Antiemetic effect of ginger in gynecologic oncology patients receiving cisplatin

To determine whether ginger had antiemetic effect in cisplatin-induced emesis, we conducted a randomized, double-blinded crossover study in 48 gynecologic cancer patients receiving cisplatin-based chemotherapy. Subjects were randomly allocated to regimen A or regimen B in their first cycle of the study. All patients received standard antiemetics in the first day of cisplatin administration. In regimen A, capsules of ginger root powder were given orally 1 g /day for 5 days, starting on the first day of chemotherapy. In regimen B, placebo was given on the first day and metoclopramide was given orally thereafter for 4 days. The patients were then crossed over to receive the other antiemetic regimen in their next cycle of chemotherapy. Among 43 evaluable patients who received both cycles of treatment, success in controls of nausea and emesis were not significantly different between the two regimens in both acute and delayed phases. Restlessness, as a side effect, occurred more often in metoclopramide arm compared to ginger arm (P=0.109). In conclusion, addition of ginger to standard antiemetic regimen has no advantage in reducing nausea or vomiting in acute phase of cisplatin-induced emesis. In delayed phase, ginger and metoclopramide have no statistically significant difference in efficacy.     

Antiemetic efficacy of high-dose metoclopramide, diphenhydramine, methylprednisolone and diazepam on chemotherapy-induced emesis in gynecological malignancy

The antiemetic efficacy of high-dose metoclopramide (MCP), diphenhydramine (DPH), methylprednisolone (MPL), and diazepam (DZP) was investigated in 40 gynecologic cancer patients for a total of 98 chemotherapy courses, treated with cisplatin (50 mg/m2). With MPL (500 mg i.v. x 2) plus DZP (5 mg i.m. x 2), no vomiting occurred in 0% and mild emesis (vomiting 1-2 times) occurred in 20% of 25 courses. With MCP (2 mg/kg i.v. x 5) plus DPH (40 mg i.v. x 3), no vomiting occurred in 35% and mild emesis occurred in 10% of 20 courses. With a combination of MCP plus DPH and MPL plus DZP, no vomiting occurred in 51% and mild emesis occurred in 25% of 53 courses. These results indicate that high-dose MCP plus DPH are effective in preventing cisplatin-induced vomiting. Furthermore, the antiemetic efficacy of MCP plus DPH (0-2 vomiting episodes: 45%) was significantly enhanced (p less than 0.05) by the combined use of MPL plus DZP (0-2 vomiting episodes: 76%).     

The effect of metoclopramide, dexamethasone and antihistamine in the prevention of PAC chemotherapy-induced emesis

The effect of antiemetic agents on the nausea and emesis of ovarian cancer patients treated with CDDP (45 mg/m2), ADM (45 mg/m2) and CPM (450 mg/m2) combination chemotherapy was examined in a randomized parallel study. Metoclopramide (1 mg/kg, 4 times every 2.5 hours), dexamethasone (3.8 mg, 4 times every 2.5 hours) and antihistamine (10 mg, 2 times every 5 hours) were used as antiemetic agents and these agents were gradually decreased for 5 days. The above regimen significantly suppressed the frequency and volume of vomiting on the day of the first PAC chemotherapy but showed no effect on the delayed persistent nausea during chemotherapy. The frequency and volume of vomiting on the day of chemotherapy were 1.6 times and 102 ml respectively in the antiemetic group, but 8.9 times and 352 ml, respectively, in the control group. Although this antiemetic regimen sufficiently suppressed acute drug-induced emesis during chemotherapy, delayed persistent nausea was not eliminated. We next investigated whether these combined antiemetic agents protected the quality of life of patients during maintenance chemotherapy. Our data indicated that about 2 weeks was necessary to recover health after maintenance PAC chemotherapy. These results indicated that this regimen was effective in suppressing the acute drug-induced emesis and in maintaining the quality of life following maintenance PAC chemotherapy.     

Does increasing the steroid dose enhance the efficacy of the antiemetic combination of granisetron and methylprednisolone in gynecologic cancer patients--a randomized study

OBJECTIVE: The authors administered two doses of oral methylprednisolone in combination with 3mg granisetron intravenously for the prophylaxis of cisplatin-induced emesis in gynecologic cancer patients. MATERIALS AND METHODS: Thirty-nine patients received 100mg (group A) and 25 received 200mg (group B) methylprednisolone in the antiemetic combination in a randomized prospective trial. RESULTS: No vomiting in 90.2 and 96.7%, one emetic episode in 3 and 1.1% and two episodes in 3 and 2.2% were detected in groups A and B, respectively. More than two emetic episodes were considered to be a failure and were observed only in group A (3.8%). There was no significant difference between the two treatment groups (P=0.3160). CONCLUSIONS: There was no evidence for enhanced antiemetic effect of elevated steroidal dose in combination with granisetron.     

The prevention of CDDP-induced emesis with a combination regimen including metoclopramide, dexamethasone, droperidol and diphenhydramine

The dose limiting factors of cisplatinum are nephrotoxicity and emesis. Nephrotoxicity has been reduced by hydration but nausea and vomiting caused by cisplatinum have led to refusal of potentially curative therapy by a number of patients. The prevention of nausea and vomiting by a combination of antiemetic drugs administered to ovarian patients receiving chemotherapy inducing (cisplatinum 50mg/m2, adriamycin 300 mg/m2, cyclophosphamide 300 mg/m2 and 5FU 350 mg/m2) was studied. the combination antiemetic drugs were metoclopramide (1mg/kg), dexamethasone (10mg/m2), droperidol (1mg/m2) and diphenhydramine (20mg/body). These drugs without diphenhydramine were administered intravenously 30 minutes before and 2.5 hours, 5 hours and 7.5 hours after chemotherapy. Diphenhydramine was administered intramuscularly 30 minutes before and 5 hours after chemotherapy. No vomiting was noted in 82.6% (19/23) of cases, and no patient vomited more than four times. This combination regimen provided very good protection against cisplatinum induced emesis.     

The antiemetic efficacy of oral ondansetron plus intravenous dexamethasone in patients with gynecologic malignancies receiving carboplatin-based chemotherapy

PURPOSE: The purpose of this study was to develop a cost-effective prophylactic antiemetic regimen for the prevention of carboplatin-induced emesis. METHODS: Patients being treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center with a carboplatin-based chemotherapy regimen received a prophylactic antiemetic program consisting of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) approximately 30 min prior to chemotherapy. Evaluation of the effectiveness of this antiemetic regimen was performed during a single treatment course. RESULTS: A total of 27 patients (median age, 62; range, 41-83) participated in this phase 2 trial. Three patients received single-agent carboplatin, and 24 were treated with either a carboplatin/paclitaxel or carboplatin/docetaxel regimen. The carboplatin AUC dosing level was 4, 5, or 6 in 6, 5, and 16 individuals, respectively. No patient developed vomiting; 2 (7%) individuals experienced nausea during the 24-h period following chemotherapy administration. CONCLUSION: The combination of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) is an effective prophylactic antiemetic regimen for patients receiving carboplatin-based chemotherapy.     

Prochlorperazine and transdermal scopolamine added to a metoclopramide antiemetic regimen. A controlled comparison

Cisplatin-induced nausea and vomiting occurs both acutely and over a prolonged period of time. These symptoms may be incapacitating and are frequently given as a reason to discontinue therapy. We compared prochlorperazine and transdermal scopolamine when added to a standardized metoclopramide antiemetic regimen. Twenty-seven patients receiving cisplatin at 100 mg/m2 were randomly assigned to one of the two treatment arms. Patients were observed during chemotherapy and answered a standard questionnaire 24-26 hours later. Among similar treatment groups no differences were seen regarding the number of emetic events, level of nausea, degree of sedation or overall acceptability of one treatment arm or another. While not superior to prochlorperazine, transdermal scopolamine is a useful antiemetic agent and can be combined with metoclopramide in an attempt to reduce cisplatin-induced nausea and vomiting. Further evaluation of this approach is needed.     

Antiemetic combination for PAC (cisplatin-adriamycin-cyclophosphamide) chemotherapy-induced emesis in ovarian cancer

Twenty-six patients suffering from disseminated epithelial ovarian cancer (FIGO stages III and IV) under treatment with Cisplatin (80-100 mg/m2 in 8 hours) in combination on the same day with Cyclophosphamide (500 mg/m2 IV) and Adriamycin (50 mg/m2), a severely emetogenic regimen, entered a randomized, double-blind, cross-over trial comparing the antiemetic activity of high-dose IV Metoclopramide (1 mg/kg/dose X 5 doses) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (50 mg PO X 2 doses) plus Thiethylperazine (10 mg IV X 3 doses). The antiemetic combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at the central emetic pathways (dopamine D-2, histamine H-1 and muscarinic cholinergic). This combination significantly reduced the emesis due to chemotherapy when compared with Metoclopramide alone and was also preferred by a significant number of patients after passing through both the antiemetic arms being compared.     

Antiemetic efficacy of high-dose corticosteroids and droperidol in cisplatin-induced emesis: A controlled trial with droperidol and metoclopramide

The nausea and vomiting associated with cisplatin chemotherapy make care of the patient more difficult for nurses and physicians, can cause severe metabolic and pathologic sequelae, and preclude further courses of chemotherapy. Current reports suggest that the two most efficacious agents for antiemetic prophylaxis are metoclopramide and corticosteroids. These two agents in combination with droperidol have been compared in a randomized controlled prospective fashion. Patients had less nausea and vomiting on the steroidal regimen than the nonsteroidal regimen (P less than 0.05), and the duration of nausea and vomiting was significantly less on the steroidal regimen (P less than 0.05). Patients expressed a preference for the steroidal regimen over the nonsteroidal one and the steroidal regimen retained its antiemetic effectiveness through repeated courses of chemotherapy. The results of the study suggest that corticosteroids and droperidol are superior antiemetic agents for cisplatin-induced nausea and vomiting.     

Control of Carboplatin-Induced Emesis with a Fixed Low Dose of Granisetron (0.5 mg) plus Dexamethasone

In an effort to develop a cost-effective antiemetic regimen for carboplatin-based chemotherapy, we examined a fixed (0.5 mg) low dose of granisetron (a new 5-HT₃(serotonin) antagonist) plus dexamethasone (20 mg) in 23 patients with gynecologic malignancies receiving this antineoplastic drug. Nineteen (83%) patients experienced complete control of acute emesis (nausea and vomiting) while 22 (96%) individuals demonstrated complete or major control (≤2 episodes of vomiting, ≤5 episodes of retching, minimal interference with eating) of emetic events. We conclude that this fixed low-dose granisetron plus dexamethasone regimen is a safe, convenient, and cost-effective antiemetic program for individuals receiving carboplatin-based chemotherapy.     

Effectiveness of serotonin-receptor antagonist antiemetic therapy over successive courses of carboplatin-based chemotherapy

PURPOSE: There are extremely limited data available in the general oncology or gynecologic cancer literature to document the effectiveness of antiemetic therapy over multiple courses of cytotoxic chemotherapy. METHODS: To examine this highly clinically relevant issue, we analyzed the complete treatment course of patients with gynecologic cancers receiving carboplatin-based chemotherapy regimens who had participated in one of four institutional serotonin-receptor antagonist antiemetic trials, which had specifically evaluated the benefits of such therapy during only the first treatment course. Medical records were reviewed to examine the development of emesis during subsequent chemotherapy treatment cycles. RESULTS: The 91 patients included in this analysis received a median of 6 courses (range 1-18) of carboplatin (initial AUC dose 4, 5, and 6 in 29, 29, and 32 patients, respectively). All received ondansetron or granisetron plus dexamethasone with every treatment course. Complete control of emesis (no acute or delayed nausea or vomiting) was experienced by 56 (62%) patients during every cycle. Conversely, 20% of women noted one or more episodes of nausea without vomiting and 19% developed at least one incidence of vomiting. In no case was emesis considered to be severe (grade 3), and no patient required either discontinuation of carboplatin or a dose reduction due to the development of emesis. CONCLUSION: In the large majority of patients, serotonin-receptor antagonist antiemetic therapy, administered in combination with dexamethasone, is highly effective over multiple courses in preventing significant carboplatin-induced nausea and vomiting.     

Cisplatin, vincristine, methotrexate and bleomycin (POMB) as initial or palliative chemotherapy for carcinoma of the cervix

Summary. Chemotherapy was given as initial therapy to 12 women with very advanced squamous cell carcinoma of the cervix and to 19 women with recurrent disease. They received a median of four courses of POMB which comprised vincristine 1.0 mg/m2 and methotrexate 300 mg/m2 followed by folinic acid rescue, bleomycin 30 mg as a 48-h infusion or intramuscular injection and cisplatin 100 mg/m2 as a 12-h infusion. Two of the 14 assessable patients with recurrent disease (14%) had a complete response with no disease found histologically in one, and seven (50%) had a partial response. Although the actuarial median survival of all 19 patients with recurrent disease was 8 months, five patients have remained free from tumour progression for a median of 17 months from start of chemotherapy. Six of the 10 assessable patients receiving initial chemotherapy (60%) had a complete response (confirmed histologically in two) and two (20%) had a partial response. Nine patients had additional treatment with radiotherapy and or surgery. Although only four of the patients remain disease-free at 61, 51, 7 and 4 months, all but two were initially FIGO stage IV. Although cisplatin-induced emesis is controllable and the side-effects of methotrexate can be avoided, the POMB regimen remains potentially toxic. The small number of patients with very advanced disease who are long-term survivors prompts us to study further the role of aggressive chemotherapy as the initial treatment of patients with visceral or nodal involvement from carcinoma of the cervix.     

Cisplatin, vincristine, methotrexate and bleomycin (POMB) as initial or palliative chemotherapy for carcinoma of the cervix

Chemotherapy was given as initial therapy to 12 women with very advanced squamous cell carcinoma of the cervix and to 19 women with recurrent disease. They received a median of four courses of POMB which comprised vincristine 1.0 mg/m2 and methotrexate 300 mg/m2 followed by folinic acid rescue, bleomycin 30 mg as a 48-h infusion or intramuscular injection and cisplatin 100 mg/m2 as a 12-h infusion. Two of the 14 assessable patients with recurrent disease (14%) had a complete response with no disease found histologically in one, and seven (50%) had a partial response. Although the actuarial median survival of all 19 patients with recurrent disease was 8 months, five patients have remained free from tumour progression for a median of 17 months from start of chemotherapy. Six of the 10 assessable patients receiving initial chemotherapy (60%) had a complete response (confirmed histologically in two) and two (20%) had a partial response. Nine patients had additional treatment with radiotherapy and or surgery. Although only four of the patients remain disease-free at 61, 51, 7 and 4 months, all but two were initially FIGO stage IV. Although cisplatin-induced emesis is controllable and the side-effects of methotrexate can be avoided, the POMB regimen remains potentially toxic. The small number of patients with very advanced disease who are long-term survivors prompts us to study further the role of aggressive chemotherapy as the initial treatment of patients with visceral or nodal involvement from carcinoma of the cervix.     

High-dose metoclopramide as an antiemetic in patients receiving cis-platinum-based combination chemotherapy

Thirty-seven patients with advanced malignancies, who received cis-platinum-based combination chemotherapy, were evaluated for the antiemetic efficacy of high-dose metoclopramide. Most of the patients suffered from ovarian carcinoma. The dose of metoclopramide was 7.5 or 10 mg/kg per course. A total of 69 courses were given to 37 patients and in 22% of the courses, nausea and vomiting were eliminated altogether. In an additional 48% of the courses, a partial protection from chemotherapy-induced emesis was evident. No serious side effects were observed. The administration of high-dose metoclopramide is recommended for prevention of cis-platinum chemotherapy-induced emesis.     

自噬在顺铂致宫颈癌Hela细胞死亡中的作用

目的：研究自噬在顺铂致宫颈癌Hela细胞死亡中的作用,以及自噬基因Beclin 1对Hela细胞顺铂敏感性的影响.方法：不同浓度顺铂作用Hela细胞后,丹磺酰戊二胺（MDC）法观察细胞中自噬体的形成,蛋白质印迹法（Western blot）检测自噬基因Beclin 1和LC3蛋白的表达;将自噬基因Beclin 1的真核表达载体pcDNA3.1（＋）-Beclin1转染Hela细胞,Western blot检测Beclin 1在Hela细胞中的蛋白表达,四甲基偶氮唑蓝（MTT）比色法检测顺铂对Hela半数抑制浓度（IC50）的变化,流式细胞仪检测自噬细胞与凋亡细胞的百分率.结果：顺铂作用Hela细胞后,细胞内自噬体形成增加,自噬蛋白Beclin 1和LC3表达增加,且均呈现浓度依赖性（P＜0.05）;pcDNA3.1（＋）-Beclin 1转染Hela细胞后,Beclin 1蛋白表达增加（P＜0.05）,MTT检测IC50由转染前的1.0 mg/L下降到0.5 mg/L,凋亡细胞百分率和自噬细胞百分率均升高,与对照组相比差异有统计学意义（P＜0.05）.结论：自噬参与了顺铂对宫颈癌Hela细胞的细胞毒性作用,自噬基因Beclin 1过表达能够增加Hela细胞对顺铂的敏感性.     

Weekly cisplatin ± glutathione in relapsed ovarian carcinoma

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450–650 mg m⁻² were randomized to receive cisplatin 50 mg m⁻² weekly ± 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.     

Methylprednisolone in cis-platinum induced nausea and emesis: a placebo-controlled trial

In a double-blind, placebo-controlled trial, the antiemetic efficacy of a total of 1-2 g methylprednisolone sodium succinate (MPSS) alone versus placebo was evaluated over the first three courses of chemotherapy in a group of 27 women receiving moderate to high-dose cis-platinum (50-118 mg/m2) for ovarian or cervical carcinomas. Antiemetic protection was classified as total (no emesis), major (one or two bouts), minor (three to five bouts), or minimal (six or more bouts). Total or major protection occurred in 10/26 (38.5%) of the MPSS cycles and in 6/24 (25%) of the placebo cycles (NS). A significant number of placebo patients (7/14 placebo versus 1/13 MPSS, P = 0.02) dropped out of the study due to lack of efficacy. Patient evaluations completed 24 hr before and after each course of chemotherapy indicated no treatment effect on pain, appetite, nausea, drowsiness, anxiety, sense of well-being, or sleep. Physician and patient global evaluations of antiemetic efficacy favored treatment with MPSS. Evidence of the efficacy of single-drug MPSS antiemetic therapy during non-cis-platinum or low-dose cis-platinum (less than 50 mg/m2) chemotherapy can be found in the literature. The results of this study, however, do not support the use of MPSS alone with high-dose cis-platinum chemotherapy.     

Epirubicin: clinical toxicity during the phase II program in endometrial and cervical cancer.

We have evaluated the clinical toxicity of Epirubicin 80 mg/m2 i.v., every 3 weeks in 58 patients with FIGO III-IV endometrial adenocarcinoma or squamous uterine cervix carcinoma. The median age of the whole group was 59 years (37-77); 37 patients were previously treated with radiotherapy and two with cisplatin based chemotherapy. The median KI at entry was 80. A total of 308 courses of chemotherapy were administered with a median of 5 per patient. Overall toxicity data shows that this dose level is associated with mild haematological toxicity with only two cases having grade 3 (WHO) leukopenia. Nine patients suffered emesis in spite of prophylactic therapy and were classified as grade 3. One case presented grade four diarrhoea but the relation with the antineoplastic treatment was uncertain. One woman with hepatic dysfunction at entry had grade 3 leukopenia, developed pneumonia and died. The median total cumulative dose of EPI was 360 mg/m2 (160-880) with 19 cases exposed to cumulative doses higher than 550 mg/m2. Congestive heart failure was not observed. Our data confirm the safety of EPI at these dose levels and suggest the possibility of developing new trials with higher doses of this anthracycline analog.     

A phase I study of concurrent cisplatin chemotherapy in patients with carcinoma of the cervix receiving pelvic radiotherapy

The purpose of this study was to evaluate the maximum tolerated dose (MTD) of weekly cisplatin in a sample population of South African patients with cervical carcinoma, when given in combination with radical pelvic irradiation. Patients with cervical carcinoma stage IB2-IIIB (without hydronephrosis) received up to six cycles of cisplatin at weekly intervals. Groups consisting of three patients each were treated at each of the three predetermined dose levels of cisplatin (20, 25, and 30 mg/m(2)). Eighteen patients were treated and evaluated for toxicity. All the patients who received 20 mg/m(2) (n = 3) and 25 mg/m(2) (n = 3) cisplatin had no dose-limiting toxicity (DLT). Four of the 12 patients who were given cisplatin 30 mg/m(2) experienced DLT with rising serum creatinine and declining creatinine clearance. The minimum creatinine clearance was 22 mL/min. The highest serum creatinine was 174 mumol/L. This study showed that a weekly dose of 25 mg/m(2) of cisplatin was the MTD when used in combination with pelvic irradiation for this sample of patients. This dose is lower than the recommended dose of cisplatin 40 mg/m(2)/week. The patients in this study may have reduced tolerance to higher doses of cisplatin, when compared to patients from Western countries.     

Betamethasone-dixyrazine versus betamethasone-metoclopramide as antiemetic treatment of cisplatin-doxorubicin-induced nausea in ovarian carcinoma patients

In a prospective and randomized pilot study two antiemetic regimens comprising dixyrazine (240 mg) and metoclopramide (10 mg/kg) in high doses and given by continuous i.v. infusion were compared as means of preventing cisplatin-doxorubicin-induced nausead and vomiting. Twenty chemotherapy-naive women with the diagnosis of ovarian carcinoma stages III-IV (FIGO) were included in the study. Medium doses (50 mg/m2) of cisplatin and doxorubicin were used. The antiemetic drugs (the above-mentioned ones plus betamethasone 20 mg, and biperiden 5 mg) were administered by small portable infusion pumps during 24 hours. The effects and adverse reactions were evaluated during the course of chemotherapy and the first week thereafter. Complete protection from nausea during the first 24 hours was achieved in 80% by the metoclopramide cocktail and in 50% by the dixyrazine combination. During days 2-7 there were no significant differences between the two regimens. Vomiting was not satisfactorily prevented by either treatment. Sedation was significantly more common after dixyrazine than after metoclopramide but other recorded side effects were similar for the two antiemetic regimens. Serum concentrations of dixyrazine and metoclopramide were determined.