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  Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 207-210
 

Pazopanib efficacy and toxicity in a metastatic sarcoma cohort: Are Indian patients different?


1 Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Radiation Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
5 Department of Radiodiagnosis, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication19-Jul-2019

Correspondence Address:
Sameer Rastogi
Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_105_18

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 » Abstract 


PURPOSE: There is no study till date determining the spectrum of adverse events of pazopanib in Indian patients with advanced sarcoma.
MATERIALS AND METHODS: We conducted a retrospective study by analyzing the case records of metastatic sarcoma patients treated with pazopanib from January 2016 to July 2017 in sarcoma medical oncology clinic. Toxicity was assessed according to CTCAE v.4.03 criteria. SPSS version 23 was used for statistical evaluation.
RESULTS: A total of 33 patients received pazopanib. The median age was 41 years (range, 19–75 years), with a male predominance (54.5%). Twenty-six patients (78.8%) had ECOG performance status 1 at the time of pazopanib initiation. The most common type of sarcoma was synovial sarcoma, and the mean duration of pazopanib intake in patients was 4.12 months. The median follow-up was 13 months. Median progression-free survival was 5 months, and median overall survival was 18 months. Overall response rate was 6.0%. Out of the 33 patients, 42.4% (n = 14) received it after first line of therapy. Six patients (18.2%) required dose reductions due to toxicity. Thirteen (39.4%) patients experienced CTCAE grade 3 or 4 toxicities. Most common grade 3 and 4 toxicities experienced among patients were hand–foot skin reaction (18.2%) and proteinuria (9.1%). No significant difference was seen when analyzed for variables such as age, sex, ECOG performance status, comorbidities, and number of previous lines received in patients experiencing grade 3 and 4 toxicities.
CONCLUSIONS: The spectrum of adverse events in Indian patients at doses lower than the recommended dose is distinctly different from the western population. However, this unique toxicity profile needs to be validated in prospective studies.


Keywords: Metastatic sarcoma, pazopanib, sarcoma, toxicity


How to cite this article:
Sharma A, Vanidassane I, Aggarwal A, Mridha AR, Pandey R, Dhamija E, Barwad A, Rastogi S. Pazopanib efficacy and toxicity in a metastatic sarcoma cohort: Are Indian patients different?. Indian J Cancer 2019;56:207-10

How to cite this URL:
Sharma A, Vanidassane I, Aggarwal A, Mridha AR, Pandey R, Dhamija E, Barwad A, Rastogi S. Pazopanib efficacy and toxicity in a metastatic sarcoma cohort: Are Indian patients different?. Indian J Cancer [serial online] 2019 [cited 2019 Aug 20];56:207-10. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/207/263023





 » Introduction Top


Metastatic soft tissue sarcoma (STS) is an extremely heterogenous and complex disease with dismal outcomes. However, the advent of newer drugs in the last few years has shown to improve outcomes, albeit with modest benefit.[1],[2] Pazopanib approval was based on multi- institutional, randomized, placebo-controlled PALETTE trial in advanced non-adipocytic STS with pazopanib at an oral dose of 800 mg.[3] In the PALETTE trial, pazopanib arm showed median progression-free survival (PFS) of 4.6 months compared to 1.6 months in the placebo arm [hazard ratio (HR) 0.31, 95% CI, 0.24–0.40; P < 0.0001]. The median relative dose intensity was 100% for placebo and 96% for pazopanib in the PALETTE trial. In the exploratory analysis evaluating the health-related quality of life (QOL), although pazopanib did not improve QOL, the EORTC QLQ-C30 global health status subscale between the two treatment arms were not statistically significant, indicating that QOL was maintained compared to placebo. These indicators along with low-grade 3-4 toxicities indicate that this is a fairly well tolerated drug. In another recent study in which pazopanib was used in a named patient program, the relative dose intensity of pazopanib was 92%.[4] Recently, Nakamura et al.[5] showed relatively poor toxicity profile in Japanese patients (n = 156) suffering from STS with a median PFS of 15.4 weeks; average dose intensity of pazopanib was 600 mg in that trial with 48% of the patients requiring a dose reduction or interruption in pazopanib treatment.[5] Younger patients were significantly more likely to have hand-foot syndrome and nausea.

Currently, there is no data of pazopanib efficacy and toxicity from the Indian subcontinent, and we aimed to conduct this study to learn about the real world toxicities of pazopanib in advanced STS patients.


 » Materials and Methods Top


This was a single institution retrospective study where all metastatic sarcoma patients treated with pazopanib between January 2016 and July 2017 were included using the hospital-based data system. Toxicity and outcome data were retrieved from a well-structured performa.

Treatment characteristics

Our practice in clinic is to start pazopanib on 400 mg dose and then escalate over the next few weeks to 800 mg if the patient tolerates the treatment without any grade 3 or 4 toxicities. Patients were followed up initially weekly and then every 3 weeks, with clinical examination focusing on toxicity, disease control, and laboratory investigation including complete hemogram, liver, and renal function test. Two-dimensional echocardiography was done whenever clinically seemed appropriate on the basis of symptoms and previous anthracycline dose.

Data collection and toxicity grading

Demographic details (including age, sex, ECOG performance status), diagnosis, and various treatment lines received by the patient before pazopanib were documented. Treatment response and present status of the patients were obtained telephonically and from records. Toxicity was graded using common terminology criteria for adverse events (CTCAE) version v.4.03. Toxicity data, treatment interruptions, dose reduction, and dose increments were also tabulated.

Categorical variables and ordinal variables were displayed in tabular form. All numerical variables were tabulated as whole numbers. Median and range were used to describe quantitative variables. Kaplan–Meier curve was used for survival analyses. P- values of <0.05 were considered statistically significant. IBM SPSS version 23.0. was used for statistical analysis (Armonk, New York, USA).


 » Results Top


Study population

During the study period, a total of 33 metastatic sarcoma patients received pazopanib [Patient characteristics are mentioned in [Table 1]. The median age was 41 years (range, 19–75 years) with a male predominance (54.5%). Twenty-six patients (78.8%) had ECOG performance status of 1 or more at the time of pazopanib initiation. Study population cohort was heterogeneous with the most common histopathological diagnosis being synovial sarcoma (15.1%). Other common histologies are shown in the [Table 1]. Mean duration for pazopanib exposure was 4.12 months.
Table 1: Patient characteristics

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Drug results and outcomes

Out of the total study population, most patients received the drug either first or second line (33.3%, 42.4%, respectively). Among the 11 (33.3%) patients who received pazopanib in the first line, rationale of starting the drug upfront ranged from histology-driven decisions such as angiosarcoma and lymphangiosarcoma (n = 3, 27%), older age (n = 3, 27%), patients' and physicians' preference (n = 2, 18%), or in dearth of definitive evidence of chemotherapy in rare histologies, e.g., gastric clear cell sarcoma (n = 1, 9%). Median follow-up, median progression-free survival (PFS) and median overall survival (OS) were 13 months, 5 months, and 18 months, respectively [Figure 1]. For the given cohort the overall response rate (ORR) was 6.0% [Table 2].
Figure 1: (a) Progression Free Survival. (b) Overall Survival

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Table 2: Survival data

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Toxicity analysis

Majority of the patients were not able to tolerate the full 800 mg dose. In 23 patients (69%), the dose could not be escalated beyond 400 mg due to drug toxicity. Dose escalation from 400 mg to 600 mg and 800 mg was successfully achieved in 6 (18.2%) and 4 patients (12.1%), respectively. Almost three-fourth of the patients (72.7%) experienced some form of toxicity. Dose reduction from higher doses of 800 and 600 mg was needed in 6 patients (18.2%) due to poor tolerance. Grade 3 or 4 toxicities were experienced by 13 (39.4%) patients [Figure 2]. Hand–foot skin reaction (HFSR, 18.2%) and [Figure 3] proteinuria (9.1%) were the most common grade 3 and 4 toxicities. Other less common grade 3 and 4 adverse events were liver function test (LFT) derangement/oral mucositis (6% each), hypoalbuminemia/thrombocytopenia/hypertension/diarrhea (3% each). Alopecia was not noticed, but 5 patients (15.2%) experienced hair color changes [Figure 2]. Two patients (post-anthracycline) experienced symptomatic cardiac deterioration requiring drug stoppage. A definitive cause–effect relationship is difficult to ascertain.
Figure 2: CTCAE grade 3 and 4 toxicties

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Figure 3: Hand-foot skin reaction

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None of the patient characteristics such as age, sex, ECOG performance status, comorbidity, and number of previous lines received displayed any significant association with grade 3 and 4 toxicity in univariate analysis. However, there was a trend towards grade 3 or 4 toxicity in patients who had received no previous lines versus previous lines (P = 0.1).


 » Discussion Top


In absence of any data from the Indian subcontinent, this study is the first evaluating the pazopanib tolerability in STS.

Median PFS in our cohort was 5 months (~20 weeks) which was slightly better than the other two large studies – PALETTE trial (4.6 months) and Japanese post marketing surveillance study (15.4 weeks).[3],[5] Despite our sample size being small, our cohort had comparable or marginally better outcomes. This could be attributed to the retrospective nature of the study as response assessment was not pre-planned and dependent on the discretion of physician's clinical judgement. Study population in general did well with the median follow-up of 13 months; the estimated median overall survival in our cohort was 18 months. The median OS in the two above-mentioned well described trials were 12.5 months and 11.2 months, respectively.[3],[5] The possible reason may be attributed to the younger age cohort (median age 41 years), better ECOG performance status (0 or 1, 90%), and one-third patients receiving the drug as the first line therapy.

Regarding toxicity, overall incidence of grade 3 and 4 toxicity in our cohort (39.4%) was similar to the PALETTE trail (38%) and Japanese PMS (28%, relatively less) keeping in mind that the dose our patients received was much lesser. However, the relative proportion of some of the toxicities differed in the comparable cohort. Our study population had more grade 3 or 4 HFSR (18% vs 2% vs 1%), proteinuria (9% vs NA vs <1%), mucositis (6% vs 1% vs NA), and hair color changes (15% vs 38% vs 14%) compared to the PALETTE and PMS studies [Figure 1].[3],[5] Higher HFS reaction by tyrosine kinase inhibitors (TKIs) can be attributed to the Indian population frequently dealing with manual work including cooking by hand and dealing with friction and detergent which might not be the case with western population, where there is much more use of electric appliances.[6] In our study, mucositis (6%) and diarrhea (3%) also comprised significant percentage of toxicities which was unlike that seen in the published literature. Liver toxicity was limited to enzyme derangement (6%), with no grade 3 or 4 toxicity encountered, similar to the PALETTE trial (10%) and Japanese PMS (28%).[3],[5] One hypothesis for the difference in toxicity profile of various TKI between the studies published in the west compared to Eastern or Asian counterparts can probably be attributed to regional or geographic variation.[7] Most of our patients did not tolerate the recommended pazopanib dose of 800 mg.

The limitations of our study are small sample size and the retrospective nature. However, the toxicities of the patient on a drug with palliative intent should not be overlooked. A prospective study with a larger sample size to address the toxicities and appropriate dosing of pazopanib in our population is required to confirm our findings.


 » Conclusions Top


The spectrum of adverse events in Indian patients at doses lower than the recommended dose is distinctly different from the western population. The survival and response data trends are similar or marginally better than that reported in the international literature and can be attributed to the retrospective nature of this study or a regional geographical variation. However, this unique toxicity profile needs to be validated in prospective studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Frezza AM, Stacchiotti S, Gronchi A. Systemic treatment in advanced soft tissue sarcoma: What is standard, what is new. BMC Med 2017;15:109.  Back to cited text no. 1
    
2.
Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): A randomised controlled phase 3 trial. Lancet Oncol 2017;18:1397-410.  Back to cited text no. 2
    
3.
van der Graaf WT, Blay J-Y, Chawla SP, Kim D-W, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879-86.  Back to cited text no. 3
    
4.
Gelderblom H, Judson IR, Benson C, Merimsky O, Grignani G, Katz D, et al. Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: Results of the SPIRE study. Acta Oncol 2017;56:1769-75.  Back to cited text no. 4
    
5.
Nakamura T, Matsumine A, Kawai A, Araki N, Goto T, Yonemoto T, et al. The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study. Cancer 2016;122:1408-16.  Back to cited text no. 5
    
6.
Odanaka M, Suzuki S, Kobayashi M, Funazaki H, Okuyama H, Takahashi H, et al. Risk Factor of the Hand/foot Skin Reaction Induced by Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Iryo Yakugaku Jpn J Pharm Health Care Sci 2013;39:322-6.  Back to cited text no. 6
    
7.
Liu X, Fiocco M, Swen JJ, Guchelaar H-J. Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: A meta-analysis. Acta Oncol 2017;56:582-9.  Back to cited text no. 7
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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