Preventing neuropathy during chemotherapy
Jacob Schor ND
October 11, 2007
This is the sort of newsletter that has interesting information for just a few of you. There aren't funny jokes hidden away and no recipe at the end. So if this isn't a topic that relates to you, stop here and have a nice day.
The problem with some of the newer chemotherapy drugs is that they cause neuropathy. Neuropathy means something wrong with the nerves and is usually experienced as numbness, odd sensations or various degrees of pain typically experienced in the extremities, meaning the feet and hands.
Neuropathy can be serious business and it is often the dose limiting toxicity that forces patients to lower doses of chemotherapy drugs or discontinue further treatment with the drug.
There have been several papers of interest in recent years which make suggestions of possible ways to avoid developing neuropathy when using particular drugs.
Taxol and Glutamine:
The first I am looking at is one by Linda Vahdat et al from Columbia University in New York . Published in Clinical Cancer Research in 2001, these doctors looked at the effect of l-glutamine at reducing the peripheral neuropathy in patients undergoing pacliltaxel treatment.
Paclitaxel is one of those chemotherapy drugs that are ‘natural' or at least started out as natural. a mitotic inhibitor used in cancer chemotherapy. Researchers from the National Cancer Institute discovered it in 1967 isolating it from the bark of the Pacific yew tree. The scientific name for yew tree is Taxus brevifolia and the drug got named 'taxol'. Bristol-Myers Squibb (BMS) developed a commercial version of the drug and kep the name ‘Taxol' for their trademarked version so the generic name was changed to 'paclitaxel'.
Paclitaxel or Taxol is used to treat lung, ovarian, breast cancer, head and neck cancer, and advanced forms of Kaposi's sarcoma. Paclitaxel interferes with normal microtubule growth during cell division. Together with docetaxel, it forms the drug category of the taxanes. Although the drug was initially isolated from Yew tree back, about 15 years ago, the Yew was abandoned in favor of synthetic production through bacterial fermentation. 
About one third the patients treated with high dose Taxol develop serious neuropathy. They are left with the choice of stopping treatment early or lowering the doses of the drug. Up until yesterday, Taxanes were considered normal protocol for all node positive breast cancers, but that's another story which I'll leave alone for the moment.
Various different therapies have been tried over the years in the hope of preventing these Taxol induced neuropathies including NSAIDs and steroids, which did not help. In this particular study patients were given either 10 grams of l-glutamine three times a day or a placebo starting a day after taking the drug. “For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of severe dysthesias and numbness in the fingers and toes.” Motor weakness was reduced from 56% to 25%, comparing the patients who got the placebo against the patients who took glutamine. Gait deterioration was reduced from 85% to 45%. Interference with daily living decreased from 85% to 27% and severe paresthesias down from 55 to 42%. [i]
A 2005 study done at Sloan Kettering confirmed this benefit. Stubblefied et al. writing in the June 2005 issue of Clinical Oncology describe a study in which patients receiving high dose paclitaxel weregiven glutamine or placebo. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks after treatment. Their conclusion, “Patients who received glutamine developed significantly less weakness, less loss of vibratory sensation and less toe numbness than controls.” [ii]
The effectiveness of Taxol in treating breast cancer has recently been brought into question. Never the less, Taxol remains a standard treatment for many other cancers. As glutamine is safe, inexpensive and easy to take, it would seem a reasonable adjunct for anyone undergoing therapy with Taxol.
Glutamine is also useful at decreasing cardiotoxicity caused by doxorubicin but let's stay focused here and stick with neuropathy. [iii]
Oxaliplatin and mineral infusions
Oxaliplatin is another chemotherapy drug rather famous for causing neuropathy. Its use is also often limited by these symptoms. It has a peculiar symptom of making patients incredibly sensitive to cold and also inducing muscle contractions. An interesting paper published in 2004 describes the work of several French researchers. Laurence Gamelin and colleagues noted that these symptoms resemble those of patients with congenital myotonia or tetany. The hypothesized that oxaliplatin had a unique direct effect on nerve excitability. Their thinking was that perhaps the oxalate, a metabolite of oxaliplatin and a known chelator of calcium and magnesium, might be responsible for the neurotoxicity. They experimented with giving calcium and magnesium infusions prior to and after oxaliplatin.
Oxaliplatin is often used in treating colorectal cancer combined with 5-FU and leucovorin. These researchers grabbed 161 patients being treated with this drug cocktail and gave 96 of them an IV cocktail of calcium and magnesium before and after they got their oxaliplatin dose. The other 65 got straight chemo cocktail. Of the control group, almost a third (31%) quite the study because of neurotoxic effects. Only 4% of experimental group were forced to quit by the drug's effects. Tumor response was similar in both groups. Distal paresthesia decreased from 26% to 7% in the experimental group. Acute symptoms were less frequent and less severe, the nasty things like pseudolaryngealspasm were never reported in the experimental group. At the end of the study only 20% of the calcium and magnesium group reported neuropathy compared to 45% of the control. [iv]
A Japanese study published in April 2007 confirmed this French protocol. There was no placebo group. They gave calcium and magnesium to 14 patients undergoing oxaliplatin therapy for colorectal cancer. They report, “ Only 1 patient had grade 3 toxicity (nausea and vomiting). Sensory neuropathy occurred in 8 patients (57.1%). There was no neurotoxicity with functional impairment in this study. Sensory neuropathy hardly occurred before 4 cycles.” [v]
Lipoic acid has also been suggested to be useful with this drug. [vi]
There are some interesting French studies that tell us that the time of day chemotherapy drugs are administered will change their effect. Different tissues and organs tend to be more active at different times of the day. Dosing drugs at times when certain tissues are less active will decrease the damage. In a study on ovarian cancer patients, when doxorubicin is given in the morning and cisplatin is given 12 hours later, there is a 44% five-year survival. If you shift the schedule and give doxorubicin in the evening and the cisplatin in the morning the survival rate drops to 11%. Tumors responded in 51% of the circadian dosed patients compared to only 29% of the standard dosed group. Only 14% of the circadian patients developed mucositis compared to 76% of the standard dosed control group. The same decrease was seen in neuropathy; 16% of the circadians developed neuropathy compared to 31% of the controls. Also useful in conjunction with radiation. [vii] I have yet to see an oncologist here in Denver willing to schedule chemotherapy treatments based on this information. My suggestion is not to explain but simply to try and schedule particular drugs as close to the suggested ideal time as possible.
Drug best time to take
Doxorubicin on arising ( 6 AM )
Cisplatin 4-6 PM
Oxaliplatin 6 PM
Carboplatin 6 PM
5-Fluorouracil 11 PM to 4 AM
5-Fluorouracil & Leucovorin 11 PM to 4 AM
FUDR 11 PM to 4 AM
Cisplatin is another nasty drug that is neurotoxic and causes peripheral neuropathies. Various things have been shown to be protective. Vitamin E dosed at 600 mg a day reduced neurotoxic effects in a group of patients from 68.5 % in the control group. [viii]
Glutathione and supplements which enhance glutathione production have been suggested to prevent cisplatin toxicity. In practice, I not hesitate to follow these recommendations. My concern is simple. The desired action of both chemotherapy and radiation is to increase ROS generation in the cell in order to trigger apoptosis. Glutathione neutralizes ROS. Many of the supplements we use from our side of the oncology fence for their anti-tumor effect also increase ROS in cancer cells. My concern with glutathione enhancement is that it will not only interfere with chemotherapy but even the action of the supplements used to attack cancer cells. Thus we discourage the use of glutathione (Oral or IV), N-acetyl-cysteine and whey proteins. These whey proteins deserve their own chapter to explain the situation which is not as simple as one would prefer. I may have even written it already and misplaced it.
To sum up the whey story in a paragraph or so, there are a great many studies explaining that whey protein supplementation is beneficial for a range of conditions and that this benefit is in part due to its ability to increase glutathione. Whey, or at least high quality whey, contains large amounts of the amino acid l-cysteine. This amino acid is often the rate limiting step in making glutathione. Give a critter more l-cysteine and it will make more glutathione. Much of the promotion of whey proteins stems from a Canadian company called Immunotec. This is a multi level marketing company.
There are several published clinical trials in which cancer patients did better using the whey protein supplement this company markets. Immunotec is promoting a theory that, in cancer patients, whey protein will actually lower glutathione production. This is an interesting idea but at this point I have not read published work that convinces me of its validity. Thus, in practice I continue to be cautious and avoid whey protein with cancer patients.
There are nutritional tricks that will lessen the chance of getting neuropathy or reduce its intensity and duration. These vary with each drug. Most work best if given before or during treatment. They are protective; they rarely do much good after neuropathy has already started.
Reduction of paclitaxel-induced peripheral neuropathy with glutamine.
Division of Medical Oncology and Hematology, Department of Medicine, The Herbert Irving Comprehensive Cancer Center of Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. firstname.lastname@example.org
PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.
PMID: 11350883 [PubMed - indexed for MEDLINE]
Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study.
Department of Neurology, Rehabilitation Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York City, NY 10021, USA. email@example.com
AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.
PMID: 15997923 [PubMed - indexed for MEDLINE]
Glutamine protects against doxorubicin-induced cardiotoxicity.
Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock , Arkansas , 72205 , USA .
Doxorubicin (DOX) dose-intensive therapy for breast cancer is limited by a cardiomyopathy that often results in overt congestive heart failure. We hypothesized that dietary glutamine (GLN) can diminish DOX-induced cardiotoxicity by maintaining tissue glutathione (GSH) levels and thus preventing the proposed mechanism of cardiac injury: oxidation. METHODS: Forty-two female Fisher 344 rats were randomized into one of six groups: GLN + saline (SAL), GLN + DOX, freamine (FA) + SAL, FA + DOX, H2O + SAL, and H2O + DOX. Rats were pair-fed chow and gavaged with 1 g/kg/day GLN or an isonitrogenous amount of FA or H2O for 28 days. Rats were injected intravenously with a single dose of SAL or 9 mg/kg DOX on day 7 of gavage. At 28 days (21 days post-DOX), rats were sacrificed and blood and cardiac tissue were assayed for GLN and GSH content and lipid peroxidation (LP). RESULTS: There were no differences in cardiac GSH levels and cardiac lipid peroxidation in GLN + SAL versus GLN + DOX groups. However, blood and cardiac GSH levels were significantly decreased in H2O + DOX and FA + DOX groups compared to controls (H2O + SAL and FA + SAL). CONCLUSION: These data suggest that dietary GLN supplementation may diminish DOX-induced oxidative damage and thus cardiotoxicity through upregulation of cardiac GSH metabolism. Copyright 1999 Academic Press.
Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer.
Department of Medical Oncology and Oncopharmacology, INSERM U564, Anticancer Centre Paul Papin, Angers Cedex , France .
PURPOSE: Oxaliplatin is active in colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. It may come from an effect on neuronal voltage-gated Na channels, via the liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate chelators. EXPERIMENTAL DESIGN: A retrospective cohort of 161 patients treated with oxaliplatin + 5-fluorouracil and leucovorin for advanced colorectal cancer, with three regimens of oxaliplatin (85 mg/m(2)/2w, 100/2w, 130/3w) was identified. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not. RESULTS: Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group versus 31% in the control group (P = 0.000003). The tumor response rate was similar in both groups. The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7 versus 26%, P = 0.001). Acute symptoms such as distal and lingual paresthesia were much less frequent and severe (P = 10(-7)), and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P = 0.003). Patients with grade 2 and 3 at the end of the treatment in the 85 mg/m(2) oxaliplatin group recovered significantly more rapidly from neuropathy than patients without Ca/Mg. CONCLUSIONS: Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage.
PMID: 15217938 [PubMed - indexed for MEDLINE]
[Reduction of oxaliplatin-related neurotoxicity by calcium and magnesium infusions]
[Article in Japanese]
Division of Surgery, Nakadori General Hospital .
PURPOSE: Oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX) have emerged as the standard of care in the therapy of advanced-stage colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. We decided to use Ca and Mg for prevention of oxaliplatin-related neurotoxicity with reference to the report of Gamelin et al. METHODS: The subjects were 14 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m(2)) was given intravenously as FOLFOX regimen. All 14 patients received infusions of Ca gluconate and Mg sulfate before and after oxaliplatin. RESULTS: Only 1 patient had grade 3 toxicity (nausea and vomiting). Sensory neuropathy occurred in 8 patients (57.1%). There was no neurotoxicity with functional impairment in this study. Sensory neuropathy hardly occurred before 4 cycles. CONCLUSIONS: Ca/Mg infusions seem to prevent acute oxaliplatin-induced neurotoxic.
PMID: 17431344 [PubMed - indexed for MEDLINE]
[vi] J Clin Oncol. 2002 Aug 1;20(15):3359-61.
Effective treatment of oxaliplatin-induced cumulative polyneuropathy with alpha-lipoic acid.Gedlicka C, Scheithauer W, Schüll B, Kornek GV.
PMID: 12149316 [PubMed - indexed for MEDLINE]
[vii] Chronobiol Int. 2002 Jan;19(1):237-51.
Circadian chemotherapy for gynecological and genitourinary cancers.
Kobayashi M, Wood PA, Hrushesky WJ.
WJB Dorn VA Medical Center/Department of Developmental Biology and Anatomy, The University of South Carolina School of Medicine, Columbia 29209, USA.
The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin ( 06:00 h) and cisplatin ( 18:00 h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00 h and 21:00 h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.
PMID: 11962679 [PubMed - indexed for MEDLINE]
A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results.
Argyriou AA ,
Chroni E ,
Koutras A ,
Iconomou G ,
Kalofonos HP .
EMG/ENG Laboratory, Department of Neurology, University of Patras Medical School , Rion-Patras , Greece .
AIM: A randomized, open label with blind assessment, controlled trial was performed to assess efficacy and adverse-event profile of vitamin E, given as supplementation for prophylaxis against cisplatin-induced peripheral neuropathy (CIPN). PATIENTS AND METHODS: A total of 30 patients scheduled to receive six courses of cumulative cisplatin-based regimens were randomly allocated to treatment and control groups and were then studied by means of neurological examination and electrophysiological study. Patients assigned to group I (n=14) orally received vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of group II (n=16), who received no vitamin E supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified Peripheral Neuropathy (PNP) score. RESULTS: The incidence of neurotoxicity differed significantly between groups, occurring in 3/14 (21.4%) of patients assigned to the vitamin E supplementation group and in 11/16 (68.5%) of controls (p=0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of controls, RR=2.51, 95% C.I.=1.16-5.47. Mean PNP scores were 4.99+/-1.33 for patients of group I and 10.47+/-10.62 for controls, (p=0.023). None of the adverse events or deaths occurred, were judged as likely to be related to the vitamin E supplementation. CONCLUSION: Vitamin E effectively and safely protects patients with cancer from occurrence of cisplatin neurotoxicity.
PMID: 16622646 [PubMed - in process]