Table 3;
Prevention and Treatment of PIPN in prospective randomized placebo-controlled clinical trials
| Intervention | Proposed mechanism of action |
Chemotherapy drug |
Sample size | Outcome measure |
Results | Reference |
|---|---|---|---|---|---|---|
| Prevention | ||||||
| Amifostine (AM) | Cytoprotective agent via detoxification and ROS scavenging | Platinum | 242 AM:122 PL: 120 |
NCI-CTC after 6 cycles | NCI-CTC grade 1 toxicity: AM: 29%, PL: 31%, grade 2: AM: 29%, PL: 35%, grade 3: AM: 9%, PL: 15%, P=0.029 |
Kemp 1996145 |
| Amifostine (AM) | Cytoprotective agent via detoxification and ROS scavenging | Carboplatin/paclitaxel | 187 AM: 93 PL: 94 |
NCI-CTC Grade 3-4 neurotoxicity | AM: 3.7% (95% CI, 2.1 to 5.3) PL: 7.2% (95% CI, 5.0 to 9.4) P=0.021 |
Lorusso 2003146 |
| Amitiptyline (AMI) | Affects descending noradrenergic pathways | Vinca alcaloids, platinum, or taxanes | 99 AMI:54 PL: 45 |
Visual analogue scale (VAS) twice per week | No significant difference in neuropathy score at median of 19-21 wk follow up between AMI and PL groups P=n.s. |
Kautio 2009147 |
| Calcium and magnesium (CaMg) infusions | Inhibits oxalate’s action on Na+ channels | Oxaliplatin | 353 CaMg/CaMg:118, CaMg/PL:116 PL/PL: 119 |
Sensory subscale of the EORTC QLQ-CIPN20 and CTCAE | CTCAE grade ≥ 2 neurotoxicity CaMg/CaMg: 43%, CaMg/PL: 46%, PL/PL: 45% P=n.s. |
Loprinzi 2013148 |
| Diethyldithio-carbamate (DDTC) | Chelation tissue-bound platinum | Platinum | 214 DDTC: 106 PL: 108 |
NCI-CTC | DDTC: 13%, PL: 12%; P=n.s. |
Gandara 1995149 |
| Glutathione (GSH) | Antioxidant; decreases DRG platinum | Paclitaxel/carboplatin | 185 GSH: 94 PL: 91 |
EORTC-QLQ-CIPN20 and CTCAE | Peripheral Neuropathy: P=0.21 CTCAE grade ≥ 2neurotoxicity: GSH: 38%, PL: 33% P=0.449 |
Leal 2013150 |
| Glutathione (GSH) | Antioxidant; decreases DRG platinum | Cisplatin | 151 GSH: 74 PL: 77 |
NCI-CTC | GSH: 39%, PL: 49%; P = .22 | Smyth 1997151 |
| Vitamin E (Vit. E) | Antioxidant | Taxane, cisplatin, carboplatin, oxaliplatin, or combination | 189 Vit. E: 96 PL: 93 |
CTCAE v 3.0 | Grade 2+: Vit E: 34%; PL: 29%; P=0.43 |
Kottschade 2011152 |
| Recombinant human leukemia inhibitory factor (rhuLIF) | Neuroprotective growth factor effect | Carboplatin and paclitaxel | 117 rhuLIF 2 μg/kg: 36; rhuLIF 4 μg/kg: 39; PL: 42 |
CPNE score at cycle 4 | No significant differences seen in CPNE between time points for any treatment groups P=n.s. |
Davis 2005153 |
| Calmangafodipir | Mimics the mitochondrial enzyme manganese superoxide dismutase by protecting cells from oxidative stress | FOLFOX-6 Folinic acid, 5-fluorouracil oxaliplatin | 173 PL= 60 Cal 2 μmol/kg=57; 5 μmol/kg=45, 10 μmol/kg=11 |
CTCAE; Leonard Scale Questionnaire; NCI-Sanofi ; cold allodynia test | Trend toward decreased physician graded neurotoxicity P=0.16 Decreased PRO symptoms P<0.01 |
Glimelius 2017154 |
| Stop-and-Go Approach (earlier interruption of oxaliplatin and maintenance chemotherapy without it) | Less neurotoxic chemotherapy is administered before severe neurotoxicity develops | FOLFOX4 (Arm A) vs FOLFOX7 (Arm B) | 620 | NCI-Common Terminology Criteria for Adverse Events (CTCAE) | Grade 3 sensory neuropathy in 17.9% of the patients in arm A v 13.3% of patients in arm B P=0.12 |
Tournigand 2006155 |
| Non Pharmacological Intervention Exercise (E) during chemotherapy vs Control group (C) |
Reduction of inflammation; affects sensory processing in the brain | Taxane-, platinum-, or Vinca alkaloid-based | 355 E: 155 C: 185 |
Patients reported grading of CIPN symptoms | Decreased temperature sensitivity P=0.045 Decreased sensory symptoms P=0.061 |
Kleckner, 201897 |
| Treatment | ||||||
| Gabapentin | Inhibition of voltage-dependent calcium channels in DRG | Vinca alkaloids, platinum, or taxanes | 115 G/P: 57 P/G: 58 |
NRS and ENS for ‘average’ daily pain at baseline and at the end of study | NSR scores for ‘average’ pain at study entry G/P; 4.3, P/G; 3.6 P=0.06 at 1st phase G/P; 3.3, P/G; 3.1 P=0.8 at 2nd phase G/P; 3.1 P/G 2.5 P=0.2 |
Rao, 2007156 |
| Duloxetine (Dulox) | serotonin and norepinephrine reuptake inhibitor; sodium channel inhibition | Taxane or platinum | 231 Grp A: 115, dulox then cross over PL Grp B: 116, PL then cross over to dulox |
BPI-SF “average pain” item | Grp A average pain decreased more than Grp B P=0.003 |
Smith 2013157 |
| Topical amitriptyline, ketamine, with or without Baclofen (BAK) | Amitriptyline: alters sodium channel and adenosine A receptor Ketamine: blocks NMDA receptors Baclofen: GABA agonist |
Vina alcaloids, platinum, taxanes, or thalidomide | 203 BAK: 101 PL: 102 |
Change in sensory subscale EORTC-QLQ-CIPN20 score at 4 wks | Mean change from baseline of sensory subscale for BAK (8.1) versus PL (3.8) P=0.053 |
Barton 2011158 |
| Lamotrigine (Lam) | Inhibits sodium channels, blocking release of glutamate and aspartate | Vinca alcaloids, platinum, or taxanes | 131 Lam: 63; PL: 62 |
NRS and ENS at 10 wks | Mean NRS change from baseline for Lam (0.3) versus PL (0.5) P=0.56 Mean ENS change from baseline for Lam (0.4) versus PL (0.3) P=0.3 |
Rao 2008159 |
BPI-SF: Brief Pain Inventory-Short Form; CPNE: Standardized Composite Peripheral Nerve Electrophysiology Score; CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; DRG: Dorsal Root Ganglia; ENS: Eastern Cooperative Oncology Group Neuropathy Scale; EORTC QLQ-CIPN20: European Organization for the Treatment of Cancer quality of life questionnaire-CIPN twenty item scale; NCI-CTC, National Cancer Institute Common Toxicity Criteria; NCI-Sanofi: oxaliplatin Sanofi questionnaire; NRS: Numerical Rating Scale; n.s: Not Statistically Significant; PL: Placebo; PRO: Patient Reported Outcome; ROS: Reactive Oxygen Species; VAS: Visual Analogue Scale;