Support Care Cancer DOI 10.1007/s00520-015-2865-8
ORIGINAL ARTICLE
Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study Young Mi Seol 1 & Hyo Jeong Kim 1 & Young Jin Choi 1 & Eun Mi Lee 2 & Yang Soo Kim 2 & Sung Yong Oh 3 & Su Jin Koh 4 & Jin Ho Baek 4 & Won Sik Lee 5 & Young Don Joo 6 & Hyun Gi Lee 7 & Eun Young Yun 7 & Joo Seop Chung 1
Received: 12 January 2015 / Accepted: 27 July 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to
* Joo Seop Chung [email protected] 1
Division of Hemato-Oncology, Department of Internal Medicine, Pusan National University Hospital Medical Research Institute, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, South Korea
2
Division of Hemato-Oncology, Department of Internal Medicine, Kosin University Gospel Hospital, Busan, South Korea
3
Division of Hemato-Oncology, Department of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, Busan, South Korea
4
Division of Hemato-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
5
Division of Hemato-Oncology, Department of Internal Medicine, Inje University Paik Hospital, Inje University College of Medicine, Busan, South Korea
6
Division of Hemato-Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea
7
Department of Biostatistician, Pusan National University Hospital Medical Research Institute, Busan, South Korea
deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. Material and method A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, openlabel, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0–24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Results Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.6–4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients’ satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe.
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Conclusion Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC. Keywords CINV . Transdermal granisetron . Palonosetron
Introduction Nausea and vomiting are the most problematic symptoms experienced by patients with cancer who are receiving chemotherapy [1]. Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on patients’ quality of life, which is frequently a major cause factor for treatment abandonment [2]. Many neurotransmitters in the central nervous system and the afferent vagus nerve endings of the gastrointestinal tract are involved in CINV although the exact mechanisms of CINV are not fully understood [3, 4]. However, among neurotransmitters, serotonin (5-hydroxytryptamine [5-HT3]) is considered to play a main role in initiating CINV. 5-Hydroxytryptamine 3 receptor antagonists (5-HT3RAs) are now the standard therapy for preventing CINV [5, 6]. The first generation of 5-HT3RAs, such as ondansetron, granisetron, dolasetron, and tropisetron, shows considerable efficacy in preventing acute CINV, with acute responses for single agents ranging from 50 to 70 % [7]. Therefore, according to current evidence-based and consensus guidelines, these 5-HT3RAs are equivalent with regard to efficacy and are therapeutically interchangeable when used at equipotent doses [8–10]. Although 5-HT3RAs are effective for the prevention of CINV, a substantial portion of patients who received moderately or highly emetogenic chemotherapy still suffer from acute and delayed CINV [11]. Therefore, there is a need to use newly developed and clinically available agents to improve control rates for acute and delayed CINV. Among 5-HT3RAs, the granisetron transdermal delivery system (GTDS; Sancuso®, ProStrakan Pharmaceuticals) and palonosetron are recently developed [12]. Transdermal delivery offers a convenient non-invasive option for sustained antiemetic administration and could enable continuous antiemetic prophylaxis throughout a multi-day chemotherapy regimen. Moreover, in the comparative clinical studies, GTDS had noninferior efficacy in the acute and delayed CINV than other first-generation 5-HT3RAs [13]. Palonosetron, the secondgeneration 5-HT3RA and a potent and highly selective 5HT3RAs with strong binding affinity to the receptor and a long plasma-elimination half-life (about 40 h), has shown efficacy as a single-dose treatment in preventing both acute and delayed CINV associated with moderately and highly emetogenic chemotherapy [14–17]. The most recent metaanalysis of randomized controlled trials comparing palonosetron with other available 5-HT3RAs demonstrated that palonosetron was significantly more effective in
preventing acute and delayed nausea and vomiting for both moderately and highly emetogenic chemotherapy agents [18]. To our knowledge, there is no study that has compared the efficacy of GTDS with palonosetron in the prevention of CINV. Therefore, the present study was aimed to compare the efficacy and tolerability of the GTDS to them of palonosetron for the control of CINV following moderately emetogenic chemotherapy (MEC).
Methods Patients and treatment The present study was conducted at six tertiary referral hospitals in Korea as a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study. Eligible patients were men and women aged 20 or over who were scheduled to receive a MEC, combining 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) in two consecutive chemotherapy cycles. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and to be expected over 3 months of survival. Exclusion criteria were the following: severe, uncontrolled, concurrent illness other than neoplasia; asymptomatic metastases to the brain; seizure disorder needing anticonvulsants unless clinically stable; gastric outlet or intestinal obstruction; any vomiting, retching, or grade 2 or higher nausea according to Common Terminology Criteria for Adverse Events (CTCAE); a known hypersensitivity to palonosetron, granisetron, or other 5-HT3RAs or dexamethasone ingredients; patients who met the following discontinuation criteria were withdrawn from the study: appeared not to be eligible; received an antiemetic drug within 72 h before administration of study drug; and vomiting, retching, or grade 2 or higher nausea according to CTCAE within 72 h before administration of study drug. Eligible patients were randomized to GP or PG group. GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (intravenous (IV) 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC in two consecutive cycles, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle (Fig. 1). Due to the gradual dermal penetration of GTDS, patches were applied to the upper arm for 24–48 h before the start of chemotherapy by the investigator or the patient and left in place for 7 days. Intravenous injection of palonosetron 0.25 mg was administered at 30 min before chemotherapy on day 1. Prophylactic dexamethasone (IV 10 mg) within 30 min before chemotherapy on day 1 was treated. This study was approved by the Institutional Review Board of participating hospitals, and written informed consent was obtained from each patient.
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Fig. 1 Cross-over design GP group is assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second cycle before receiving MEC in two consecutive cycles, and PG group is assigned to receive palonosetron in the first cycle and GTDS in the second cycle
Efficacy parameters The primary end point was the proportion of patients achieving a complete response (CR; defined as no
Fig. 2 Trial profile
emetic episode and no use of rescue medication) during the first 24 h following MEC. Secondary end points were the following: the proportion of patients achieving a CR during the delayed 24–72-h time period and the cumulative overall 0–72-h time period, as well as CR rates during successive 24-h time periods (i.e., 24–48 h, 48–72 h); the proportion of patients achieving complete control (CC; defined as no emetic episode, no need for rescue medication, and no more than mild nausea) for the 0–24, 24–72, and 0–72 h intervals; the proportion of patients achieving total control (TC; defined as no emetic episode, no nausea and no need for rescue medication) for the 0–24, 24–72, and 0–72 h intervals number of emetic episodes daily and cumulatively for the 24–72 and 0–72 h intervals; severity of nausea measured daily for the 0–72 h interval; patient global satisfaction with antiemetic therapy and quality of life (QoL), measured via a modified functional living index-emesis (FLI-E) questionnaire, which specifically addresses the impact
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of nausea and emesis on daily functioning, for 0–72 h interval; higher score represented higher level of symptoms.
for a period of 15 days (30 days for serious AEs); vital sign measurements. Statistical analysis
Evaluation procedures Consenting patients were initially screened for eligibility within 7 days prior to the study commencement as following: physical examination; vital signs and weight; laboratory tests [complete blood count (CBC) with differential, platelet counts, blood chemistry, and urine analysis]; past medical history; concomitant medications; and history of nausea and vomiting. All subjects were followed for a total of 15 days. Patient diaries were used to record the following: emetic episodes; use of rescue medication; patch adhesion; and severity of nausea, which was evaluated daily until day 4 assessed by the CTCAE. Safety was assessed by the following: adverse event (AE) reporting
The hypothesis of the study was that GTDS was non-inferior to the palonosetron using a maximum δ of 15 % for CR at 24 h. Sample size was calculated by Siz program ver. 1.0 (Cytel Inc., Cambridge, MA, USA). Allowing an α error of 2.5 % and a ß error of 20 %, it was estimated that 148 patients were distributed into two groups based on the assumption of a responder rate of 72.2 % in the palonosetron group, and GTDS group would be required to show 15 % difference. Assuming a 10 % drop out rate, 83 patients per group needed to be enrolled. Chi-square or Fisher exact test was used for statistical analysis. A two-sided p < 0.05 was considered statistically significant. Statistical analyses were performed using the SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA).
Table 1 Patient demographics and baseline characteristics (ITT cohort, n = 188) Age (years) Gender Smoking
Alcohol consumption
Previous radiotherapy Previous chemotherapy Chemotherapy regimen ECOG
Weight (kg) Height (cm) QTc interval
GP (N = 91)
PG (N = 97)
p valueb
Mean ± SD Min-max Male Female Non-smoker Smoker Ex-smoker
58.88 ± 10.53 29–85 54 (59.3) 37 (40.7) 66 (72.5) 6 (6.6) 19 (20.9)
60.41 ± 10.06 32–83 63 (65.0) 34 (35.1) 74 (76.3) 7 (7.2) 16 (16.5)
0.309a
None 1–2 times/week 3–4 times/week 5–6 times/week
77 (84.6) 9 (9.9) 3 (3.3) 2 (2.2)
88 (90.7) 6 (6.2) 1 (1.0) 1 (1.0)
0.595c
More than 7 times/week Yes No Yes No FOLFOX FOLFIRI 0 1 2 Mean ± SD Min-max Mean ± SD Min-max Mean ± SD Min-max
0 (0.0) 6 (6.6) 85 (93.4) 60 (65.9) 31 (34.1) 25 (24.5) 66 (72.5) 30 (33.0) 54 (59.3) 7 (7.7) 57.10 ± 0.95 32.6–84.0 162.1 ± 8.38 134.0–178.0 429.9 ± 24.82 353–493
1 (1.0) 9 (9.3) 88 (90.7) 70 (72.2) 27 (27.8) 35 (36.1) 62 (63.9) 33 (34.0) 53 (54.6) 11 (11.3) 59.94 ± 8.83 43.5–88.4 162.9 ± 7.37 144.1–180.0 424.3 ± 42.36 94–514
ITT intension to treat, SD standard deviation a
t test
b
Chi-square test
c
Fisher’s exact test
0.428b 0.741b
0.497b 0.355b 0.206b 0.654a
0.031a 0.471a 0.270a
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Results Patient characteristics and baseline demographics Between August 17, 2012, and February 14, 2014, 196 patients from six institutions in Korea were randomized to GP or PG group. Eight patients did not receive first chemotherapy cycle, and 22 patients did not receive second chemotherapy cycle. Three hundred forty-eight cycles (173 in the palonosetron cycle and 175 in the GTDS cycle) were assessed for safety. Three hundred thirty-three cycles were included in the per protocol analysis—165 cycles for the GTDS and 168 cycles for the palonosetron were analyzed (Fig. 2). The distribution of patients by gender, age, performance status, body surface area, history of alcohol consumption, and chemotherapy regimen were similar between the two groups (Table 1). Efficacy The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles, and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.6–4.4). There was no significant difference in complete response rate of acute phase after first cycle and the Table 2
a
second cycle between GP group and PG group (p = 0.405, p = 0.074) (Table 2). The stratified analysis showed that GTDS was not different to palonosetron in terms of the risk factors of CINV, such as female sex, age, alcohol history. For secondary efficacy analyses, similar proportions of cycles with a complete response were noted in the palonosetron cycle and GTDS cycle during the overall 0–72-h period. Response was assessed every day; the proportion of cycles with a CR was not significant difference in the palonosetron cycle and GTDS cycle (Fig. 3a). The proportion of cycles with a CC and TC was not significant difference in the palonosetron cycle and GTDS cycle during the acute period and the overall period (Fig. 3b, c). The severity of nausea, vomiting, and/or retching per day and total days of treatment was not different between the groups. In the both groups, small portion of patients had severe nausea during acute phase (3 of 175 patients in the GTDS cycle and 1 of 173 patients in the palonosetron cycle). Overall satisfaction with antiemetic therapy was measured by FLI-E. FLI-E scores of patients in the palonosetron cycle were equal to those of patients in the GTDS cycle during 0–72 h after the start of chemotherapy in the GTDS cycle [median score, 1626 (range 1341–1751.5)] vs. in the palonosetron cycle [median
Complete responses (defined as no emetic episodes and no use of rescue medication) difference between two groups in the per protocol cohort
n.s. (not significant):chi-square test
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Patch adhesion The adhesive properties of GTDS were assessed. Of 175 cycles receiving the GTDS, 112 (64 %) had ≥90 % adhesion and 158 (90.3 %) had ≥75 % adhesion. Three patients (1.7 %) had a completely detached patch. Grade 3 skin rash occurred in a patient, so GTDS was removed. Tolerability A total of 368 cycles were evaluable for safety. Total 96 AEs were observed. Most AEs were mild in intensity, and 80 (84 %) of them were as associated with the patient’s cancer and/or chemotherapy treatment. Post hoc analysis revealed no differences in AEs commonly associated with 5-HT3RAs therapy (i.e., constipation, diarrhea, insomnia). Grade 3 skin rash occurred at the attached area in a patient. Table 3 provides a list of treatment-emergent, drugrelated AEs. Total 24 (6.62 %) adverse drug reactions (i.e., AEs considered to be treatment related) occurred in 17 patients. Among them, 12 events (50 %, 8 patients) occurred in GTDS cycle and 12 events (50 %, 9 patients) in palonosetron cycle.
Discussion
Fig. 3 a Complete response of CINV per day of chemotherapy. The GTDS displayed non-inferiority to palonosetron during the acute phase: complete response was achieved by 75.2 % of patients in the GTDS cycles, and 79.8 % in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.5–4.3). b Complete control of CINV per day of chemotherapy. c Total control of CINV per day of chemotherapy
score, 1648 (range 1311.0–1791.0)]. But FLI-E scores of GTDS cycle in GP group patients were lower than those of palonosetron cycle (median 1589.0 in GTDS cycle, median 1666.5 in palonosetron cycle).
Table 3 Treatment-related adverse event occurring in each treatment cycle in the safety cohort (N = 348)
The current randomized trial represents the direct comparison of the efficacy of a GTDS with the second-generation 5-HT3RA by cross-over method. Palonosetron was significantly more effective than other first-generation 5HT3RAs (containing oral, IV granisetron) in preventing acute and delayed nausea and vomiting for both moderately and highly emetogenic chemotherapy agents. This fact led to the hypothesis that palonosetron would have stronger and longer antiemetic effects compared with granisetron transdermal delivery system. The results of the primary efficacy assessments indicated that the GTDS was non-inferior to palonosetron in the control of CINV in patients receiving MEC. Although previous comparative studies of palonosetron with ondansetron, granisetron, and dolasetron have showed superior antiemetic effects of palonosetron [19], extended release of
Drug-related AEs
GTDS (N = 175), n (%)
Palonosetron (N = 173), n (%)
Constipation Diarrhea Insomnia Rash
5 (2.7 2 (1.1 4 (2.1 1 (0.5
9 (5.0 %) 1 (0.6 %) 2 (1.1 %) 0 (0 %)
AEs adverse events
%) %) %) %)
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granisetron over 7 days may enhance the duration of antiemetic effect. Transdermal delivery of granisetron carries an important advantage over repeated oral dosing in terms of patient convenience, compliance, and reduced pill burden. It may be especially valuable in patients for whom swallowing is difficult or absorption of oral medications is uncertain, such as patients with gastrointestinal surgery [19]. The convenience of the GTDS is supported by its good adhesive properties, as presented in the present study. Effectiveness of transdermal granisetron is influenced by duration of application because of its delivery mechanism. However, actual application time of the patch by patients was not clearly investigated in the process of the study. To achieve therapeutic levels of granisetron more rapidly and improve the effectiveness, the addition of oral or intravenous granisetron to the first day of GTDS therapy should be included in further investigations. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by individual patient variability (e.g., age, sex, prior chemotherapy, history of alcohol use). In this study, cross-over design can offset individual patient variability and find the preferred patients characteristics to each antiemetic treatment. The proportion of no emetic episodes in this study was similar to those reported previously with palonosetron 0.25 mg IV bolus. The proportion of no emetic episodes ranges from 63 to 81 % for acute CINV, 54 to 74 % for delayed CINV, and 46 to 69.3 % for overall CINV in other similarly designed phase III trials of palonosetron for prevention of moderate emetogenic risk of chemotherapy [16, 18]. The consistency of these rates with those reported in the current study (80.4 % for acute CINV, 68.5 % for delayed CINV, and 62.5 % for overall CINV) highlights the validity of this study. GTDS therapy improved control of CINV, particularly for delayed emesis, and was not inferior to palonosetron on any day of the chemotherapy. All treatments were well tolerated, with no significant differences between the groups. Most AEs (including serious AEs) were assessed as to be unlikely related to study medication but rather to the patient’s underlying cancer or chemotherapeutic treatment. Constipation was the most frequently reported drug-related AE in all treatment groups. There were no significant treatmentrelated changes in laboratory measures, vital signs, or ECG. The study showed similar safety profile compared to previous GTDS studies and safety of other drugs in the same class. And the degrees of adverse reactions are low. This study demonstrated GTDS is non-inferior to palonosetron for relieving CINV in patients receiving MEC and patient’s satisfaction with GTDS being higher than with palonosetron. On the basis of the results of
trial, GTDS could be a good therapeutic option for patients receiving MEC. Conflict of interest The authors declare that they have no competing interests.
References 1.
2.
3.
4.
5.
6. 7.
8.
9.
10.
11.
12.
13.
14.
15.
Griffin AM, Butow PN, Coates AS, et al (1996) On the receiving end. V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 7:189–195 Almeida EP, Gutierrez MG, Adami NP (2004) Monitoring and evaluation of side effects of chemotherapy in patients with colon cancer. Rev Lat Am Enfermagem 12:760–766 Andrews PL, Sanger GJ (2002) Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2:650–656 Fukui H, Yamamoto M, Sato S (1992) Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. Jpn J Pharmacol 59:221–226 Balfour JA, Goa KL (1997) Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs 54:273–298 Hasler WL (1999) Serotonin receptor physiology: relation to emesis. Dig Dis Sci 44(8 suppl):108S–113S Hesketh PJ (2000) Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Investig 18:163–173 Forni C, Ferrari S, Loro L, et al (2000) Granisetron, tropisetron, and ondansetron in the prevention of acute emesis induced by a combination of cisplatin–adriamycin and by high-dose ifosfamide delivered in multi-day continuous infusions. Support Care Cancer 8: 131–133 Gralla RJ, Osoba D, Kris MG, et al (1999) Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 17:2971–2994 Koeller JM, Aapro MS, Gralla RJ, et al (2002) Antiemetic guidelines: creating a more practical approach. Support Care Cancer 10: 519–522 Kaizer L, Warr D, Hoskins P, et al (1994) Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: a phase III trial by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12:1050–1057 Howell J, Smeets J, Drenth HJ, Gill D (2009) Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapyinduced nausea and vomiting. J Oncol Pharm Pract 15:223–231 Boccia RV, Gordan LN, Clark G, et al (2011) Sancuso Study Group. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer 19(10):1609–1617 Aapro MS, Grunberg SM, Manikhas GM, et al (2006) A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 17:1441–1449 Eisenberg P, Figueroa-Vadillo J, Zamora R, et al (2003) Improved prevention of moderately emetogenic chemotherapy-induced
Support Care Cancer nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 98:2473–2482 16. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A (2004) Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose ranging clinical study. Ann Oncol 15:330–337 17. Gralla R, Lichinitser M, Van Der Vegt S, et al (2003) Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial
18.
19.
comparing single doses of palonosetron with ondansetron. Ann Oncol 14:1570–1577 Botrel TE, Clark OA, Clark L, et al (2011) Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer 19:823–832 Kraut L, Fauser AA (2001) Anti-emetics for cancer chemotherapy induced emesis: potential of alternative delivery systems. Drugs 61: 1553–1562
ORIGINAL ARTICLE
Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study Young Mi Seol 1 & Hyo Jeong Kim 1 & Young Jin Choi 1 & Eun Mi Lee 2 & Yang Soo Kim 2 & Sung Yong Oh 3 & Su Jin Koh 4 & Jin Ho Baek 4 & Won Sik Lee 5 & Young Don Joo 6 & Hyun Gi Lee 7 & Eun Young Yun 7 & Joo Seop Chung 1
Received: 12 January 2015 / Accepted: 27 July 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to
* Joo Seop Chung [email protected] 1
Division of Hemato-Oncology, Department of Internal Medicine, Pusan National University Hospital Medical Research Institute, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, South Korea
2
Division of Hemato-Oncology, Department of Internal Medicine, Kosin University Gospel Hospital, Busan, South Korea
3
Division of Hemato-Oncology, Department of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, Busan, South Korea
4
Division of Hemato-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
5
Division of Hemato-Oncology, Department of Internal Medicine, Inje University Paik Hospital, Inje University College of Medicine, Busan, South Korea
6
Division of Hemato-Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea
7
Department of Biostatistician, Pusan National University Hospital Medical Research Institute, Busan, South Korea
deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. Material and method A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, openlabel, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0–24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Results Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.6–4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients’ satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe.
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Conclusion Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC. Keywords CINV . Transdermal granisetron . Palonosetron
Introduction Nausea and vomiting are the most problematic symptoms experienced by patients with cancer who are receiving chemotherapy [1]. Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on patients’ quality of life, which is frequently a major cause factor for treatment abandonment [2]. Many neurotransmitters in the central nervous system and the afferent vagus nerve endings of the gastrointestinal tract are involved in CINV although the exact mechanisms of CINV are not fully understood [3, 4]. However, among neurotransmitters, serotonin (5-hydroxytryptamine [5-HT3]) is considered to play a main role in initiating CINV. 5-Hydroxytryptamine 3 receptor antagonists (5-HT3RAs) are now the standard therapy for preventing CINV [5, 6]. The first generation of 5-HT3RAs, such as ondansetron, granisetron, dolasetron, and tropisetron, shows considerable efficacy in preventing acute CINV, with acute responses for single agents ranging from 50 to 70 % [7]. Therefore, according to current evidence-based and consensus guidelines, these 5-HT3RAs are equivalent with regard to efficacy and are therapeutically interchangeable when used at equipotent doses [8–10]. Although 5-HT3RAs are effective for the prevention of CINV, a substantial portion of patients who received moderately or highly emetogenic chemotherapy still suffer from acute and delayed CINV [11]. Therefore, there is a need to use newly developed and clinically available agents to improve control rates for acute and delayed CINV. Among 5-HT3RAs, the granisetron transdermal delivery system (GTDS; Sancuso®, ProStrakan Pharmaceuticals) and palonosetron are recently developed [12]. Transdermal delivery offers a convenient non-invasive option for sustained antiemetic administration and could enable continuous antiemetic prophylaxis throughout a multi-day chemotherapy regimen. Moreover, in the comparative clinical studies, GTDS had noninferior efficacy in the acute and delayed CINV than other first-generation 5-HT3RAs [13]. Palonosetron, the secondgeneration 5-HT3RA and a potent and highly selective 5HT3RAs with strong binding affinity to the receptor and a long plasma-elimination half-life (about 40 h), has shown efficacy as a single-dose treatment in preventing both acute and delayed CINV associated with moderately and highly emetogenic chemotherapy [14–17]. The most recent metaanalysis of randomized controlled trials comparing palonosetron with other available 5-HT3RAs demonstrated that palonosetron was significantly more effective in
preventing acute and delayed nausea and vomiting for both moderately and highly emetogenic chemotherapy agents [18]. To our knowledge, there is no study that has compared the efficacy of GTDS with palonosetron in the prevention of CINV. Therefore, the present study was aimed to compare the efficacy and tolerability of the GTDS to them of palonosetron for the control of CINV following moderately emetogenic chemotherapy (MEC).
Methods Patients and treatment The present study was conducted at six tertiary referral hospitals in Korea as a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study. Eligible patients were men and women aged 20 or over who were scheduled to receive a MEC, combining 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) in two consecutive chemotherapy cycles. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and to be expected over 3 months of survival. Exclusion criteria were the following: severe, uncontrolled, concurrent illness other than neoplasia; asymptomatic metastases to the brain; seizure disorder needing anticonvulsants unless clinically stable; gastric outlet or intestinal obstruction; any vomiting, retching, or grade 2 or higher nausea according to Common Terminology Criteria for Adverse Events (CTCAE); a known hypersensitivity to palonosetron, granisetron, or other 5-HT3RAs or dexamethasone ingredients; patients who met the following discontinuation criteria were withdrawn from the study: appeared not to be eligible; received an antiemetic drug within 72 h before administration of study drug; and vomiting, retching, or grade 2 or higher nausea according to CTCAE within 72 h before administration of study drug. Eligible patients were randomized to GP or PG group. GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (intravenous (IV) 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC in two consecutive cycles, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle (Fig. 1). Due to the gradual dermal penetration of GTDS, patches were applied to the upper arm for 24–48 h before the start of chemotherapy by the investigator or the patient and left in place for 7 days. Intravenous injection of palonosetron 0.25 mg was administered at 30 min before chemotherapy on day 1. Prophylactic dexamethasone (IV 10 mg) within 30 min before chemotherapy on day 1 was treated. This study was approved by the Institutional Review Board of participating hospitals, and written informed consent was obtained from each patient.
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Fig. 1 Cross-over design GP group is assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second cycle before receiving MEC in two consecutive cycles, and PG group is assigned to receive palonosetron in the first cycle and GTDS in the second cycle
Efficacy parameters The primary end point was the proportion of patients achieving a complete response (CR; defined as no
Fig. 2 Trial profile
emetic episode and no use of rescue medication) during the first 24 h following MEC. Secondary end points were the following: the proportion of patients achieving a CR during the delayed 24–72-h time period and the cumulative overall 0–72-h time period, as well as CR rates during successive 24-h time periods (i.e., 24–48 h, 48–72 h); the proportion of patients achieving complete control (CC; defined as no emetic episode, no need for rescue medication, and no more than mild nausea) for the 0–24, 24–72, and 0–72 h intervals; the proportion of patients achieving total control (TC; defined as no emetic episode, no nausea and no need for rescue medication) for the 0–24, 24–72, and 0–72 h intervals number of emetic episodes daily and cumulatively for the 24–72 and 0–72 h intervals; severity of nausea measured daily for the 0–72 h interval; patient global satisfaction with antiemetic therapy and quality of life (QoL), measured via a modified functional living index-emesis (FLI-E) questionnaire, which specifically addresses the impact
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of nausea and emesis on daily functioning, for 0–72 h interval; higher score represented higher level of symptoms.
for a period of 15 days (30 days for serious AEs); vital sign measurements. Statistical analysis
Evaluation procedures Consenting patients were initially screened for eligibility within 7 days prior to the study commencement as following: physical examination; vital signs and weight; laboratory tests [complete blood count (CBC) with differential, platelet counts, blood chemistry, and urine analysis]; past medical history; concomitant medications; and history of nausea and vomiting. All subjects were followed for a total of 15 days. Patient diaries were used to record the following: emetic episodes; use of rescue medication; patch adhesion; and severity of nausea, which was evaluated daily until day 4 assessed by the CTCAE. Safety was assessed by the following: adverse event (AE) reporting
The hypothesis of the study was that GTDS was non-inferior to the palonosetron using a maximum δ of 15 % for CR at 24 h. Sample size was calculated by Siz program ver. 1.0 (Cytel Inc., Cambridge, MA, USA). Allowing an α error of 2.5 % and a ß error of 20 %, it was estimated that 148 patients were distributed into two groups based on the assumption of a responder rate of 72.2 % in the palonosetron group, and GTDS group would be required to show 15 % difference. Assuming a 10 % drop out rate, 83 patients per group needed to be enrolled. Chi-square or Fisher exact test was used for statistical analysis. A two-sided p < 0.05 was considered statistically significant. Statistical analyses were performed using the SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA).
Table 1 Patient demographics and baseline characteristics (ITT cohort, n = 188) Age (years) Gender Smoking
Alcohol consumption
Previous radiotherapy Previous chemotherapy Chemotherapy regimen ECOG
Weight (kg) Height (cm) QTc interval
GP (N = 91)
PG (N = 97)
p valueb
Mean ± SD Min-max Male Female Non-smoker Smoker Ex-smoker
58.88 ± 10.53 29–85 54 (59.3) 37 (40.7) 66 (72.5) 6 (6.6) 19 (20.9)
60.41 ± 10.06 32–83 63 (65.0) 34 (35.1) 74 (76.3) 7 (7.2) 16 (16.5)
0.309a
None 1–2 times/week 3–4 times/week 5–6 times/week
77 (84.6) 9 (9.9) 3 (3.3) 2 (2.2)
88 (90.7) 6 (6.2) 1 (1.0) 1 (1.0)
0.595c
More than 7 times/week Yes No Yes No FOLFOX FOLFIRI 0 1 2 Mean ± SD Min-max Mean ± SD Min-max Mean ± SD Min-max
0 (0.0) 6 (6.6) 85 (93.4) 60 (65.9) 31 (34.1) 25 (24.5) 66 (72.5) 30 (33.0) 54 (59.3) 7 (7.7) 57.10 ± 0.95 32.6–84.0 162.1 ± 8.38 134.0–178.0 429.9 ± 24.82 353–493
1 (1.0) 9 (9.3) 88 (90.7) 70 (72.2) 27 (27.8) 35 (36.1) 62 (63.9) 33 (34.0) 53 (54.6) 11 (11.3) 59.94 ± 8.83 43.5–88.4 162.9 ± 7.37 144.1–180.0 424.3 ± 42.36 94–514
ITT intension to treat, SD standard deviation a
t test
b
Chi-square test
c
Fisher’s exact test
0.428b 0.741b
0.497b 0.355b 0.206b 0.654a
0.031a 0.471a 0.270a
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Results Patient characteristics and baseline demographics Between August 17, 2012, and February 14, 2014, 196 patients from six institutions in Korea were randomized to GP or PG group. Eight patients did not receive first chemotherapy cycle, and 22 patients did not receive second chemotherapy cycle. Three hundred forty-eight cycles (173 in the palonosetron cycle and 175 in the GTDS cycle) were assessed for safety. Three hundred thirty-three cycles were included in the per protocol analysis—165 cycles for the GTDS and 168 cycles for the palonosetron were analyzed (Fig. 2). The distribution of patients by gender, age, performance status, body surface area, history of alcohol consumption, and chemotherapy regimen were similar between the two groups (Table 1). Efficacy The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles, and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.6–4.4). There was no significant difference in complete response rate of acute phase after first cycle and the Table 2
a
second cycle between GP group and PG group (p = 0.405, p = 0.074) (Table 2). The stratified analysis showed that GTDS was not different to palonosetron in terms of the risk factors of CINV, such as female sex, age, alcohol history. For secondary efficacy analyses, similar proportions of cycles with a complete response were noted in the palonosetron cycle and GTDS cycle during the overall 0–72-h period. Response was assessed every day; the proportion of cycles with a CR was not significant difference in the palonosetron cycle and GTDS cycle (Fig. 3a). The proportion of cycles with a CC and TC was not significant difference in the palonosetron cycle and GTDS cycle during the acute period and the overall period (Fig. 3b, c). The severity of nausea, vomiting, and/or retching per day and total days of treatment was not different between the groups. In the both groups, small portion of patients had severe nausea during acute phase (3 of 175 patients in the GTDS cycle and 1 of 173 patients in the palonosetron cycle). Overall satisfaction with antiemetic therapy was measured by FLI-E. FLI-E scores of patients in the palonosetron cycle were equal to those of patients in the GTDS cycle during 0–72 h after the start of chemotherapy in the GTDS cycle [median score, 1626 (range 1341–1751.5)] vs. in the palonosetron cycle [median
Complete responses (defined as no emetic episodes and no use of rescue medication) difference between two groups in the per protocol cohort
n.s. (not significant):chi-square test
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Patch adhesion The adhesive properties of GTDS were assessed. Of 175 cycles receiving the GTDS, 112 (64 %) had ≥90 % adhesion and 158 (90.3 %) had ≥75 % adhesion. Three patients (1.7 %) had a completely detached patch. Grade 3 skin rash occurred in a patient, so GTDS was removed. Tolerability A total of 368 cycles were evaluable for safety. Total 96 AEs were observed. Most AEs were mild in intensity, and 80 (84 %) of them were as associated with the patient’s cancer and/or chemotherapy treatment. Post hoc analysis revealed no differences in AEs commonly associated with 5-HT3RAs therapy (i.e., constipation, diarrhea, insomnia). Grade 3 skin rash occurred at the attached area in a patient. Table 3 provides a list of treatment-emergent, drugrelated AEs. Total 24 (6.62 %) adverse drug reactions (i.e., AEs considered to be treatment related) occurred in 17 patients. Among them, 12 events (50 %, 8 patients) occurred in GTDS cycle and 12 events (50 %, 9 patients) in palonosetron cycle.
Discussion
Fig. 3 a Complete response of CINV per day of chemotherapy. The GTDS displayed non-inferiority to palonosetron during the acute phase: complete response was achieved by 75.2 % of patients in the GTDS cycles, and 79.8 % in the palonosetron cycles (treatment difference, −4.6 %; 95 % confidence interval, −13.5–4.3). b Complete control of CINV per day of chemotherapy. c Total control of CINV per day of chemotherapy
score, 1648 (range 1311.0–1791.0)]. But FLI-E scores of GTDS cycle in GP group patients were lower than those of palonosetron cycle (median 1589.0 in GTDS cycle, median 1666.5 in palonosetron cycle).
Table 3 Treatment-related adverse event occurring in each treatment cycle in the safety cohort (N = 348)
The current randomized trial represents the direct comparison of the efficacy of a GTDS with the second-generation 5-HT3RA by cross-over method. Palonosetron was significantly more effective than other first-generation 5HT3RAs (containing oral, IV granisetron) in preventing acute and delayed nausea and vomiting for both moderately and highly emetogenic chemotherapy agents. This fact led to the hypothesis that palonosetron would have stronger and longer antiemetic effects compared with granisetron transdermal delivery system. The results of the primary efficacy assessments indicated that the GTDS was non-inferior to palonosetron in the control of CINV in patients receiving MEC. Although previous comparative studies of palonosetron with ondansetron, granisetron, and dolasetron have showed superior antiemetic effects of palonosetron [19], extended release of
Drug-related AEs
GTDS (N = 175), n (%)
Palonosetron (N = 173), n (%)
Constipation Diarrhea Insomnia Rash
5 (2.7 2 (1.1 4 (2.1 1 (0.5
9 (5.0 %) 1 (0.6 %) 2 (1.1 %) 0 (0 %)
AEs adverse events
%) %) %) %)
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granisetron over 7 days may enhance the duration of antiemetic effect. Transdermal delivery of granisetron carries an important advantage over repeated oral dosing in terms of patient convenience, compliance, and reduced pill burden. It may be especially valuable in patients for whom swallowing is difficult or absorption of oral medications is uncertain, such as patients with gastrointestinal surgery [19]. The convenience of the GTDS is supported by its good adhesive properties, as presented in the present study. Effectiveness of transdermal granisetron is influenced by duration of application because of its delivery mechanism. However, actual application time of the patch by patients was not clearly investigated in the process of the study. To achieve therapeutic levels of granisetron more rapidly and improve the effectiveness, the addition of oral or intravenous granisetron to the first day of GTDS therapy should be included in further investigations. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by individual patient variability (e.g., age, sex, prior chemotherapy, history of alcohol use). In this study, cross-over design can offset individual patient variability and find the preferred patients characteristics to each antiemetic treatment. The proportion of no emetic episodes in this study was similar to those reported previously with palonosetron 0.25 mg IV bolus. The proportion of no emetic episodes ranges from 63 to 81 % for acute CINV, 54 to 74 % for delayed CINV, and 46 to 69.3 % for overall CINV in other similarly designed phase III trials of palonosetron for prevention of moderate emetogenic risk of chemotherapy [16, 18]. The consistency of these rates with those reported in the current study (80.4 % for acute CINV, 68.5 % for delayed CINV, and 62.5 % for overall CINV) highlights the validity of this study. GTDS therapy improved control of CINV, particularly for delayed emesis, and was not inferior to palonosetron on any day of the chemotherapy. All treatments were well tolerated, with no significant differences between the groups. Most AEs (including serious AEs) were assessed as to be unlikely related to study medication but rather to the patient’s underlying cancer or chemotherapeutic treatment. Constipation was the most frequently reported drug-related AE in all treatment groups. There were no significant treatmentrelated changes in laboratory measures, vital signs, or ECG. The study showed similar safety profile compared to previous GTDS studies and safety of other drugs in the same class. And the degrees of adverse reactions are low. This study demonstrated GTDS is non-inferior to palonosetron for relieving CINV in patients receiving MEC and patient’s satisfaction with GTDS being higher than with palonosetron. On the basis of the results of
trial, GTDS could be a good therapeutic option for patients receiving MEC. Conflict of interest The authors declare that they have no competing interests.
References 1.
2.
3.
4.
5.
6. 7.
8.
9.
10.
11.
12.
13.
14.
15.
Griffin AM, Butow PN, Coates AS, et al (1996) On the receiving end. V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 7:189–195 Almeida EP, Gutierrez MG, Adami NP (2004) Monitoring and evaluation of side effects of chemotherapy in patients with colon cancer. Rev Lat Am Enfermagem 12:760–766 Andrews PL, Sanger GJ (2002) Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2:650–656 Fukui H, Yamamoto M, Sato S (1992) Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. Jpn J Pharmacol 59:221–226 Balfour JA, Goa KL (1997) Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs 54:273–298 Hasler WL (1999) Serotonin receptor physiology: relation to emesis. Dig Dis Sci 44(8 suppl):108S–113S Hesketh PJ (2000) Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Investig 18:163–173 Forni C, Ferrari S, Loro L, et al (2000) Granisetron, tropisetron, and ondansetron in the prevention of acute emesis induced by a combination of cisplatin–adriamycin and by high-dose ifosfamide delivered in multi-day continuous infusions. Support Care Cancer 8: 131–133 Gralla RJ, Osoba D, Kris MG, et al (1999) Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 17:2971–2994 Koeller JM, Aapro MS, Gralla RJ, et al (2002) Antiemetic guidelines: creating a more practical approach. Support Care Cancer 10: 519–522 Kaizer L, Warr D, Hoskins P, et al (1994) Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: a phase III trial by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12:1050–1057 Howell J, Smeets J, Drenth HJ, Gill D (2009) Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapyinduced nausea and vomiting. J Oncol Pharm Pract 15:223–231 Boccia RV, Gordan LN, Clark G, et al (2011) Sancuso Study Group. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer 19(10):1609–1617 Aapro MS, Grunberg SM, Manikhas GM, et al (2006) A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 17:1441–1449 Eisenberg P, Figueroa-Vadillo J, Zamora R, et al (2003) Improved prevention of moderately emetogenic chemotherapy-induced
Support Care Cancer nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 98:2473–2482 16. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A (2004) Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose ranging clinical study. Ann Oncol 15:330–337 17. Gralla R, Lichinitser M, Van Der Vegt S, et al (2003) Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial
18.
19.
comparing single doses of palonosetron with ondansetron. Ann Oncol 14:1570–1577 Botrel TE, Clark OA, Clark L, et al (2011) Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer 19:823–832 Kraut L, Fauser AA (2001) Anti-emetics for cancer chemotherapy induced emesis: potential of alternative delivery systems. Drugs 61: 1553–1562
