Strategy On Prevention And Treatment Of Chemotherapy-induced Peripheral Neuropathy And Investigation Of Its’ Related Cytokines In Multiple Myeloma

Objective:Multiple myeloma (MM) is a malignant disease caused by the expansion of monoclonal plasma cells in bone marrow. So far, the incidence of MM has been increasing annually, which outnumbered acute leukemia to be the second most common hematological malignancy. In the past 5-10 years, the treatment of MM has advanced and the survival time of MM patients has been prolonged thanks to the introduction of novel drugs. Meanwhile, more attention are being paid to peripheral neuropathy (PN) related to novel drugs such as thalidomide, bortezomib. The incidence of chemotherapy-induced peripheral neuropathy (CiPN) in MM was relatively high. For instance, the incidence of thalidomide-induced peripheral neuropathy (TiPN) ranged from 25%to 75%, bortezomib-induced peripheral neuropathy (BiPN) 40%-60%. When thalidomide and bortezomib was applied as first-line therapy to treat MM, the incidence of grade3-4 PN was 5%-15% and 6%-16%, respectively. Clinical manifestations of PN include paraesthesia of skin, muscle weakness and(or)http://dict.youdao.com/w/Paraesthesia /javascript:void(0):autonomic dysfunction, which negatively affects quality of life in patients and restricts drug dose. There is very limited therapeutic means for CiPN in MM. Current strategies include:1.neurotrophic drugs and analgesics. However, common prescription analgesics have no effect on neuropathic pain. Moreover, symptoms cannot be completely alleviated through feasible treatment.2.reduce the dose and numbers of chemotherapy cycles. Such approaches will improve the neurologic symptoms as well as inevitably compromise the efficacy.For all the MM patients who received treatment in our medical center in the past 5 years, we have systematacially supervised their neuropathy in prevention, evaluation and treatment in order to explore the clinical experience of prevention and treatment of CiPN. Intravenous amifostine before chemotherapy was given to patients to prevent PN. Subcutaneous bortezomib was administered to reduce the incidence of PN instead of intravenous. We innovatively applied traditional Chinese medicine (TCM) acupuncture combined with methylcobalamin to treat PN of grade 2 or more and observed the safety and efficacy. Moreover, we took a combination of neurological scale and electromyography to measure nerve conduction velocity to evaluate therapeutic effect more accurately. Mechanism of CiPN is not yet fully elucidated. Previous research has shown that autoimmune and inflammatory cytokine play essential roles in the initiation and progression of CiPN. We quantitatively determined and investigated serum cytokine concentrations in MM patients with no PN and different levels of PN. Also, self-control study was carried about cytokine concentrations pre-and after-PN in the same patient. We preliminarily discussed the change of cytokine during the progression of CiPN with expectation to find biological indicators for early screening and evaluating PN, furthermore, to search for important targets of PN therapy.Part 1 The prevention of multiple myeloma chemotherapy-induced peripheral neuropathy1.1 The protective effect of amifostine injection for bortezomib-induced peripheral neuropathy in multiple myeloma patientsMethods:To observe the protective effect of amifostine injection to BiPN in MM patients,94 MM patients who received bortezomib-based combination chemotherapy in the First Affiliated Hospital of Zhejiang University from January 2012 to December 2013 were enrolled. All of them were free from PN symptoms before bortezomib (velcade)-based chemotherapy.94 patients were divided into amifostine protection group and control group.53 patients in the protection group received intravenous amifostine 300mg/m2pre-chemotherapy.Other 41 patients without pre-chemotherapy amifostine usage were assigned to the control group.PN severity and adverse effects for every patient were graded by NCI CTCAE, version 3.0. All patients were observed until 3 months after bortezomib withdrawal. PN of all grades and all the other grade 3-4 adverse events (AE) were recorded.Results:Compared to the control group, the incidence of overall PN and grade 1-2 PN did not decrease in the amifostine protection group. While the incidence of grade 3-4 PN was lower in the amifostine protection group with significant trend (0.05<P<0.1). As to the recovery condition within 3 months after bortezomib withdrawal,78% of patients in the amifostine protection group recovered with an advantage over the control group (50% PN recovered). The difference is significant (P<0.05). Comparing hematological AE and other common non-hematological AE in the two groups, it revealed that amifostine had no obvious protection against neither myelosuppression in MM patients who received bortezomib-based combination chemotherapy, nor diarrhea/constipation, infection (including varicella-zoster virus infection). Considering the treatment effect, amifostine use did not impair or enhance chemotherapeutic efficacy.Conclusions:To some extent, amifostine injection is protective against BiPN by reducing the incidence of grade 3-4 PN and improving PN recovery condition within 3 months after bortezomib withdrawal. Nevertheless, it has no obvious protection against chemotherapeutics-induced hematological toxicities and AE such as infection. Amifostine did not influence chemotherapeutic efficacy significantly and side effects can be tolerated.1.2 The protective effect of subcutaneous bortezomib to peripheral neuropathy related to bortezomib-based chemotherapy in multiple myeloma patientsMethods:This study enrolled 70 patients who were treated with bortezomib (velcade) for initial or relapsed MM. Patients were randomly divided into intravenous bortezomib (IV) group and subcutaneous bortezomib(SC) group and each group contained 35 patients. Apart from patients who were dropped out,34 patients in each group were involved in statistics. There were no statistic differences in age, gender, stage of MM, cumulative velcade dose and chemotherapy regimen between two groups. All patients received bortezomib-based three-drug combination chemotherapy, including BAD, BCD and BTD,21 days for each cycle. All patients completed at least 2 cycles (2-6 cycles) of chemotherapy except for dropped out patients. Aciclovir was routinely given for the prophylaxis of herpes zoster. Adverse effect was evaluated by NCI CTCAE version 3.0. Methylcobalamin (Trade name:mecobalamin) was administrated for neurotrophy. Frequency and dose of bortezomib was adapted according to medicine instruction if PN was observed. PN of all levels and all grade 3 and 4 adverse events (AE) were recorded. Based on IMWG efficacy evaluation standard, efficacy evaluation was defined as complete remission (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progression of disease (PD), overall response rate (ORR=CR+VGPR+PR). Efficacy was evaluated every cycle and the best one during the whole therapy was included into statistics. GraphPad.Prism 5.01 standard statistic software was used for analysis. Data between the two groups were compared by chi-square test, Fisher’s exact probability method. P< 0.05 for the difference was statistically significant.Results:Totally 68 eligibility patients completed 2 cycles of chemotherapy mentioned above and there were 34 for each group.4 out of 34 patients (12%) in SC group achieved CR,19 patients (56%) VGPR and 3 patients (9%) PR. ORR was 77%(26/34). As for IV group,6 of 34 patients (18%) achieved CR,10 patients (29%) VGPR and 9 patients (26%) PR with the ORR73%(25/34). Comparing the efficacy between two groups, VGPR in SC was significantly higher than IV (P=0.049). But there are no differences in CR, PR and ORR between SC and IV group (P>0.05). In this study,30 out of 34 patients (88%) in IV group presented grade 3 or higher AE, leading to reduction of chemotherapy dosage in 10 cases (29%) and discontinuation of therapy in 8 patients (24%).24 of 34 patients in SC group presented grade 3 or higher AE, resulting in reduction of chemotherapy dosage in 7 cases (21%) and discontinuation of therapy in 5 patients (15%). No differences were observed between the two groups. Thrombocytopenia was most common grade 3 and higher AE in hematology with the incidence of 18% in both IV and SC group, followed by infection and gastrointestinal symptoms (diarrhea or constipation).21 of 34 (62%) in IV group developed PN, of which 16(47%) were grade1-2 PN and 5 (15%) were grade3-4 PN. By contrast, PN was seen in only 10 of 34 (29%) in SC group PN, of which 7 (21%) were grade 1-2 and 3 (9%) were grade 3-4. The total incidence of PN was significantly lower in SC group (P=0.014). The incidence of grade 1-2 PN were significantly lower in SC group as well (P=0.039). However, no difference was seen in the incidence of grade 3-4 PN between the two groups.Conclusions:Subcutaneous bortezomib reduces the incidence of PN without affecting efficacy compared with intravenous bortezomib, with slight local response and good clinical safety. Subcutaneous bortezomib can be the substitute administration for intravenous injection in clinical treatment.Part 2:Acupuncture Combined with Methylcobalamin in Treatment of Chemotherapy-induced Peripheral Neuropathy in Patients with Multiple MyelomaMethods:104 MM patients who met the inclusion criteria in our center were randomly assigned into a solely Methylcobalamin therapy group (10 times of 500μg intramuscular Methylcobalamin injection every other day followed by 2 months of oral Methylcobalamin application) and Acupuncture combined with Methylcobalamin group (Methylcobalamin used the same way as above accompanied by 3 cycles of acupuncture).98 out of 104 completed the treatment and follow-up. There were 49 cases in each group. The evaluating parameters included visual analogue scale (VAS) pain score, FACT/the GOG-Ntx questionnaire scores, and electromyographic (EMG) nerve conduction velocity (NCV) determinations. We evaluated the changes of the parameters in each group after the therapy and made a comparison between the two groups.Results:After 84 days (3 cycles) of therapy, the pain was significantly mitigated in both groups, with a significant higher decrease in the acupuncture treated group (P <0.01). The patients’daily activity evaluated by FACT/the GOG-Ntx questionnaire improved in the acupuncture treatment group (p<0.001). The NCV in the acupuncture treatment group improved significantly while amelioration in the control group was not observed.Conclusions:This study suggests that acupuncture combined with Methylcobalamin in the treatment of CiPN showed a better outcome than Methylcobalamin administration alone.Part 3 Study of cytokines associated with chemotherapy-induced peripheral neuropathy in multiple myelomaMethods:111 MM patients who met the inclusion criteria in our center from June2014 to December2015 were enrolled, including 68 male and 43 female(median age:60 years old, range from 31 to 84 years old). All patients received the assessment of disease stage, investigation of previous treatment and evaluation of disease remission status at enrollment. The patients accepted cytokine detection by CBA flow cytometry every time when admitted to hospital, and every patient received at least one test. According to the National Cancer Institute’s Common Terminology Criteria Adverse Events (NCI CTCAE version 3.0), patients were assigned into Non-PN group and PN group based on whether they suffered from PN when accepted cytokines detection; PN group included grade 1 PN(1-PN) and grade 2-3 PN(2-3-PN).Results:There were a total of 154 tests of cytokines detection in Non-PN group and 94 tests in PN group(63 tests in 1-PN and 31 tests in 2-3-PN). There was no significant difference in the serum concentration of these cytokines(IL-2, IL-4, IL-6, IL-10, TNF-a, IFN-y, IL-17A) between Non-PN and PN group(P>0.05). Further analysis showed that there was still no significant difference in the concentration of these cytokines above between Non-PN and 1-PN as well as concentration of IL-4, IL-10, IFN-y, IL-17A between Non-PN and 2-3-PN group, but the serum concentration of IL-2, IL-6, TNF-a in 2-3-PN were significantly higher than Non-PN group(P=0.0230, P=0.0138, P=0.0080 respectively). These results suggested that IL-2, IL-6, TNF-a were associated with the development of 2-3-PN(P<0.05), of which TNF-a had the greatest relevance(P<0.01).Also, self-control study was carried about cytokine concentrations change pre and after PN in 14 MM patient, and the serum concentration of IL-6(P=0.0347), IL-10(P=0.0475), TNF-a(P=0.0004) significantly increased when patients began to suffer from PN, and TNF-a increased the most obviously. But the difference of IL-2, IL-14, IFN-y, IL-17A before and after PN was not observed(P>0.05).Conclusions:The serum concentration of IL-2, IL-6, TNF-a in 2-3-PN were significantly higher than Non-PN group and IL-6, IL-10, TNF-a serum levels were remarkably increased when patients began to suffer from PN, of which TNF-a increased most obviously. The study suggested that cytokines such as TNF-a, IL-6 played key roles during the progression of CiPN and further studies are still needed to clarify the mechanisms.