1192 Vol. 7, 1192–1197, May 2001 Clinical Cancer Research Reduction of Paclitaxel-induced Peripheral Neuropathy with Glutamine1 Linda Vahdat,2 Kyriakos Papadopoulos, interference with activities of daily living (85 versus 27%; Moderate to severe paresthesias in the fingers .(0.001 ؍ Dale Lange, Shelby Leuin, Elizabeth Kaufman, P Diana Donovan, Deborah Frederick, and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically Emilia Bagiella, Amy Tiersten, Gwen Nichols, significant. All of these toxicities were reversible over time. Thomas Garrett, David Savage, Karen Antman, Conclusions: Glutamine may reduce the severity of pe- Charles S. Hesdorffer, and Casilda Balmaceda ripheral neuropathy associated with high-dose paclitaxel; Division of Medical Oncology and Hematology, Departments of however, results from randomized, placebo-controlled clin- Medicine [L. V., K. P., S. L., E. K., D. D., D. F., A. T., G. N., T. G., ical trials will be needed to fully assess its impact, if any. D. S., K. A., C. H.] and Neurology [D. L., C. B.], and Division of Trials are currently ongoing to assess its efficacy for stan- Biostatistics [E. B.], The Herbert Irving Comprehensive Cancer Center of Columbia University College of Physicians and Surgeons, dard-dose paclitaxel in breast cancer and other tumors for New York, New York 10032 which peripheral neuropathy is the dose-limiting toxicity. ABSTRACT INTRODUCTION Purpose: Dose-limiting toxicity of many newer chemo- Peripheral neuropathy is a common side effect of a wide therapeutic agents is peripheral neuropathy. Prior attempts variety of cancer chemotherapeutic agents. The mechanisms of to reduce this side effect have been unsuccessful. We report this neuropathy are usually attributed to microtubule disruption on the possible successful reduction of peripheral neuropa- (taxanes, Vinca alkaloids) or a direct toxic effect (platinum thy with glutamine administration after high-dose pacli- compounds). Dose-limiting peripheral neuropathy is most often taxel. observed in the setting of advanced cancer necessitating a Experimental Design: Patients entered a high-dose change in therapy while the patient is still actively responding to chemotherapy protocol in which the first high-dose cycle the agent. Even when alternative schedules are used (shorter was paclitaxel at 825 mg/m2 given over 24 h. The first cohort versus longer infusion) peripheral neuropathy Ն grade 2, as of patients did not receive glutamine, and the second cohort evidenced by moderate motor and sensory symptoms, is noted in of patients received glutamine at 10 g orally three times a up to 30% of patients receiving paclitaxel (1, 2). The options of day for 4 days starting 24 h after completion of paclitaxel. stopping treatment early or dose reducing are equally undesir- Neurological assessment was performed at baseline, and at able in the advanced disease setting but may have greater least 2 weeks after paclitaxel, and consisted of a complete implications in the adjuvant setting because taxanes may be- neurological exam and nerve conduction studies. come part of the standard treatment of node-positive breast Results: There were paired pre- and post-paclitaxel cancer. In the adjuvant setting, the potential for affecting larger evaluations on 33 patients who did not receive glutamine numbers of patients increases, because it is estimated that at and 12 patients who did. The median interval between pre- least 56,000 patients will be considered for adjuvant taxane use and post-exams was 32 days. For patients who received for node-positive disease (30% of all breast cancers). If the glutamine, there was a statistically significant reduction in node-negative trials reveal an advantage with adjuvant taxanes, the severity of peripheral neuropathy as measured by devel- then, potentially, the number of patients affected by peripheral opment of moderate to severe dysesthesias and numbness in neuropathy will widen considerably. the fingers and toes (P < 0.05). The degree and incidence of Paclitaxel has a broad spectrum of activity against a wide -as variety of neoplasms, including breast, ovary, lung, and gastro (0.04 ؍ motor weakness was reduced (56 versus 25%; P -and intestinal tumors. It is generally well tolerated with dose-limit (0.016 ؍ well as deterioration in gait (85 versus 45%; P ing neutropenia and peripheral neuropathy after multiple cycles. The neuropathy, generally a sensory polyneuropathy af- fecting large fibers, can also lead to cranial nerve palsies, motor Received 11/3/00; revised 2/13/01; accepted 2/20/01. weakness, and autonomic dysfunction (3, 4). The costs of publication of this article were defrayed in part by the Several avenues have been explored to ameliorate the payment of page charges. This article must therefore be hereby marked neurotoxicity associated with paclitaxel, including the use of advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. nonsteroidal anti-inflammatory agents, corticosteroids, and ami- 1 Supported in part by USPHS Grant PO1CA-40053 and P20CA66244-01 fostine; and these treatments have been uniformly unsuccessful and by Grant-in-Aid programs from Bristol Myers Squibb Oncology and (5, 6). Recently, Savarese et al. (7) reported the successful Amgen. reduction of paclitaxel-associated myalgias and arthralgias by 2 To whom requests for reprints should be addressed, at The Blood and glutamine in five patients treated with paclitaxel doses ranging Marrow Transplant Unit, Division of Medical Oncology, MHB 6N 435, 2 177 Fort Washington Avenue, New York, NY 10032. Phone: (212) 305- from 175 to 200 mg/m . All of the patients had debilitating 2486; Fax: (212) 305-6798; Email: [email protected]. paclitaxel-associated myalgias/arthralgias associated with their Downloaded from clincancerres.aacrjournals.org on October 3, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 1193 Table 1 Clinical trials using glutamine to prevent toxicity from chemotherapy Author (Ref.) na Chemotherapy Glutamine dose (po) Results Rubio (10) 9 MTXb 0.5 g/kg/day No mucositis seen Skubitz (19) 14 varied 4 g BID ϫ 28 days Decreased stomatitis Savarese (7) 5 paclitaxelc 10 g TID ϫ 4 days Prevention of myalgias/arthralgias Ohkuno (16) 66 5FU 4 g BID ϫ 14 days No difference in mucositis from controls a n, number of patients; MTX, methotrexate; BID, twice a day; 5 FU, 5-fluorouracil. b Escalating dose methotrexate from 40 to 100 mg/m2. c Paclitaxel-containing regimen. first cycle of therapy. For subsequent cycles, they received MATERIALS AND METHODS 3 glutamine (10 g p.o. t.i.d.) for 4 days starting 24 h after the Patients with histologically documented stage 4 breast can- completion of paclitaxel. No patient had a recrudescence of cer were eligible for participation in this study if their disease symptoms while on glutamine (7). had responded (partial or complete response) to conventional Glutamine is a neutral gluconeogenic nonessential amino dose chemotherapy. Patients were excluded if they had central acid stored primarily in skeletal muscle (75%) and liver (25%); nervous system metastases, prior progression while on a taxane, (8). Among its many functions, glutamine serves as the primary compromised organ function, or a baseline neuropathy from carrier of nitrogen between tissues; it is also the main energy chemotherapy that was disabling. All of the patients gave in- source for rapidly proliferating cells such as intestinal epithe- formed consent. This study was approved by the Institutional lium, activated lymphocytes (9), and fibroblasts (8). Glutamine Review Board of Columbia University. is depleted in stress states such as major surgery, sepsis, and cancer (8). It is also essential for maintenance of gut epithelium Treatment Plan for patients on total parenteral nutrition as its omission hastens Mobilization. Peripheral blood hematopoietic progenitor villous atrophy (9). cells were mobilized, harvested and cryopreserved using previ- Preclinical data suggest that glutamine supplementation ously published techniques (24). does not augment tumor cell growth and may augment response High-dose chemotherapy with stem cell support included: to chemotherapy (10–13). Clinical studies have assessed the (a) intensification 1, paclitaxel. After standard premedication, efficacy of glutamine with different doses and schedules to paclitaxel at 825 mg/m2 was administered as a continuous prevent gastrointestinal toxicity (mucositis, diarrhea) in patients infusion over 24 h on day Ϫ4 prior to stem cell infusion; (b) receiving a variety of chemotherapy agents or radiation therapy intensification 2, melphalan. With recovery to an ANC Ն 1000/ (Ref. 10, 14–19; Table 1). ␮l, and in the absence of platelet refractoriness or disease The efficacy of high-dose chemotherapy with stem cell progression, patients received melphalan at 90 mg/m2/day for 2 support in breast cancer is currently being studied in the United consecutive days (180 mg/m2 total) on days Ϫ2 and Ϫ1 prior to States and Europe. Although the benefit is still undetermined, stem cell infusion; (c) intensification 3, CTCb. After recovery numerous pilot studies incorporate high doses of newer drugs from intensification 2, patients were admitted for cyclophosph- such as paclitaxel into some of the more common regimens. amide (6000 mg/m2), thiotepa (500 mg/m2), and carboplatin There is laboratory evidence of a dose-concentration effect of (800 mg/m2) over 96 h on days Ϫ7toϪ4 prior to stem cell paclitaxel in MCA-4 transplanted tumors in C3Hf/Kam mice infusion. Mesna (7500 mg/m2; 1500 mg/m2/day) was adminis- that supports a dose-concentration/response effect in breast can- tered by continuous infusion over 120 h. All of the cycles were cer (20, 21), although only a modest dose-response effect has also supported with G-CSF (5 ␮g/kg/day s.c.) until the ANC Ն been observed in the clinical setting (22). We conducted a series 1000/␮l for 2 consecutive days. of sequential high-dose chemotherapy trials in which high-dose paclitaxel was the first of three high-dose cycles.