC and thus, we can possibly be around for one of the new developments.

Intermittent Weekly Single Agent Taxanes

The last two decades of therapy and trials has focused on a maximum tolerated dose (MTD) escalation as the technology of supportive care of the damage done to non-cancerous cells advanced. But as Schipper, et al. and Kamen, et al. discussed (6), some current thinking is to concentrate on low-dose therapy that targets the vascular system of the tumor and keeps it constantly ‘bathed’ with the agent in order to be present on cell division; and, the timing of exposing the cells to the cyototoxic agent is more important than the quantity of the agent dose. (6) Moreover, recent theories propose that frequent low-dose therapy produces an antiangiogenetic effect and starves the cancer into apoptosis. (6,10,11,12)

Single agent weekly Taxotere has proven to be effective in patients with refactory cancer and the toxicity profile was markedly altered by a decrease (re Q21 protocols) in myelosuppression, neuropathy, and arthragia (joint pain)/myalgia (muscle pain). (13) Weekly Taxotere @ 36 mg/m2 6/8 weeks was active and well-tolerated with a RR of 47%. (14) Single agent weekly Taxol has activity @ 150 mg/m2 6/8 weeks with a RR of 39% and minimal toxicity, except peripheral neuropathy. (15)

Petrylak, et al. (16) introduced the concept of intermittent chemotherapy when five patients in this trial were given a treatment rest when their PSA nadired at <4.0 ng/dl. The patients’ rests were from 14 to 28 weeks off treatment and when their PSA returned to 19-29 they were re-treated. This cycle has been successfully repeated three times. In this trial, 77% (of 35 patients) survived the first year and the MDS had not been reached. The RR for this trial is 75% of the patients had PSA reductions of >50%, and 45%>80%. These are the best statistics of any trial I have reviewed.

My logic after my three month search (6) was that weekly Taxotere was the least toxic chemotherapy protocol, and should it fail to reduce my PSA I could always add weekly low-dose Emcyt. After six weeks of 3/4 weekly infusions at 35 mg/m2 I elected to lower the Taxotere dose to 25 mg/m2 and not skip a week. Therefore, I had two cycles of 3/4 weeks @ 35 mg/m2 and eleven straight weeks @ 25 mg/m2. Also, when I lowered the Taxotere dose, I decided to add Celebrex @ 100 X 2/day in an effort to approximate metronomic dosing with a chemotherapy agent + an antiangiogenetic.

My combined radiation, Aredia, Taxotere, and Celebrex resulted in a reduction of pain and a PSA decline from 13.7 in June 2000 to 1.55 on October; and a further decline to 1.2 in December, one month after stopping Taxotere.

But, I think I continued the chemotherapy too long as I had reached a PSA of 4.4 after seven infusions (30 August 2000) and should have ‘rested’ after nine (12 September 2000) instead of continuing eight more infusions and being forced to rest due to extreme peripheral neuropathy. My deep nail neuropathy began to manifest itself after twelve infusions (4 October 2000) and became progressively worse over the last five infusions. I was too greedy, suffered extreme toxicity, and have been off treatment since 8 November 2000. However, my last PSA was 2.2 on 8 January 2001 after being off treatment two months. Who knows what my next PSA test will show? Also, even if it has increased significantly, I don’t know when my deep nail neuropathy will heal to the extent that I can re-start a chemotherapy treatment protocol. If I can re-start single agent Taxotere, I will begin @ 25 mg/m2 6/8 weeks and ‘rest’ if my PSA reaches <4.0.

I believe that single agent Taxotere on an intermittent basis (if you respond) is a viable treatment to extend quality survival. While this protocol is not a walk in the park (for one thing, you are married to the chemo suite every week for an elapsed time of four hours) and I did feel a bit ‘puky’ shortly after every session. But, notwithstanding the peripheral neuropathy, I felt better during chemotherapy than I felt in the first three months of HDK and certainly better than my three months on PC SPES (serious stomach problems and leg cramps).

What is next? My medical oncologists suggests weekly Taxol because he believes it might be less toxic. But----

TAXOL VS TAXOTERE

We all see statements on the Internet that Taxotere is 100 times stronger than Taxol. I assume this originated from some studies that reported that Taxotere, in vitro, was 100-fold more potent than Taxol in bcl-2 phosphorylation (17) and apoptotic cell death. (11) Bcl-2 is considered the ‘guardian of microtubule integrity’ and Taxotere is capable of inducing bcl-2 phosphorylation and cell death at 100-fold lower concentrations than Taxol. (18) But Stein (19) says that Taxotere has a somewhat higher affinity for microtubules than Taxol (approximately two-fold) and in some circumstances may be a more potent inducer of bcl-2 phosphrylation, however, it is not clear whether these Taxotere-events are directly related to its anti-prostate cancer effects. Garcia (20) reported that the effects of Taxotere as compared to Taxol appeared at a two-fold lower concentration. A pharmacology sheet says that Taxotere, like Taxol, prevents the mitotic spindle from being broken down by stabilizing the microtubule bundles, but clinical trials indicate it is about twice as effective as Taxol in doing so. (21)

So, is Taxotere 100-fold more potent than Taxol, or two-fold more potent, or is the transformation of bcl-2 related to anti-prostate effects? In general, the taxane protocols call for Taxol at twice the mg/m2 of Taxotere. Both drugs stabilize cellular microtubules and thus, interfere with mitosis (reproduction) and cause cell death. Taxotere has linear pharmacokinetics, a longer plasma life, and longer intercellular retention. (22) Based on the above analysis Taxotere is my drug of choice, if I have a choice.

Regarding toxicities, Hortobagyi (11) states that potential advantages of Taxotere over Taxol include reduction in peripheral neuropathies and lack of arthalgia (joint pain)/myalgia (muscular pain) syndrome. Unless my medical oncologist has different citations, I doubt that Taxol is less toxic than Taxotere and if I have one, Taxotere is still my drug of choice notwithstanding the toxicities.

One interesting recent trial combined weekly Taxotere @ 35 mg/m2 + weekly Taxol @ 65 mg/m2 for 4 weeks, dubbed a ‘taxane package’. (23) In this study Lokich reports that this dosing protocol increases the taxane dose intensity by a factor of 1.65 over normal dosing and thus, increases the taxane cytotoxic injury and takes advantage of the fact that the two agents lack complete cross-resistance; if some tumors are nonresponders to one of the agents, the other will zap it, and vice versa. Interesting salvage therapy if you fail either of the drugs?

PROTECTION AGAINST CHEMOTHERAPY TOXICITY

I began to experience peripheral neuropathy following the first Taxotere infusion, notwithstanding 20 mg of Decadron IV as pre-medication Paresthesais in my legs/feet and hands began about 6 hours after infusion and escalated with each treatment. I asked my medical oncologist and urologist about drugs to lessen this toxicity and both said that there are none and if the patient cannot tolerate it, the condition becomes dose- or treatment-limiting

However, after I was suffering from deep nail neuropathy, a fellow PCa patient told me about glutamine as a protectant against chemotherapy toxicities. Glutamine is a neutral gluconeogenic amino acid that is vital in whole-body nitrogen metabolism and it is depleted by many traumas such as surgery, infections, and cancer. Replacement thereof is necessary for the body to function properly. Powdered glutamine is readily available in drug stores and health food stores and costs about $45 for 500 grams. Its most common use is by body builders or athletes following a strenuous work-out.

A significant body of peer-reviewed trials and reports exist detailing the chemoprotectant qualities of glutamine. Saverese, et al. (24) reported that up to 75% of Taxol patients experience myalgias (muscular pain) and arthralgias (joint pain) and that 10 g p.o. t.i.d. (orally, 3 X/day) is a cost-effective, nontoxic method of preventing/lessening these toxicities. Vahdat (25) reported that 10 g p.o. t.i.d. for 4 days started 24 hours before chemo infusion significantly reduced peripheral neuropathy, dysethesias (numbness) in fingers/toes, deterioration of gait, and paresthesais (burning, tingling) resulting from Taxol infusions. Fahr, et al. (26) reported that glutamine may decrease tumor growth by enhancing NK (natural killer) cells. Rouse K, et al. (27) reported that oral glutamine enhances the selectivity of antitumor drugs by protecting normal tissues and possibly sensitizing tumor cells to chemotherapy treatment related injury.

Klimberg, et al (28) reported that a tumor acts as a ‘glutamine trap’ depleting the host of glutamine and resulting in cachexia (weight loss); supplemental glutamine does not make tumors grow, but in fact results in decreased growth through stimulation of the immune system; and when given with chemotherapy, glutamine protects the host and increases the selectivity of therapy for the tumor. Anderson, et al (29) states that oral glutamine (as a mouthwash) is simple to use and increases the comfort of many patients at high risk of developing stomatitis (mouth sores) as a result of intensive cancer chemotherapy. Miller (30) reported that the use of glutamine seems to prevent gut and oral toxic side-effects, and may increase the effectiveness of some chemotherapy drugs. Myers CE (31) states that the body’s need for glutamine can increase dramatically following injury, infection, or the progression of cancer and in these cases, the need for glutamine can exceed the ability of the body to supply it; glutamine is one of the major energy sources needed for the gastrointestinal tract cells to recover from chemotherapy; a glutamine mouthwash 2 X/day will dramatically lessen stomatitis (mouth sores) in patients on chemotherapy; glutamine plays a critical role in the body’s ability to defend itself against cancer.

In summary, significant benefits are claimed in medical literature for glutamine supplementation during chemotherapy (and during radiation): a.) it provides the necessary energy-producing amino acid to replace that which is lost during chemotherapy, b.) it minimizes chemotherapy side effects, including neuropathy, arthralgia (joint pain), myalgia (muscular pain), paresthesias (burning, tingling sensations), dysethesias (impairment of sensation), and stomatitis (mouth sores); by eliminating or lessening these side effects, it is possible to extend the duration or dose of chemotherapy to induce apoptosis (cell death), c.) it prevents cachexia (weight loss), and d.) it enhances the immune system to produce natural killer (NK) cells, thus suppressing tumor growth.

If one collectively considers these benefits it is reasonable to assume that there is a strong potential for increased survival as a result of glutamine supplementation during chemotherapy (or radiation).

However, two reports (32) state that since tumors require glutamine, providing dietary glutamine may stimulate growth in some tumors. Myers (31) addresses this issue by stating that while glutamine is needed for tumor growth, it also plays a critical role in the ability of our body to defend itself against cancer. Myers continues with a caution to not treat yourself with glutamine without first discussing this in detail with your doctor.

Obviously, I am taking oral glutamine now and intend to notify my medical oncologist that I will be taking 10 g X 4/day during any renewed chemotherapy treatments, since there appears to be no side-effects. Glutamine is most effective in powder form; it is odorless and tasteless and should be mixed with a cool drink, as hot drinks lessen the effectiveness. A discussion of glutamine (and other amino acids), suggested dosing schedules, and suggested support additives thereto can be found in a book by Sahley, et al. (33).

At the suggestion of a PCa friend I also searched another chemoprotectant that seems to be very effective. I found 22 trials and reports detailing the efficacy of Amifostine (Ethyol) to relieve most toxicities from cancer chemotherapy. But after searching and briefing the 22 reports, I retrieved the specification sheets regarding the drug and decided that I definitely prefer glutamine as my chemoprotectant. Amifostine is infused immediately before chemotherapy, but you must have 2 pre-medicines to protect from the protectant; you must be laying down (supine position) and your vital signs are checked every 5 minutes; it can cause severe nausea and vomiting; systolic blood pressure may decrease significantly and the infusion must be stopped; you must drink sufficient liquids because amifostine causes severe dehydration; you may experience hypocalcemia (burning, tingling, muscle cramps) during infusion, dizziness, flushing, and/or hiccups.

While amifostine seems to be effective in eliminating/reducing chemotoxicity, this solution seems worse than the effects of chemotherapy toxicities and I prefer glutamine (simple to use, with no reported side-effcts) as my chemoprotectant.

CONCLUSION

With a progressing disease after exhausting CHT, AAWR, SR 89, HDK, PC SPES and radiation, I had no choice but to select a chemotherapy treatment. After extensive review (6) I elected weekly single agent low-dose Taxotere and my disease responded with a significant decrease in PSA and manageable pain levels. Therefore, I suggest that this protocol is a viable and meaningful protocol for disease containment, while protecting yourself from dose-/-treatment limiting toxicities.

Moreover, I suggest that this protocol has the possibility of a survival benefit if your disease responds. If your PSA declines to <4.0 and thus, provides a rest period for your body to recover, then the treatment can be repeated when your PSA returns to 10.0+. If these cycles can be repeated and the disease continues to respond, I suggest that this protocol can possibly extend a quality life while awaiting the magic bullet.

Also, I suggest that this protocol might be appropriate much earlier in treatment and in conjunction with hormone ablation therapies. If chemotherapy can be used when your body is strong and the tumor burden is small and not mutated by repeated hormone manipulations, the protocol could possibly be more effective.

Bill Aishman

NOTE: I am not a doctor and can not give medical advice. I am not a medical researcher. I am a prostate cancer patient and I performed this layman’s analysis for my own decision-making purposes. In conjunction with a medical team, every cancer patient must make their own decisions regarding treatment options. I make no claim that this analysis is definitive or complete. Every HRPC patient should thoroughly review the Life Extension Foundation’s web site www.lef.org Prostate Cancer-Late Stage. I invite any and all additive contributions to my analysis that will provide patients a framework which will enhance their ability to make informed decisions regarding the use of chemotherapy protocols in their struggle with prostate cancer.

REFERENCES

(1) Oh WK: Chemotherapy for patients with advanced prostate carcinoma. Cancer 2000 Jun;88(S12):3015-3021.

(2) Esinberger MA, et al.: A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostate cancer. J Clin Oncol 1985:3:827-41.

(3) Yagoda A, Petrylak D: Cytotoxic Chemotherapy for Advanced Hormone-Resistent Prostate Cancer. Cancer 1993;71:1098-1109.

(4) Morris MJ, Scher HI: Novel Strategies and Therapeutics for the Treatment of Prostate Cancer. Cancer, Sept 15, 2000’Vol 89,No6:1329-48.

(5) Beedassy A, Cardi G:Chemotherapy in Advanced Prostate Cancer. Semin Oncol,Vol26,No 4(Aug), 1999:428-38.

(6) See Part 1, Chemotherapy for Hormone Refactory prostate Cancer; www.cooleyville.com/cancer/cachrpc.htm

(7) Roth BJ: Androgen-Independent Prostate Cancer: Not so Chemorefactory After All: Semin Oncol 1999 Dec;26(6 Suppl 18):43-50.

(8) Smith D: Chemotherapy For Hormone Refactory Prostate Cancer. Urol Clinics of North America;Vol 26,No 2,May 1999.

(9) Soul H letter of 21 October 2000 sumarizing the CaP CURE annual Retreat at Lake Tahoe.

(10) Hainsworth, et al: Ann Oncol 6:325-41, 1995.

(11) Hortobagyi G: Recent Progress in the Clinical Development of Docetaxel (Taxotere). Semin Oncol,Vol 26,No 3, Suppl 9 (Jun), 1999:32-36.

(12) Belotti et al.: the microtubule-affecting drug pacitaxel has antiangiogenic activity. Clin Cancer Res 1996 Nov;2(11):1843-9.

(13) Hainsworth et al.: Phase I of docetaxel administered by weekly infusion in patients withadvanced refactory cancer. J Clin Oncol 1998 Jun;16(6):2164-8.

(14) Beer TM, et al.: Phase II Study of Weekly Docetaxel (Taxotere) in Hormone Refactory Metastatic Prostate Cancer. ASCO 2000, abstract 1368.

(15) Trivedi C, et al.: Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients withhormone-refactory prostate carcinoma. Cancer 2000 Jul 15;89(2):431-6.

(16) Petrylak, et al.: Response and Preliminary Survival Results of a Phase II study of Docetaxel (D) + Estramustine (E) in Patients (Pts) with Androgen-independent Prostate Cancer (AIPCA). ASCO 2000, abstract 1312.

(17) Phosphorylation=addition of a phosphate to an organic compound through the action of kinase. Kinase=an enzyme catalyzing the conversion of a proenzyme to an active emzyme.

(18) Haldar S, et al: Bcl-2 is the guardian of microtubule integrity. Cancer res 1997 Jan 15;57(2):229-33.

(19) Stein CA: Mechanisms of action of Taxanes in prostate cancer. Semin Oncol 1999 Oct;26(5 Suppl 17):3-7.

(20) Garcia P, et al.: Comparative effects of Taxol and taxotere on two different human carcinoma lines. Cancer Chemother Pharmacol 1994;34(4):335-43.

(21) Pharmacology of Paclitaxel and Docetaxel; http://biotech.icmb.utexas.edu/botany/tax.html

(22) Crown J: The taxanes: an update. Lancet 2000; April 1, 2000.

(23) Lokich J: Phase I Clinical Trial of Weekly Combined Paclitaxel plus Docetaxel in Patients with Solid Tumors. Cancer 89:2309-14,2000.

(24) Saverese D, et al: Glutamine Treatment of Paclitaxel-Induced Myalgias and Arthralgias. J Clin Oncol;Vol 16,No 12:3918-19, 1998.

(25) Vadhat L: Reduction of Paclitaxel-Induced Peripheral Neuropathy With Glutamine. Chemotherapy Foundation Symposium XVII;Nov 8-11, 2000, abstract 41.

(26) Fahr MJ, et al.: Glutamine enhances immunoregulation of tumor growth. JPEN J Parenter Entral Nutr 1994 Nov-Dec;18(6):471-6.

(27) Rouse K, et al.: Glutamine enhances selectivity of chemotherapy through chenges in glutathione metabolism. Ann Surg 1995 Apr;22(4):420-6.

(28) Klimberg VS, et al.: Glutamine, Cancer, and its Therapy. Am J Surg 1996 nov;172(5):418-24.

(29) Anderson PM, et al.: Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1998 Oct 1:83(7):1433-9.

(30) Miller AL: Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev 1999 Aug;4(4):239-48.

(31) Myers CE: Prostate Forum, March 2000;Vol 5, No 34.

(32) Altern Med Rev 1999;4:239-48; and J Surg Res 1990;48:319-23.

(33) Heal with Amino Acids and Nutrients; Billie J Staley, Ph.D. , et al.