A Narrative Review of Tropisetron and Palonosetron for the Control of Chemotherapy-Induced Nausea and Vomiting

Yunpeng Yang; Li Zhang

Chin Clin Oncol. 2020;9(2):17

Abstract and Introduction

Abstract

Review the clinical evidence of tropisetron or palonosetron, an old- and new-generation serotonin (5-hydroxytryptamine) type 3 (5-HT₃) receptor antagonist (RA), respectively, for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer, and evaluate any difference in efficacy trends. A literature search of the EMBASE and PubMed databases was performed to identify publications of intravenous (IV) tropisetron (generic forms or Navoban®) for the treatment of CINV in patients with various cancers. Data from the pivotal clinical studies evaluating the IV formulation of Aloxi® (palonosetron HCl) were also considered. The effectiveness and safety of each antiemetic was summarized. Sixteen papers for tropisetron fulfilled the inclusion criteria and were extracted for full analysis; publications from six pivotal palonosetron clinical trials were considered. No direct data comparisons could be made between the two drugs, due to the varying definitions of efficacy endpoints between studies. For tropisetron, the rates of no emesis were lower in patients receiving highly emetogenic chemotherapy (HEC) versus moderately emetogenic chemotherapy (MEC). For palonosetron, the rates of complete response (no emesis, no rescue medication) were comparable in the MEC and HEC settings, demonstrating the effectiveness of this agent in patients receiving HEC. Both antiemetics offered some protection against nausea, although lower rates of no nausea were achieved compared with rates of no emesis. Two trials that evaluated the efficacy of palonosetron and tropisetron within the same study reported that palonosetron was more effective than tropisetron in controlling delayed vomiting in the HEC and MEC settings, with significantly higher rates of no emesis observed (P≤0.01). Palonosetron was non-inferior or more efficacious in controlling CINV compared with other older 5-HT₃RAs, such as dolasetron, ondansetron, and granisetron. Conversely, tropisetron was no more efficacious than ondansetron or granisetron. Both tropisetron and palonosetron were generally well tolerated, with adverse event profiles consistent with drugs of this class (e.g., headache, constipation, and diarrhea). These data suggest that palonosetron is a highly selective prophylactic agent that may have an improved therapeutic profile compared with tropisetron, and is a feasible treatment option for controlling CINV in patients with cancer.

Introduction

Chemotherapy-induced nausea and vomiting (CINV), a highly distressing and frequent complication in patients with cancer,^[1] can negatively impact quality of life and adherence to therapy,^[2–5] and may be associated with considerable healthcare costs.^[6]

CINV is a complex and multifactorial process mediated by multiple neurotransmitters, including serotonin, substance P, and dopamine.^[7] Serotonin (5-hydroxytryptamine) type 3 (5-HT₃) receptor antagonists (RAs) block 5-HT₃ receptors involved in regulating nausea and vomiting in the acute (0–24 hours after chemotherapy) setting. Thought to act via the central nervous system and the vagus and splanchnic nerves in the gastrointestinal tract,^[8] 5-HT/5-HT₃ receptor signaling may also influence delayed (24–120 hours after chemotherapy) nausea and vomiting, possibly by sensitizing the vagus nerve to chemicals such as substance P.^[9–11]

5-HT₃ RAs, which may be described as old and new generation, form the cornerstone of antiemetic regimens recommended by international guidelines.^[12–14] Currently used older 5-HT₃ RAs include azasetron;^[15] dolasetron, granisetron, and ondansetron; tropisetron;^[16] and ramosetron.^[17] At the recommended dose, these agents show similar efficacy and safety,^[8,18–20] with cost being the main differentiator. Despite their effectiveness in controlling CINV in the acute phase, they are not as effective in the delayed phase,^[21–23] prompting the development of a new 5-HT₃ RA, palonosetron.

Both palonosetron and tropisetron are used as first-line agents to prevent CINV in China, although anecdotal evidence suggests that tropisetron may be favored, despite the lack of evidence to support its superior efficacy. Tropisetron, one of the first 5-HT₃ RAs to be developed,^[24] has shown promising antiemetic properties in pilot studies,^[25,26] with acute CINV control rates of approximately 70%.^[26] Palonosetron is a pharmacologically and clinically distinct new-generation 5-HT₃ RA^[27,28] that various meta-analyses have shown to be more effective than older 5-HT₃ RAs.^[29–32] It exhibits a higher binding affinity for 5-HT₃ receptors and synergistically interacts with the neurokinin 1 (NK₁) receptor signaling pathway,^[27,33] which may partially account for palonosetron's effectiveness in the delayed phase. Palonosetron comes in two formulations, oral (0.50 mg) and intravenous (IV; 0.25 mg).

This review aimed to summarize the clinical data on tropisetron IV and Aloxi® (palonosetron HCl) IV, in the first-line setting in patients with CINV, and evaluate the 5-HT₃ RA benefit to patients in terms of preventing nausea and/or vomiting.

1 2 3 4

Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Description of the search strings used to retrieve tropisetron publications from EMBASE and PubMed
Database	Search string
EMBASE^a	('tropisetron'/exp OR tropisetron) AND ('chemotherapy induced nausea and vomiting' OR 'chemotherapy induced emesis'/de OR 'chemotherapy nausea and vomiting' OR cinv) AND ([article]/lim OR [article in press]/lim) AND [humans]/lim
PubMed	Tropisetron AND ("chemotherapy induced nausea and vomiting" OR "chemotherapy induced emesis" OR "chemotherapy nausea and vomiting") NOT Review[Publication Type]

ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; MASCC, Multinational Association of Supportive Care in Cancer. ^a, as the EMBASE search will only capture ASCO and ESMO abstracts, a manual search of the MASCC conference archives from their first online availability [2012] to the most recently published [2017] was also undertaken.

Table 2. Inclusion and exclusion criteria used for identification of papers used in this review
Parameter	Inclusion	Exclusion
Treatment	Tropisetron IV, 0.5 mg	Any other CINV therapies, or where tropisetron effect cannot be determined
Data type	Clinical (human)	Preclinical (animal or in vitro studies)
Therapy area	Oncology	Any therapy area other than oncology
Setting	CINV	Anything other than CINV (e.g., PONV or treatment of cancer)
Publication/data type	Clinical trials, prospective observational studies, retrospective observational studies published as original articles or conference abstracts (ASCO, ESMO, MASCC)	Meta-analyses, systematic literature reviews, pooled analyses, guidelines, narrative reviews, letters to the editor, case series, case reports

ASCO, American Society of Clinical Oncology; CINV, chemotherapy-induced nausea and vomiting; ESMO, European Society for Medical Oncology; IV, intravenous; MASCC, Multinational Association of Supportive Care in Cancer; PONV, post-operative nausea and vomiting.

Table 3. Summary of study designs for the tropisetron IV and palonosetron IV studies
Author, year	No. of patients [no. receiving tropisetron]	Tropisetron/palonosetron dose/regimen	Comparator	Steroids	Chemotherapy	Tumor type
Tropisetron
Anderson et al., 1994 (35)	102 [51]	Tropisetron 5 mg IV on day 1 and PO on days 2–4	Metoclopramide 2–5 mg/kg on day 1 and 3× 20–40 mg PO on days 2–4	No	HEC/MEC: carboplatin 300 or 140 mg/m² + cyclophosphamide 600 or 300 mg/m² alternating with ifosfamide 5 or 2.5 g/m² + doxorubicin 50 or 25 mg/m², doxorubicin 75 mg/m², carboplatin 300 mg/m² + ifosfamide 5 g/m² + etoposide 120 mg/m² on days 1 and 2 and 240 mg/m² on day 3	Breast, lung cancer, head, and ovarian cancer, and soft tissue sarcoma
Bruntsch et al., 1994 (36)	87 [87]	Tropisetron monotherapy: 5 mg IV during chemotherapy, followed by 1× 10 mg PO	Tropisetron + D: tropisetron (5 mg IV during chemotherapy, followed by 1× 10 mg PO) + D (1× 20 mg D IV on days 1 and 2 followed by 1× 4 mg PO or IV until the end of chemotherapy and 1× 4 mg PO after cessation of chemotherapy); tropisetron + low-dose metoclopramide: tropisetron (5 mg IV during chemotherapy, followed by 1× 10 mg PO) + metoclopramide (1× 20 mg IV, then 2× 10 mg PO on day 1, followed by 3× 10 mg PO)	D 20 mg IV on days 1 and 2 followed by 1× 4 mg PO or IV until the end of chemotherapy	HEC: cisplatin ≥50 mg/m², ifosfamide ≥1.5 g/m², cyclophosphamide ≥750 mg/m², carboplatin ≥300 mg/m² on day 1 of the course	NR
Bruntsch et al., 1993 (37)	231 [115]	Tropisetron 5 mg/day PO evening before day 1 chemotherapy and mornings for at least 5 days (depending on duration of chemotherapy); IV infusion (15 mins) on day 1 of chemotherapy; investigators discretion whether to continue tropisetron in subsequent chemotherapy courses	Standard antiemetic therapy (investigators discretion, optimized individual patients)	No	92% HEC	Breast cancer, gynecological cancers, lung cancer, genitourinary cancer, lymphomas, other tumors
Drechsler et al., 1997 (38)	193 [193]	Arm A: tropisetron 5 mg IV on days 1 and 2 and then 10 mg PO	Arm B: tropisetron 5 mg IV on days 1 and 2, and then 10 mg PO + D 20 mg IV on days 1 and 2 and then 4 mg PO or IV; Arm C: tropisetron 5 mg IV on days 1 and 2 and then 10 mg PO + metoclopramide 20 mg IV along with 2× 10 mg PO on day 1 and then 3× 10 mg PO	In arm B	HEC: cisplatin ≥50 mg/m² or carboplatin ≥300 mg/m² or cyclophosphamide ≥750 mg/m² or ifosfamide ≥1.5 g/m². Combinations with other chemotherapeutics allowed	Histologically or cytologically verified malignant tumors
Herrstedt et al., 2007 (39)	81 [81]	Tropisetron 5 mg IV on days 1–5 and PO on day 6 + placebo 30 mg PO tid on day 1 and qid on days 2–6	Tropisetron 5 mg IV on days 1–5 and PO on day 6 + metopimazine 30 mg PO tid on day 1 and qid on days 2–6	No	MEC: cisplatin 20 or 40 mg/m² on days 1–5/21 + etoposide 100 mg/m² on days 1–21/21 + bleomycin 15 mg/m² on day 2/21 for 4 cycles	Germ cell cancer
Hulstaert et al., 1994 (40)	460 [460]	Tropisetron 5 mg IV on day 1 and PO on days 2–6	Tropisetron 5 mg IV on day 1 and PO on days 2–6 + D 0.2 mg/kg IV on day 1 and 8 mg on days 2–6; tropisetron 5 mg IV on day 1 and PO on days 2–6 + alizapride 0.2 mg/kg IV on day 1 and 8 mg on days 2–6	D 8 mg in Arm B	HEC/MEC: cisplatin >50 mg/m²/day or >75 mg/m², cyclophosphamide >600 mg/m², cytarabine >500 mg/m², ifosfamide >1,000 mg/m², carboplatin >300 mg/m², epirubicin 70 mg/m², doxorubicin >50 mg/m² or >25 mg/m² in combination, mitoxantrone >10 mg/m² in combination, mitomycin >10 mg/m² in combination, or mustine, carmustine, dactinomycin, or dacarbazine at any dose	Breast cancer, lung cancer, head and neck cancer, ovarian cancer
Nicolaides et al., 1998 (41)	40 [40]	Tropisetron 5 mg single IV dose as 10-minute infusion before chemotherapy	NR	No	MEC: epirubicin 110 mg/m² IV every 2 or 4 weeks with G-CSF subcutaneous 5 μg/kg days 2–13	Breast cancer
Ma et al., 2015 (42)	82 [40 tropisetron alone; 42 tropisetron + palonosetron]	Tropisetron 5 mg IV on days 1–3	Palonosetron 25 mg IV on days 1 and 3 + tropisetron 5 mg IV on days 1–3, both 30 min before chemotherapy	D 10 mg	HEC: docetaxel 60–75 mg/m² on day 1, cisplatin 75 mg/m² on day 1–3/21 per cycle	Non-small cell lung cancer
Sorbe et al., 1994 (43)	259 [132]	Tropisetron 5 mg IV on day 1 and PO on days 2–6	Metoclopramide 3 mg IV + D 20 mg IV on day 1 and 10 mg PO or 20 mg suppository on days 2–6	D in comparator arm	HEC: cisplatin 50–89 mg/m²	Gynecological tumors, lung cancer, head and neck cancer, bladder cancer
Sorbe et al., 1994 (44)	630 [630] of which 619 evaluable	Tropisetron 5 mg IV on day 1 and PO on days 2–6	NA	No	HEC/MEC: common therapies were cisplatin, carboplatin, dacarbazine, anthracyclines, cyclophosphamide, etoposide, fluorouracil	Gynecologic tumors, lung cancer, breast cancer, lymphoma
Sorbe et al., 1998 (45)	300 [141]	Tropisetron 5 mg IV on day 1 and PO on days 2–6 + D 20 mg IV on day 1 and 3 mg PO on days 2–6	Placebo 5 mg PO on days 2–6 + D 20 mg IV on day 1 and 3 mg PO on days 2–6	D 20 mg IV on day 1 and 3 mg PO on days 2–6	HEC/MEC: cisplatin 50–100 mg/m² or carboplatin (AUC = 7) on day 1. Combination with other cytostatic agents (epidoxorubicin, doxorubicin, cyclophosphamide, paclitaxel, teniposide, etoposide, vincristine, and bleomycin) was allowed	Gynecologic malignancies
Tsavaris et al., 2008 (46)	60 [60]	Tropisetron 5 mg IV on days 1–3 in cycle 1	Tropisetron 5 mg + D 8 mg IV on days 1–3, before chemotherapy in cycle 2; tropisetron 5 mg IV + 0.25 mg alprazolam tablets on days 1–3, before chemotherapy in cycle 3	D 8 mg	HEC/MEC: carboplatin (AUC =7) + paclitaxel 225 mg/m² or docetaxel 100 mg/m² on day 1/21 for 3 cycles	Non-small cell lung cancer
Yalçin et al., 1999 (47)	54 [17]	Tropisetron 5 mg IV	Ondansetron 8 mg IV or granisetron 3 mg IV	No	MEC: FAC, FEC, or CMF for 1 day	Breast cancer
Tropisetron and palonosetron
Qiu et al., 2011 (48)	155 [155]	Tropisetron 5 mg IV	Palonosetron 0.25 mg IV	NR	HEC/MEC: cisplatin ≥60 mg/m² or doxorubicin ≥40 mg/m², pirarubicine ≥40 mg/m², epirubicin ≥60 mg/m²	Malignant solid tumors
Li et al., 2012 (49)	128 [97]	Tropisetron 5 mg IV	Palonosetron 0.25 mg IV	D 10 mg IV	Cisplatin 75 mg/m²	Malignant solid tumors
Palonosetron
Aapro et al., 2006 (50)	667 [446]	Palonosetron 0.25 mg IV	Palonosetron 0.75 mg IV; ondansetron 32 mg IV	D 20 mg IV (15 min before chemotherapy initiation) was allowed at the physician's discretion	HEC: cisplatin ≥60 mg/m², cyclophosphamide >1,500 mg/m², carmustine [BCNU] > 250 mg/m², dacarbazine [DTIC], or mechlorethamine) on day 1	Ovarian cancer, lung cancer, Hodgkin's lymphoma, gastric cancer, breast cancer
Eisenberg et al., 2003 (51)	569 [378]	Palonosetron 0.25 mg IV	Palonosetron 0.75 mg IV; dolasetron 100 mg IV	A late protocol amendment, and at the discretion of the investigator, a single dose of D 20 mg IV (or, if unavailable, a single dose of D 20 mg PO or methylprednisolone 125 mg IV), administered 15 minutes before chemotherapy, was permitted	MEC: carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, mitoxantrone, methotrexate (>250 mg/m²), cyclophosphamide (<1,500 mg/m²), doxorubicin (>25 mg/m²), or cisplatin (<50 mg/m²)	Malignant disease (including breast cancer, lung cancer and non-Hodgkin lymphoma)
Gralla et al., 2003 (52)	563 [378]	Palonosetron 0.25 mg IV	Palonosetron 0.75 mg IV; ondansetron 32 mg IV	No	MEC: any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan or mitoxantrone; methotrexate >250 mg/m²; cyclophosphamide <1,500 mg/m²; doxorubicin >25 mg/m²; or cisplatin <50 mg/m²	Malignant disease including: breast, lung, bladder, colon, rectal, small-cell lung and gastric cancers
Boccia et al., 2013 (53)	651 [639]	Palonosetron 0.25 mg IV	Palonosetron 0.25 mg PO; palonosetron 0.50 mg PO; palonosetron 0.75 mg PO	Randomized 1:1 to D 8 mg IV or placebo on day 1	MEC: any dose of oxaliplatin, carboplatin, epirubicin, idarubicin, doxorubicin, ifosfamide, irinotecan, daunorubicin or cyclophosphamide <1,500 mg/m², or cytarabine >1 g/m²	Malignant disease including breast and colon cancers and lung neoplasms
Karthaus et al., 2015 (54)	743 [743]	Palonosetron 0.25 mg IV	Palonosetron 0.50 mg PO	D 20 mg on day 1 then 8 mg bid on days 2–4	HEC: cisplatin-based regimen	Malignant solid tumors including gastric, head and neck, lung/respiratory tract/ovarian and bladder
Saito et al., 2009 (55)	1,143 [555]	Palonosetron 0.75 IV	Granisetron 40 μg/kg	D 16 mg IV on day 1	HEC: cisplatin ≥50 mg/m² or anthracycline and cyclophosphamide regimen	Malignant solid tumors including non-small cell lung cancer, small-cell lung cancer, and breast cancer

AUC, area under the curve; bid, twice a day; CMF, cyclophosphamide, methotrexate, fluorouracil; D, dexamethasone; FAC, fluorouracil, adriamycin, cyclophosphamide; FEC, fluorouracil, epirubicin, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; HEC, highly emetogenic chemotherapy; IV, intravenous; MEC, moderately emetogenic chemotherapy; NR, not reported; PO, orally; qid, four times a day; tid, three times a day.

Table 4. Summary of efficacy parameters for tropisetron
Trial	Emetogenic potential	Patient number, total [number receiving tropisetron 5 mg]	D dose in tropisetron arm	No emesis, %			No nausea, %			No emesis and/or no vomiting), %			TRAEs incidence in tropisetron arm
Trial	Emetogenic potential	Patient number, total [number receiving tropisetron 5 mg]	D dose in tropisetron arm	A	Del	O	A	Del	O	A	Del	O	TRAEs incidence in tropisetron arm
Bruntsch et al., 1993 (37)	93% HEC	231 [115]	N	52	55–75	NR	32	29–60	NR	NR	NR	NR	71/115
Bruntsch et al., 1994 (36)	HEC	87 [30 for tropisetron alone; 30 for tropisetron + D]	Y in cycle 2 (20 mg IV on days 1 and 2; then 4 mg PO or IV until end of treatment	−D: 69; +D: 92	−D: 70; +D: 90	−D: 45; +D: 76	−D: 69; +D: 81	−D: 63–83; +D: 76–88	−D: 34+D: 59	NR	NR	NR	−D: 7/30; +D: 9/30
Drechsler et al., 1997 (38)	HEC	193 [65 tropisetron alone; 60 for tropisetron +D]	Y (in comparator arm; 20 mg IV on days 1 and 2, then 4 mg IV/PO thereafter)	−D: 80; +D: 97	−D: 53; +D: 80	NR	−D: 75; +D: 90	−D: 46; +D: 58	NR	~63	NR	−D: 26+D: 49	−D: 26/65; +D: 37/60
Ma et al., 2015 (42)	HEC	82 [40 tropisetron alone]	10 mg	75.0	50.0	42.5	35.0	65.0	NR	NR	NR	NR	64.3
Mantovani et al., 1996 (34)	HEC	117 [40]	NR	NR	NR	NR	NR	NR	NR	72.5	NR	NR	Total AEs NR but none severe and incidence of headache was <10%
Sorbe et al., 1994 (43)	HEC	259 [131]	N	63	NR	37	40	NR	21	NR	NR	NR	NR
Herrstedt et al., 2007 (39)	HEC	82 [40]	N	90	NR	22.5	62.5	NR	12.5	NR	NR	NR	No absolute figures given
Nicolaides et al., 1998 (41)	HEC	40 [40]	N	NR	NR	NR	NR	NR	NR	62.5	52.5	NR	6/40
Sorbe et al., 1998 (45)	HEC	300 [141]	Y (20 mg IV on day 1; 3 mg PO on days 2–6)	87	77	NR	77	42	NR	NR	NR	NR	75%
Tsavaris et al., 2008 (46)	MEC	60 [60]	Y (tropisetron 8 mg in + D in the second cycle)	−D: 28.3; +D: 41.7	NR	NR	−D: 30; +D: 38.3	NR	NR	NR	NR	NR	NR
Yalçin et al., 1999 (47)	MEC	54 [17]	N	58.8	52.9	NR	NR	NR	NR	NR	NR	NR	NR
Hulstaert et al., 1994 (40)	HEC/MEC	1,072 [1,072]	N in first cycle (data reported)	NR	NR	NR	NR	NR	NR	72	NR	48	NR
Sorbe et al., 1994 (44)	HEC/MEC	630 [630]	N	NR	NR	NR	NR	NR	NR	64	45–58	NR	19–37% frequency
Anderson et al., 1994 (35)	HEC/MEC	102 [51]	N	45	~50–80	NR	25	~50–85	NR	NR	NR	NR	63%

A, acute; AE, adverse event; D, dexamethasone; Del, delayed; HEC, highly emetogenic chemotherapy; IV, intravenous; MEC, moderately emetogenic chemotherapy; N, no; NR, not reported; O, overall; PO, orally; TRAE, treatment-related adverse event; Y, yes

Table 5. Summary of efficacy parameters for palonosetron
Trial	Emetogenic potential	Patient number, total [number receiving palonosetron 0.25 mg]	D dose in palonosetron arm	No emesis (%)			No nausea (%)			Complete response (no emesis, no rescue medication), %			TRAEs incidence in palonosetron arm for layout
Trial	Emetogenic potential		D dose in palonosetron arm	A	Del	O	A	Del	O	A	Del	O	TRAEs incidence in palonosetron arm for layout
Aapro et al., 2006 (50)	HEC	667 [223]	20 mg IV, day 1 (but only in 66.7% of patients)	68.2	56.5	46.6	NR	NR	NR	59.2	45.3	40.8	72%
Karthaus et al., 2015 (54)	HEC	743 [369]	20 mg IV, day 1; 8 mg bid, days 2–4	NR	77.5	73.2	75.6	53.4	47.4	86.2	74.8	70.2	51.8%
Saito et al., 2009 (55)	HEC	1,143 [555]	16 mg IV on day 1; additional dose on days 2–3	77.5	63.2	57.5	58.7	37.8	31.9	75.3	56.8	51.5	30.5%
Eisenberg et al., 2003 (51)	MEC	592 [189]	20 mg IV, day 1 at investigator's discretion	V	V	V	V	V	V	63.0	54.0	46.0	V
Gralla et al., 2003 (52)	MEC	570 [189]	N	V	V	V	V	V	V	81.0	74.1	69.3	61.0%
Boccia et al., 2013 (53)	MEC	651 [163]	Patients randomized 1:1 to D, 8 mg IV or placebo	77.2	74.7	67.3	57.4	47.5	42.6	70.4	65.4	59.3	47–50%

A, acute; bid, twice a day; Del, delayed; D, dexamethasone; HEC, highly emetogenic chemotherapy; IV, intravenous; MEC, moderately emetogenic chemotherapy; N, no; NR, not reported; O, overall; TRAE, treatment-related adverse event; V, no absolute values reported, only figures depicting the data.