ORIGINAL ARTICLE
The Efficacy of Palonosetron Plus Dexamethasone in Preventing Chemoradiotherapy-induced Nausea and Emesis in Patients Receiving Daily Low-dose Cisplatin-based Concurrent Chemoradiotherapy for Uterine Cervical Cancer A Phase II Study Akira Mitsuhashi, MD, PhD,* Hirokazu Usui, MD, PhD,* Kyoko Nishikimi, MD,* Noriko Yamamoto, MD, PhD,* Shinsuke Hanawa, MD,* Shinichi Tate, MD, PhD,* Miho Watanabe-Nemoto, MD, PhD,w Takashi Uno, MD, PhD,w and Makio Shozu, MD, PhD*
Objectives: The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT. Methods: This is a nonrandomized, prospective, single-center, open phase II study. Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m2/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment. Results: Planned daily low-dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m2. No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment. Conclusions: Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT. Key Words: palonosetron, dexamethasone, cervical cancer, concurrent chemoradiotherapy, cisplatin
(Am J Clin Oncol 2014;00:000–000)
From the Departments of *Reproductive Medicine; and wRadiology, Graduate School of Medicine, Chiba University, Chiba, Japan. The authors declare no conflicts of interest. Reprints: Akira Mitsuhashi, MD, PhD, Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000117
American Journal of Clinical Oncology
T
he management of chemotherapy-induced nausea and vomiting (CINV) has recently been improved because of the availability of several new antiemetic drugs. Current guidelines recommend the use of a combination of palonosetron and dexamethasone, as antiemetic prophylaxis, for moderate emetogenic risk, and the addition of aprepitant for high emetogenic risk.1,2 In contrast, the management of radiation-induced nausea and vomiting (RINV) is not well established.3 Pelvic radiotherapy is classified as low risk for RINV. Current guidelines recommend that low-risk patients should receive antiemetic prophylaxis or rescue treatment with a 5-hydroxytryptamine (5-HT3) receptor antagonist. However, a consensus on optimal antiemetic treatment during concurrent chemoradiotherapy (CCRT) has not been established. A meta-analysis has confirmed the therapeutic benefit of cisplatin-based CCRT, which is now a standard treatment for advanced cervical cancer.4 Cisplatin is a chemotherapeutic agent with a high emetogenic risk and is generally administered in a dose of 40 mg/m2 every week for the treatment of cervical cancer in CCRT.5,6 To enhance treatment compliance, we have previously introduced a daily low-dose (8 mg/m2) cisplatin-based CCRT regimen, which resulted in a high total dosage of cisplatin compared with that of weekly CCRT.7,8 However, in this regimen, nausea and vomiting of grade 2 and higher occurred in 26% patients despite administering a firstgeneration 5-HT3 receptor antagonist.8 Prevention of emesis during CCRT is difficult because the dosage period of cisplatin is long in both daily and weekly administration. In addition, the delayed side effects may overlap with acute side effects, and the adverse events induced by both radiation and chemotherapy can occur together. Palonosetron is a second-generation 5-HT3 receptor antagonist, a potent and highly selective 5-HT3 receptor antagonist with strong binding affinity to receptor and a long plasmaelimination half-life, indicated for the prevention of both acute and delayed CINV.9 It has been proven superior to first-generation agents, such as granisetron, in a randomized double-blind trial of prevention of CINV in the delayed phase.10–12 However, the safety and efficacy of its long-term use over 5 weeks during radiotherapy and CCRT have not been well established. Furthermore, the safety of the long-term use over 5 weeks of antiemetic drugs, such as dexamethasone, has not been
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mitsuhashi et al
American Journal of Clinical Oncology
established. Therefore, we conducted this prospective phase II study to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during cisplatinbased CCRT.
MATERIALS AND METHODS This was a prospective, single-center, open phase II study registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN 000007638.
Eligibility Criteria Patients were eligible for inclusion in this study if they met the following criteria: (i) histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma); (ii) clinical FIGO stage Ib2 to IVa cancer in whom daily low-dose cisplatin-based CCRT was planned as both primary and adjuvant treatments; (iii) no prior chemotherapy or radiotherapy; (iv) age 20 years and above with an Eastern Cooperative Oncology Group performance status of 0 to 2; and (v) adequate bone marrow, renal, and liver function. Patients with any of the following conditions were excluded from the study: (i) severe systemic or uncontrolled disease (uncontrolled diabetes mellitus or hypertension); (ii) clinically unstable seizure disorder requiring anticonvulsants; (iii) massive pleural effusion or ascites; (iv) gastric outlet or intestinal obstruction; and (v) a known hypersensitivity to palonosetron, granisetron, or other 5-HT3 receptor antagonists or dexamethasone ingredients. Patients were also excluded if they had received any drug with potential antiemetic efficacy within 24 hours of this study initiation or had any vomiting or grade 2 to 3 nausea in the 24hour period before the first dose of cisplatin. Informed consent was obtained from all patients before study enrollment.
Treatment The daily chemoradiation regimen comprised pelvic external beam radiotherapy (2 Gy/d, 25 fractions, 5 times a week) with daily low-dose cisplatin (8 mg/m2/d).7,8 Brachytherapy was administered to potentially curative cases through external beam radiotherapy with central shielding. The daily dose of cisplatin was reconstituted in 100 mL of normal saline and 0.75 mg of palonosetron was administered 1 hour before cisplatin on day 1 of each week. Post-cisplatin hydration was achieved with intravenous infusion of 1 L normal saline over 2 hours. All patients received a dose of oral dexamethasone (2 mg twice daily) from day 1 to the end of the treatment period. Dexamethasone was withheld in the case of grade 1 or higher toxicity with Cushingoid appearance, such as moon face. Dexamethasone and palonosetron were withheld during interruption of cisplatin because of acute toxicity.
Assessment The primary endpoint of this study was treatment efficacy, as measured by the percentage of patients achieving a complete response. Complete response was defined as no emetic episodes and no antiemetic rescue medication during the treatment period that started at administration of cisplatin and the end of CCRT. The secondary endpoints were complete control (defined as no emetic episodes, no rescue medication, and no more than mild nausea), the severity of nausea, adverse effects, and time to administration of rescue therapy. Endpoints were evaluated at the end of CCRT if patients interrupted cisplatin because of acute toxicity. Patients recorded emetic
2 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
episode, nausea, and rescue antiemetics received in a daily journal. The degree of nausea was assessed daily using a 10-point horizontal visual analogue scale (VAS) with a total score (range, 0 to 400) calculated on the basis of the daily scores obtained until the end of the treatment period. The definition of the degree of total VAS score were as follows: 200 = severe nausea. We evaluated the any emetic episodes, nausea grade, use of rescue medication, and the total VAS score. If emesis occurred the patient completed the current study diary. All adverse events were recorded and graded according to the common toxicity criteria of the National Cancer Institute, version 4.0.
RESULTS Patient Characteristics From January 2012 to April 2013, 26 consecutive patients with diagnosed FIGO stage IB2 to IVa cervical carcinoma treated with radiotherapy at the Chiba University Hospital were enrolled for the study. Patient characteristics are listed in Table 1. The median age was 59 years (range, 31 to 74 y). All patients were administered daily low-dose cisplatinbased CCRT. Radiotherapy was completed according to the planned regimen without discontinuation. Chemotherapy was successfully performed without interruption in 46% (12/26) of the patients. Chemotherapy was interrupted for 12 patients because of acute toxicity. Mean interruption of cisplatin was 2.9 times (range, 1 to 5). The mean dose of total cisplatin was 184 mg/m2 (range, 136 to 200 mg/m2). The median total treatment period was 38 days (range, 35 to 40 d).
Efficacy Endpoint No patient vomited during the treatment period. The complete response rate during CCRT was 100%. During almost 5 weeks of treatment, 21 of 26 patients (81%) were completely free from nausea and achieved a total VAS score of 0. The remaining 5 patients had grade 1 nausea and had a mean total VAS score of 20 points (range, 15 to 45). Complete control was achieved in all 26 (100%) patients; however, weight loss higher than grade 1 occurred in 7 (27%) patients. TABLE 1. Patient Characteristics No. patients Median age (range) (y) Stage Ib2 II III IVa Adjuvant External beam radiation therapy Primary therapy Pelvic Pelvic + EFRT Adjuvant therapy Pelvic Brachytherapy +
26 59 (31-74) 5 9 5 3 4 14 8 4 18 8
EFRT indicates extended field radiotherapy.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
TABLE 2. Acute Toxicity (NCI-CTC Version 4.0)
Grade Toxicity
1
2
3
4
5
Nausea Vomiting Weight loss Weight gain Diarrhea Constipation Headache Cushingoid feature
5 0 5 2 10 5 0 5
0 0 2 0 6 0 0 0
0 0 0 0 3 0 0 0
0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
Z2 (n [%]) 0 0 2 0 9 0 0 0
(0) (0) (8) (0) (34) (0) (0) (0)
Safety All patients were evaluated for toxicity (Table 2). Of the 26 patients, 13 (50%) reported the use of magnesium for constipation before treatment. In 5 (19%) patients, constipation worsened after palonosetron administration. By the third week of CCRT, the symptoms of constipation changed to diarrhea in these 5 patients. Five patients reported symptoms of grade 1 Cushingoid features of moon face, which developed after completion of treatment in 1 patient and during the fourth week in 4. All treatment-related side effects were either confirmed remission or recovery after completion of the treatment.
DISCUSSION Despite recent advances, the management of nausea and vomiting remains problematic during CCRT. In the present study, we demonstrated the efficacy and safety of a combination of palonosetron and dexamethasone in the prevention of nausea and vomiting in patients receiving daily low-dose cisplatin-based CCRT for the treatment of uterine cervical cancer. This therapy achieved 100% prevention of emetic episodes and all other adverse effects were maintained at tolerable levels. Nausea and vomiting are common adverse effects of cisplatin-based chemoradiotherapy. A Japanese phase II study of weekly cisplatin-based CCRT (40 mg/m2) for cervical cancer revealed that 20% patients suffered grade 2 nausea and vomiting, each during CCRT.13 The protocol of this trial recommended the administration of granisetron and dexamethasone; however, the dosage method of these antiemetic drugs remains unclear. A phase II study of weekly cisplatinbased CCRT (40 mg/m2) by Kato et al14 revealed that the frequency of nausea and vomiting of grade 2 or higher was 32%. Antiemetics, such as 5-HT3 receptor antagonists, metoclopramide, and dexamethasone, were given both before and after cisplatin administration in this study. We previously reported the results of a phase II study of daily cisplatin-based CCRT (8 mg/m2) for the treatment of uterine cervical cancer.8 In that study, we administered daily antiemetic premedication with 5-HT3 receptor antagonists without dexamethasone during administration of cisplatin. We predicted that emetic episodes would occur less often in daily CCRT than in weekly CCRT because the cisplatin dose used in the daily regimen was small. However, nausea and vomiting of grade 2 and higher occurred in 26% patients despite administering an antiemetic drug. In the present study, the prevention of emetic episodes was superior to our previous study. We believe that there are 2 reasons for this improvement. First, we changed the antiemetic drug to palonosetron from a first-generation 5-HT3 receptor antagonist because palonosetron has been reported to be more efficacious than granisetron by Sato and colleagues.10–12 r
2014 Lippincott Williams & Wilkins
Palonosetron and Dexamethasone in Chemoradiation
Second, we administered dexamethasone every day to the patients during the treatment period. A recent prospective study of the prevention of nausea and emesis during weekly cisplatin-based CCRT revealed that an antiemetic prophylaxis consisting of weekly palonosetron (0.25 mg) and prednisolone (200 mg/wk) is insufficient for the prevention of nausea and vomiting.15 After 5 cycles of weekly cisplatin (40 mg/m2), only 23% patients were continuously free from nausea. In contrast, the rate of prevention of emetic episodes was 100% in the present study, and 81% patients were free from nausea. In Japan, palonosetron is available at dose of 0.75 mg because of the tendency for better efficacy with the 0.75 mg dose than with the 0.25 mg.12,16,17 We believe that these positive results are because of a higher dose of palonosetron (0.75 mg) and daily administration of dexamethasone in the present study, rather than the differences in dosage regimes of cisplatin (weekly vs. daily low dose). There are no reports regarding long-term oral administration of dexamethasone to prevent emetic episodes. Furthermore, the safety of the long-term use of steroids, such as dexamethasone, has not been established.12,18,19 In the present study, dexamethasone was administrated at a maximum total dose of 128 mg during the treatment period. To the best of our knowledge, this is the first report to show the advantages and safety of long-term dexamethasone administration for antiemesis. There were no serious side effects other than Cushingoid features, such as moon face, which resolved after discontinuation of dexamethasone. Dexamethasone was administered at 2 mg twice daily in the present study; however, emetic episodes may be preventable using lower doses such as 1 mg. Nonetheless, it remains unknown whether dexamethasone administration is actually necessary on each day of cisplatin treatment. The most common adverse effects of palonosetron are headache and constipation.17 In this study, these adverse effects were minimal; however, it is important to consider that palonosetron-induced constipation may be masked because diarrhea is a major side effect of CCRT, and the beneficial effects of 5-HT3 receptor antagonists for the prevention of radiation-induced diarrhea have been previously reported.20 However, there have been no previous reports regarding weekly administration of palonosetron. The results of the present study indicated that the weekly administration of palonosetron (0.75 mg) was well tolerated and safe. Finally, it was difficult to establish whether the onset of the emesis experienced by patients undergoing multiple-day cisplatin administration was acute or delayed, because both events may repeatedly overlap. Our results demonstrated that the administration of weekly palonosetron (0.75 mg) and daily oral dexamethasone (4 mg) provided complete protection from nausea and vomiting during daily CCRT. Therefore, the results of this study provide useful information that will aid in proposing a candidate treatment for patients suffering from combined RINV and CINV. REFERENCES 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189–4198. 2. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232–v243. 3. Feyer PC, Maranzano E, Molassiotis A, et al. Radiotherapyinduced nausea and vomiting (RINV): MASCC/ESMO guideline
www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mitsuhashi et al
4.
5.
6. 7. 8.
9. 10.
11.
12.
American Journal of Clinical Oncology
for antiemetics in radiotherapy: update 2009. Support Care Cancer. 2011;19(suppl 1):S5–S14. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001;358:781–786. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340:1154–1161. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144–1153. Mitsuhashi A, Uno T, Tanaka N, et al. Phase I study of daily cisplatin and concurrent radiotherapy in patients with cervical carcinoma. Gynecol Oncol. 2005;96:194–197. Mitsuhashi A, Uno T, Usui H, et al. Daily low-dose cisplatin-based concurrent chemoradiotherapy in patients with uterine cervical cancer with emphasis on elderly patients: a phase 2 trial. Int J Gynecol Cancer. 2013;23:1453–1458. Siddiqui MA, Scott LJ. Palonosetron. Drugs. 2004;64:1125–1132. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473–2482. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570–1577. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, doubledummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10:115–124.
4 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
13. Toita T, Kitagawa R, Hamano T, et al. Feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high-dose rate intracavitary brachytherapy (HDR-ICBT) and 40-mg/m2 weekly cisplatin for japanese patients with cervical cancer: results of a multi-institutional phase 2 study (JGOG1066). Int J Gynecol Cancer. 2012;22:1420–1426. 14. Kato S, Ohno T, Thephamongkhol K, et al. Multi-institutional phase II clinical study of concurrent chemoradiotherapy for locally advanced cervical cancer in East and Southeast Asia. Int J Radiat Oncol Biol Phys. 2010;77:751–757. 15. Ruhlmann CH, Belli C, Dahl T, et al. Palonosetron and prednisolone for the prevention of nausea and emesis during fractionated radiotherapy and 5 cycles of concomitant weekly cisplatin-a phase II study. Support Care Cancer. 2013;21:3425–3431. 16. Miura S, Watanabe S, Sato K, et al. The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy-induced nausea and vomiting in lung cancer patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21:2575–2581. 17. Maemondo M, Masuda N, Sekine I, et al. A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy. Ann Oncol. 2009;20:1860–1866. 18. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15: 1293–1300. 19. Wong RK, Paul N, Ding K, et al. 5-hydroxytryptamine-3 receptor antagonist with or without short-course dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19). J Clin Oncol. 2006;24:3458–3464. 20. Franzen L, Nyman J, Hagberg H, et al. A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol. 1996;7:587–592.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Efficacy of Palonosetron Plus Dexamethasone in Preventing Chemoradiotherapy-induced Nausea and Emesis in Patients Receiving Daily Low-dose Cisplatin-based Concurrent Chemoradiotherapy for Uterine Cervical Cancer A Phase II Study Akira Mitsuhashi, MD, PhD,* Hirokazu Usui, MD, PhD,* Kyoko Nishikimi, MD,* Noriko Yamamoto, MD, PhD,* Shinsuke Hanawa, MD,* Shinichi Tate, MD, PhD,* Miho Watanabe-Nemoto, MD, PhD,w Takashi Uno, MD, PhD,w and Makio Shozu, MD, PhD*
Objectives: The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT. Methods: This is a nonrandomized, prospective, single-center, open phase II study. Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m2/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment. Results: Planned daily low-dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m2. No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment. Conclusions: Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT. Key Words: palonosetron, dexamethasone, cervical cancer, concurrent chemoradiotherapy, cisplatin
(Am J Clin Oncol 2014;00:000–000)
From the Departments of *Reproductive Medicine; and wRadiology, Graduate School of Medicine, Chiba University, Chiba, Japan. The authors declare no conflicts of interest. Reprints: Akira Mitsuhashi, MD, PhD, Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000117
American Journal of Clinical Oncology
T
he management of chemotherapy-induced nausea and vomiting (CINV) has recently been improved because of the availability of several new antiemetic drugs. Current guidelines recommend the use of a combination of palonosetron and dexamethasone, as antiemetic prophylaxis, for moderate emetogenic risk, and the addition of aprepitant for high emetogenic risk.1,2 In contrast, the management of radiation-induced nausea and vomiting (RINV) is not well established.3 Pelvic radiotherapy is classified as low risk for RINV. Current guidelines recommend that low-risk patients should receive antiemetic prophylaxis or rescue treatment with a 5-hydroxytryptamine (5-HT3) receptor antagonist. However, a consensus on optimal antiemetic treatment during concurrent chemoradiotherapy (CCRT) has not been established. A meta-analysis has confirmed the therapeutic benefit of cisplatin-based CCRT, which is now a standard treatment for advanced cervical cancer.4 Cisplatin is a chemotherapeutic agent with a high emetogenic risk and is generally administered in a dose of 40 mg/m2 every week for the treatment of cervical cancer in CCRT.5,6 To enhance treatment compliance, we have previously introduced a daily low-dose (8 mg/m2) cisplatin-based CCRT regimen, which resulted in a high total dosage of cisplatin compared with that of weekly CCRT.7,8 However, in this regimen, nausea and vomiting of grade 2 and higher occurred in 26% patients despite administering a firstgeneration 5-HT3 receptor antagonist.8 Prevention of emesis during CCRT is difficult because the dosage period of cisplatin is long in both daily and weekly administration. In addition, the delayed side effects may overlap with acute side effects, and the adverse events induced by both radiation and chemotherapy can occur together. Palonosetron is a second-generation 5-HT3 receptor antagonist, a potent and highly selective 5-HT3 receptor antagonist with strong binding affinity to receptor and a long plasmaelimination half-life, indicated for the prevention of both acute and delayed CINV.9 It has been proven superior to first-generation agents, such as granisetron, in a randomized double-blind trial of prevention of CINV in the delayed phase.10–12 However, the safety and efficacy of its long-term use over 5 weeks during radiotherapy and CCRT have not been well established. Furthermore, the safety of the long-term use over 5 weeks of antiemetic drugs, such as dexamethasone, has not been
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mitsuhashi et al
American Journal of Clinical Oncology
established. Therefore, we conducted this prospective phase II study to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during cisplatinbased CCRT.
MATERIALS AND METHODS This was a prospective, single-center, open phase II study registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN 000007638.
Eligibility Criteria Patients were eligible for inclusion in this study if they met the following criteria: (i) histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma); (ii) clinical FIGO stage Ib2 to IVa cancer in whom daily low-dose cisplatin-based CCRT was planned as both primary and adjuvant treatments; (iii) no prior chemotherapy or radiotherapy; (iv) age 20 years and above with an Eastern Cooperative Oncology Group performance status of 0 to 2; and (v) adequate bone marrow, renal, and liver function. Patients with any of the following conditions were excluded from the study: (i) severe systemic or uncontrolled disease (uncontrolled diabetes mellitus or hypertension); (ii) clinically unstable seizure disorder requiring anticonvulsants; (iii) massive pleural effusion or ascites; (iv) gastric outlet or intestinal obstruction; and (v) a known hypersensitivity to palonosetron, granisetron, or other 5-HT3 receptor antagonists or dexamethasone ingredients. Patients were also excluded if they had received any drug with potential antiemetic efficacy within 24 hours of this study initiation or had any vomiting or grade 2 to 3 nausea in the 24hour period before the first dose of cisplatin. Informed consent was obtained from all patients before study enrollment.
Treatment The daily chemoradiation regimen comprised pelvic external beam radiotherapy (2 Gy/d, 25 fractions, 5 times a week) with daily low-dose cisplatin (8 mg/m2/d).7,8 Brachytherapy was administered to potentially curative cases through external beam radiotherapy with central shielding. The daily dose of cisplatin was reconstituted in 100 mL of normal saline and 0.75 mg of palonosetron was administered 1 hour before cisplatin on day 1 of each week. Post-cisplatin hydration was achieved with intravenous infusion of 1 L normal saline over 2 hours. All patients received a dose of oral dexamethasone (2 mg twice daily) from day 1 to the end of the treatment period. Dexamethasone was withheld in the case of grade 1 or higher toxicity with Cushingoid appearance, such as moon face. Dexamethasone and palonosetron were withheld during interruption of cisplatin because of acute toxicity.
Assessment The primary endpoint of this study was treatment efficacy, as measured by the percentage of patients achieving a complete response. Complete response was defined as no emetic episodes and no antiemetic rescue medication during the treatment period that started at administration of cisplatin and the end of CCRT. The secondary endpoints were complete control (defined as no emetic episodes, no rescue medication, and no more than mild nausea), the severity of nausea, adverse effects, and time to administration of rescue therapy. Endpoints were evaluated at the end of CCRT if patients interrupted cisplatin because of acute toxicity. Patients recorded emetic
2 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
episode, nausea, and rescue antiemetics received in a daily journal. The degree of nausea was assessed daily using a 10-point horizontal visual analogue scale (VAS) with a total score (range, 0 to 400) calculated on the basis of the daily scores obtained until the end of the treatment period. The definition of the degree of total VAS score were as follows: 200 = severe nausea. We evaluated the any emetic episodes, nausea grade, use of rescue medication, and the total VAS score. If emesis occurred the patient completed the current study diary. All adverse events were recorded and graded according to the common toxicity criteria of the National Cancer Institute, version 4.0.
RESULTS Patient Characteristics From January 2012 to April 2013, 26 consecutive patients with diagnosed FIGO stage IB2 to IVa cervical carcinoma treated with radiotherapy at the Chiba University Hospital were enrolled for the study. Patient characteristics are listed in Table 1. The median age was 59 years (range, 31 to 74 y). All patients were administered daily low-dose cisplatinbased CCRT. Radiotherapy was completed according to the planned regimen without discontinuation. Chemotherapy was successfully performed without interruption in 46% (12/26) of the patients. Chemotherapy was interrupted for 12 patients because of acute toxicity. Mean interruption of cisplatin was 2.9 times (range, 1 to 5). The mean dose of total cisplatin was 184 mg/m2 (range, 136 to 200 mg/m2). The median total treatment period was 38 days (range, 35 to 40 d).
Efficacy Endpoint No patient vomited during the treatment period. The complete response rate during CCRT was 100%. During almost 5 weeks of treatment, 21 of 26 patients (81%) were completely free from nausea and achieved a total VAS score of 0. The remaining 5 patients had grade 1 nausea and had a mean total VAS score of 20 points (range, 15 to 45). Complete control was achieved in all 26 (100%) patients; however, weight loss higher than grade 1 occurred in 7 (27%) patients. TABLE 1. Patient Characteristics No. patients Median age (range) (y) Stage Ib2 II III IVa Adjuvant External beam radiation therapy Primary therapy Pelvic Pelvic + EFRT Adjuvant therapy Pelvic Brachytherapy +
26 59 (31-74) 5 9 5 3 4 14 8 4 18 8
EFRT indicates extended field radiotherapy.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
TABLE 2. Acute Toxicity (NCI-CTC Version 4.0)
Grade Toxicity
1
2
3
4
5
Nausea Vomiting Weight loss Weight gain Diarrhea Constipation Headache Cushingoid feature
5 0 5 2 10 5 0 5
0 0 2 0 6 0 0 0
0 0 0 0 3 0 0 0
0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
Z2 (n [%]) 0 0 2 0 9 0 0 0
(0) (0) (8) (0) (34) (0) (0) (0)
Safety All patients were evaluated for toxicity (Table 2). Of the 26 patients, 13 (50%) reported the use of magnesium for constipation before treatment. In 5 (19%) patients, constipation worsened after palonosetron administration. By the third week of CCRT, the symptoms of constipation changed to diarrhea in these 5 patients. Five patients reported symptoms of grade 1 Cushingoid features of moon face, which developed after completion of treatment in 1 patient and during the fourth week in 4. All treatment-related side effects were either confirmed remission or recovery after completion of the treatment.
DISCUSSION Despite recent advances, the management of nausea and vomiting remains problematic during CCRT. In the present study, we demonstrated the efficacy and safety of a combination of palonosetron and dexamethasone in the prevention of nausea and vomiting in patients receiving daily low-dose cisplatin-based CCRT for the treatment of uterine cervical cancer. This therapy achieved 100% prevention of emetic episodes and all other adverse effects were maintained at tolerable levels. Nausea and vomiting are common adverse effects of cisplatin-based chemoradiotherapy. A Japanese phase II study of weekly cisplatin-based CCRT (40 mg/m2) for cervical cancer revealed that 20% patients suffered grade 2 nausea and vomiting, each during CCRT.13 The protocol of this trial recommended the administration of granisetron and dexamethasone; however, the dosage method of these antiemetic drugs remains unclear. A phase II study of weekly cisplatinbased CCRT (40 mg/m2) by Kato et al14 revealed that the frequency of nausea and vomiting of grade 2 or higher was 32%. Antiemetics, such as 5-HT3 receptor antagonists, metoclopramide, and dexamethasone, were given both before and after cisplatin administration in this study. We previously reported the results of a phase II study of daily cisplatin-based CCRT (8 mg/m2) for the treatment of uterine cervical cancer.8 In that study, we administered daily antiemetic premedication with 5-HT3 receptor antagonists without dexamethasone during administration of cisplatin. We predicted that emetic episodes would occur less often in daily CCRT than in weekly CCRT because the cisplatin dose used in the daily regimen was small. However, nausea and vomiting of grade 2 and higher occurred in 26% patients despite administering an antiemetic drug. In the present study, the prevention of emetic episodes was superior to our previous study. We believe that there are 2 reasons for this improvement. First, we changed the antiemetic drug to palonosetron from a first-generation 5-HT3 receptor antagonist because palonosetron has been reported to be more efficacious than granisetron by Sato and colleagues.10–12 r
2014 Lippincott Williams & Wilkins
Palonosetron and Dexamethasone in Chemoradiation
Second, we administered dexamethasone every day to the patients during the treatment period. A recent prospective study of the prevention of nausea and emesis during weekly cisplatin-based CCRT revealed that an antiemetic prophylaxis consisting of weekly palonosetron (0.25 mg) and prednisolone (200 mg/wk) is insufficient for the prevention of nausea and vomiting.15 After 5 cycles of weekly cisplatin (40 mg/m2), only 23% patients were continuously free from nausea. In contrast, the rate of prevention of emetic episodes was 100% in the present study, and 81% patients were free from nausea. In Japan, palonosetron is available at dose of 0.75 mg because of the tendency for better efficacy with the 0.75 mg dose than with the 0.25 mg.12,16,17 We believe that these positive results are because of a higher dose of palonosetron (0.75 mg) and daily administration of dexamethasone in the present study, rather than the differences in dosage regimes of cisplatin (weekly vs. daily low dose). There are no reports regarding long-term oral administration of dexamethasone to prevent emetic episodes. Furthermore, the safety of the long-term use of steroids, such as dexamethasone, has not been established.12,18,19 In the present study, dexamethasone was administrated at a maximum total dose of 128 mg during the treatment period. To the best of our knowledge, this is the first report to show the advantages and safety of long-term dexamethasone administration for antiemesis. There were no serious side effects other than Cushingoid features, such as moon face, which resolved after discontinuation of dexamethasone. Dexamethasone was administered at 2 mg twice daily in the present study; however, emetic episodes may be preventable using lower doses such as 1 mg. Nonetheless, it remains unknown whether dexamethasone administration is actually necessary on each day of cisplatin treatment. The most common adverse effects of palonosetron are headache and constipation.17 In this study, these adverse effects were minimal; however, it is important to consider that palonosetron-induced constipation may be masked because diarrhea is a major side effect of CCRT, and the beneficial effects of 5-HT3 receptor antagonists for the prevention of radiation-induced diarrhea have been previously reported.20 However, there have been no previous reports regarding weekly administration of palonosetron. The results of the present study indicated that the weekly administration of palonosetron (0.75 mg) was well tolerated and safe. Finally, it was difficult to establish whether the onset of the emesis experienced by patients undergoing multiple-day cisplatin administration was acute or delayed, because both events may repeatedly overlap. Our results demonstrated that the administration of weekly palonosetron (0.75 mg) and daily oral dexamethasone (4 mg) provided complete protection from nausea and vomiting during daily CCRT. Therefore, the results of this study provide useful information that will aid in proposing a candidate treatment for patients suffering from combined RINV and CINV. REFERENCES 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189–4198. 2. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232–v243. 3. Feyer PC, Maranzano E, Molassiotis A, et al. Radiotherapyinduced nausea and vomiting (RINV): MASCC/ESMO guideline
www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mitsuhashi et al
4.
5.
6. 7. 8.
9. 10.
11.
12.
American Journal of Clinical Oncology
for antiemetics in radiotherapy: update 2009. Support Care Cancer. 2011;19(suppl 1):S5–S14. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001;358:781–786. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340:1154–1161. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144–1153. Mitsuhashi A, Uno T, Tanaka N, et al. Phase I study of daily cisplatin and concurrent radiotherapy in patients with cervical carcinoma. Gynecol Oncol. 2005;96:194–197. Mitsuhashi A, Uno T, Usui H, et al. Daily low-dose cisplatin-based concurrent chemoradiotherapy in patients with uterine cervical cancer with emphasis on elderly patients: a phase 2 trial. Int J Gynecol Cancer. 2013;23:1453–1458. Siddiqui MA, Scott LJ. Palonosetron. Drugs. 2004;64:1125–1132. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473–2482. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570–1577. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, doubledummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10:115–124.
4 | www.amjclinicaloncology.com
Volume 00, Number 00, ’’ 2014
13. Toita T, Kitagawa R, Hamano T, et al. Feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high-dose rate intracavitary brachytherapy (HDR-ICBT) and 40-mg/m2 weekly cisplatin for japanese patients with cervical cancer: results of a multi-institutional phase 2 study (JGOG1066). Int J Gynecol Cancer. 2012;22:1420–1426. 14. Kato S, Ohno T, Thephamongkhol K, et al. Multi-institutional phase II clinical study of concurrent chemoradiotherapy for locally advanced cervical cancer in East and Southeast Asia. Int J Radiat Oncol Biol Phys. 2010;77:751–757. 15. Ruhlmann CH, Belli C, Dahl T, et al. Palonosetron and prednisolone for the prevention of nausea and emesis during fractionated radiotherapy and 5 cycles of concomitant weekly cisplatin-a phase II study. Support Care Cancer. 2013;21:3425–3431. 16. Miura S, Watanabe S, Sato K, et al. The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy-induced nausea and vomiting in lung cancer patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21:2575–2581. 17. Maemondo M, Masuda N, Sekine I, et al. A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy. Ann Oncol. 2009;20:1860–1866. 18. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15: 1293–1300. 19. Wong RK, Paul N, Ding K, et al. 5-hydroxytryptamine-3 receptor antagonist with or without short-course dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19). J Clin Oncol. 2006;24:3458–3464. 20. Franzen L, Nyman J, Hagberg H, et al. A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol. 1996;7:587–592.
r
2014 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
