Amifostine

Examine the efficacy of purported chemoprotective agents to prevent or limit neurotoxicity of cisplatin and related agents

TYPE OF STUDY: Combined systematic review and meta-analysis

DATABASES USED: Cochrane Neuromuscular Disease Group Specialized Register, Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, LILACS, and CINAHL

KEYWORDS: Extensive list provided in article appendix

INCLUSION CRITERIA: Quasi-randomized or randomized clinical trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures, including nerve conduction studies or neurologic impairment rating using validated scales (secondary)

TOTAL REFERENCES RETRIEVED: Sixteen randomized trials were evaluated in the initial 2006 review. In the 2010 update, 11 additional randomized trials not among the 2006 review were identified.

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane method of evaluation for risk of bias done by two authors and finalized by consensus

• N (studies) = 6
• SAMPLE RANGE ACROSS STUDIES: 14–242
• TOTAL PATIENTS INCLUDED IN REVIEW: 1,537 participants
• KEY SAMPLE CHARACTERISTICS: Patients who received cisplatin chemotherapy

Cisplatin is considered to have neurotoxic effects, with patients developing sensory neuropathy. Symptoms of pain, numbness, and tingling are observed mostly in the extremities from a distal to proximal distribution. The neuropathy experienced by patients may recover partially or may become permanent. Neuroprotective agents such as acetylcysteine, acetyl-L carnitine, amifostine, calcium and magnesium, growth factors, glutathione, ORG 2766, oxcarbazepine, and vitamin E have been tested. The five newly added randomized controlled trials included three chemoprotective agents not previously described in the 2006 review.

From the data examined in this updated review, inconclusive evidence exists for recommending any neuroprotective agent tested to prevent or limit the neurotoxicity of platinum chemotherapy.

While 1,537 participants were included in the 2010 update, few trials were amenable to meta-analysis. Clinical trials of neuroprotective agents are plagued by issues of study design, including small sample size, unclear randomization and blinding procedures, and lack of quantitative measures, especially conventional QST or electrophysiologic evaluation.

STUDY PURPOSE: To examine the efficacy of chemoprotective agents to prevent or limit neurotoxic side effects of cisplatin and related chemotherapy agents

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 20 
• TOTAL PATIENTS INCLUDED IN REVIEW = 2459
• SAMPLE RANGE ACROSS STUDIES: 18–755
• KEY SAMPLE CHARACTERISTICS: Varied tumor types receiving platinum-based chemotherapy

PHASE OF CARE: Active antitumor treatment

There is insufficient high quality evidence to show that any agent is protective against platinum-induced neuropathy. There is some suggestion that amifostine, glutathione, and calcium and magnesium may have some effect.

• Limited number of studies included
• Low sample sizes
• There were few studies per intervention, and very few studies with small sample were included in the meta-analyses.

There is insufficient evidence to show that any agent is truly effective in protecting against neurotoxic effects of platinum-based chemotherapy. There is a continued need for well designed research using appropriate objective as well as subjective measures of neuropathy.

STUDY PURPOSE: To evaluate status of research on pharmacologic interventions for CIPN

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Medline, Embase, and China National Knowledge Internet

YEARS INCLUDED: (Overall for all databases) Information for dates of search not provided, articles included were from 1995 to 2014

INCLUSION CRITERIA: The study (a) assessed CIPN in patients with cancer, (b) compared two or more drugs or placebo, (c) provided sufficient data to assess differences, and (c) assessed incidence or severity of CIPN

EXCLUSION CRITERIA: None listed

TOTAL REFERENCES RETRIEVED: 1,839

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No description of quality evaluation

FINAL NUMBER STUDIES INCLUDED: 23

TOTAL PATIENTS INCLUDED IN REVIEW: 2,298

SAMPLE RANGE ACROSS STUDIES: 20-732

KEY SAMPLE CHARACTERISTICS: All but one of the studies focused on patients getting platinum-based chemotherapy and 12 of 23 only included people with colorectal cancer.

PHASE OF CARE: Active antitumor treatment

Contrary to the title, this article does not include any commonly prescribed prescription drugs, including gabapentin, pregabalin, or duloxetine. This review included studies of amifostine, Vitamin E, calcium and magnesium infusions, and glutathione. Eighteen studies had a placebo control group and had no control group. Neither blinding nor control were needed for inclusion. Findings indicate that Vitamin E and amifostine reduce incidence of CIPN, while glutathione and amifostine reduced severity of CIPN. There was one study (n = 20) included that had patients getting amifostine who all had cervical cancer and were receiving cisplatin with radiation therapy. The authors of this original study (Gallardo et al., 1999) found no statistically significant difference in neurotoxicity between those getting amifostine and those who did not. It is therefore unclear how the authors of the meta-analysis found otherwise. There was also only a single study of glutathione versus placebo versus calcium/magnesium (n = 93, 33 of whom received glutathione) included. The original study (Dong et al., 2010) showed no significant differences in CIPN incidence or severity between the three groups. Four studies of Vitamin E, two which were placebo controlled and two with no control group.

The limitations, including lack of quality control, small sample sizes, focus on platinum use, and GI malignancies, limit the generalizability of the findings from this meta-analysis.

• Limited search
• Limited number of studies included
• No quality evaluation
• Low sample sizes

Findings from this study suggest that amifostine, glutathione, and Vitamin E may be helpful for CIPN but no recommendations for practice can be made at this time due to limitations of this meta-analysis.

Women with ovarian cancer scheduled for treatment with carboplatin or paclitaxel-based chemotherapy were randomized to receive either IV premedication with amifostine 740 mg/m² or placebo for 30 minutes. Data were collected at baseline, after each cycle of chemotherapy, and at three and six months after completion of chemotherapy.

The sample consisted of 71 women with advanced ovarian cancer.

The study was a double-blind, randomized, placebo-controlled study.

• Measurements included vibration perception thresholds and vibration disappearance thresholds before cycle 4 and after the end of treatment. Secondary objectives were patella and Achilles tendon reflexes and two-point discrimination.
• Sensory symptoms, fine global motor activities, and quality of life were collected via questionnaire.
• Toxicity was reported according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE).

Thirty-seven women received amifostine and 34 received the placebo infusion. A significant protective effect of amifostine was found in vibration, two-point discrimination, and deep tendon reflexes. No significant differences were observed for single sensory or motor symptoms; however, amifostine improved sensory neuropathy according to the NCI-CTCAE criteria. Inconsistent results were reported in regard to quality of life.

• The study sample size may have been too small to detect group differences.
• Inconsistencies were present regarding the assessment of sensory neurotoxicity, the neurologic assessment of vibration thresholds, and quality of life.
• There were inter-observer variances with vibration sense measurement.

To determine the proportion of women who experience significant treatment-induced peripheral neuropathy

Women with gynecologic cancer received combination chemotherapy consisting of cisplatin and paclitaxel via IV 175 mg/m² over three hours, followed by amifostine 740 mg/m² and cisplatin 75 mg/m²administered over 90 minutes beginning 15 minutes after amifostine administration.

• N = 29 enrolled in this limited-access study; 21 completed all six cycles of therapy plus the three-month evaluations
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Women with ovarian, primary peritoneal, fallopian tube, endometrial, cervical, or uterine sarcoma
• OTHER KEY SAMPLE CHARACTERISTICS: Proposed treatment included both cisplatin and paclitaxel chemotherapy.
• EXCLUSION CRITERIA: Prior chemotherapy or radiation or history of neuropathy

• Phase II study

• Measures were done at baseline, before each chemotherapy cycle, and three months after completion of treatment.
• Chemotherapy-induced peripheral neuropathy (CIPN) was measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity scale, neurotoxicity subscale of the Functional Assessment of Cancer Therapy and Gynecologic Oncology Group, and vibration perception threshold (VPT) testing using the Vibratron II device.

Four of 27 assessable patients experienced dose-limiting toxicity grade 2 or higher CIPN as measured by clinical assessment and NCI CTCAE grading. The number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed.

Amifostine’s level of activity was insufficient to warrant further study in a phase III trial.

• The study contained a relatively small sample size (n = 29) and used a one-group design.
• Frequent evaluations of CIPN were performed by different professionals, but a detection bias may have been present.
• Although VPT testing is considered to be the gold standard, it can be inaccurate if the same digits are not used at each assessment.
• Low inter-observer agreement (46%) was found using the NCI CTCAE.

Women with breast cancer receiving high-dose infusional paclitaxel (725 mg/m² for 24 hours) in combination with doxorubicin (165 mg/m² for 96 hours) and cyclophosphamide (ACT) (100 mg/kg for two hours) were studied on two autologous peripheral blood stem cell transplant protocols—one with and one without amifostine (740 mg/m² administered over 10 minutes before and 12 hours after initiation of the paclitaxel infusion).

• N = 31
• KEY DISEASE CHARACTERISTICS: Women with high-risk breast cancer eligible to receive ACT with or without amifostine, and stable patients with stage IV breast cancer eligible to receive ACT with amifostine

Women in each group were evaluated before ACT and 20–40 days later with neurologic examination, a composite peripheral neuropathy score, peroneal and sural nerve conduction studies, and quantitative sensory testing. The same technologist performed all nerve conduction studies.

No significant effect was seen of amifostine on chemotherapy-induced peripheral neuropathy after high-dose paclitaxel in regard to nerve conduction parameters, quantitative sensory testing, or composite neuropathy scores.

• The study’s small sample size and lack of randomization to treatment with amifostine may bias results.

This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.

Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:

• History, related comorbid conditions, alcohol use, symptoms, pain assessment, time course, and treatment delays or discontinuation from CIPN
• Physical examination
• Patient interview questions regarding sensation of numbness or tingling, pain, bothersome sensations, weakness, difficulty walking, falls, and interference with activities of daily living
• Functional skills testing, such as straight-line walking, name writing, buttoning, pegboard tests, and timed pellet retrieval.

Proposed agents for prevention of CIPN identified include:

• Agents with positive findings: vitamin E, calcium, magnesium, glutamine, glutathione, N-acetylcysteine, oxcarbazepine, xaliproden
• Agents with negative findings: amifostine, nimodipine, Org2766, rhuLIF
• Agents being tested in trials: vitamins B12, B6, acetyl-L-carnititne, alpha lipoic acid

Agents used for pain management:

• Those with negative results in CIPN, including gabapentin, amitriptyline, notriptyline
• Other agents commonly used include duloxetine, 5% lidocaine patch, opioids, tramadol

Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.

• Limitations include a significant lack of evidence regarding effective management and prevention in this area.
• The review did not describe a search strategy or process to determine the quality of evidence used.

The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.