|Ahead of print
Pazopanib in metastatic soft tissue sarcomas: Testing the waters in developing world
Jyoti Bajpai1, Sujith Kumar Mullapally1, Akhil Kapoor1, Jaya Ghosh1, Bharat Rekhi2
1 Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra, India
|Date of Submission||14-Apr-2019|
|Date of Decision||06-Sep-2019|
|Date of Acceptance||07-Sep-2019|
|Date of Web Publication||27-Jan-2021|
Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is important to explore the feasibility (toxicity, acceptance), efficacy (response rates, survival), and optimal dose requirement of pazopanib in M-STS in India.
Methods: All patients who received pazopanib for M-STS in 2013–2018 in Tata Memorial Centre were included. Institutional ethics committee approval was obtained. Assessment for response with contrast computed tomography scans was done as per the response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Pazopanib was continued until progression or unacceptable toxicity. Clinical benefit rates and survival were evaluated by Kaplan-Meier method. All statistical calculations were done using SPSS version 21.0.
Results: Seventy-two consecutive patients with a median follow-up of 17 (4–40) months were included in this study. Median lines of prior therapy were 2 (0–2). Among 50 evaluable patients, there were 12/50 (24%) partial responses, 25/50 (50%) stable disease, and 15/50 (30%) progressive disease. Median progression-free survival was 5 (95% confidence interval (CI) 3–6.9) months and median overall survival was 11 (95% CI 6.8–15.2) months. Adverse effects (G2/G3) in patients: hand foot syndrome-28%, hyperbilirubinemia/transaminitis-10%, diarrhea-20%, hypertension-17%, hypothyroidism-15%, anemia-6%, and fatigue-17%. Notably, 40% patient required dose reduction and median dose was 600 (200–800) mg daily.
Conclusion: Pazopanib was found a feasible treatment option for M-STS in India with internationally comparable outcomes. However, significant patients required dose modifications, and median tolerated dose was lower than the standard 800 mg dose. This novel finding merits confirmation in larger cohorts for reproducibility.
Keywords: Low and middle income countries, metastaticc, pazopanib, soft tissue sarcomaKey Message Our study shows comparable efficacy and toxicity profile of pazopanib in Indian patients of metastatic soft tissue sarcoma though the tolerated doses (600mg) are less than recommended doses used in pivotal studies. Pharmacogenetic differences may be the reason and needs further evaluation.
| » Introduction|| |
Soft tissue sarcomas (STS), derived from embryonic mesoderm, are heterogeneous tumors and can arise from anywhere in the body and account for about 1% of all adult cancers. They have great variations in terms of genetic alterations, pathogenesis, and clinical behavior.? Anthracycline-based monotherapy or in combination with Ifosfamide is the standard first-line chemotherapy for metastatic STS (M-STS). However, the outcomes are dismal and the median overall survival (OS) is only about 12 months, which has not changed since last 2 decades. In India, reported median event-free survival and OS is of about 6 months and 10 months, respectively, in M-STS.
Pazopanib was approved in 2012 as the first ?nonchemotherapeutic agent that shows some activity against nonadipocytic M-STS. However, there is still paucity of data regarding clinical benefit and tolerance in patients from Indian subcontinent. Our study aimed to retrospectively analyze the clinical use of pazopanib in patients with advanced STS who were treated at our institution to see feasibility of this treatment in India and other Lower and Middle Income Countries (LMICs).
| » Materials and Methods|| |
We retrospectively reviewed the electronic medical records of all patients with M-STS who were treated with pazopanib from December 2013 to October 2018 at Tata Memorial Hospital, Mumbai. Patients with histopathological diagnosis of STS and complete clinical information including patient demographic profile, tumor characteristics, response scans and follow-up records were included in this study. The protocol for start of pazopanib at our hospital was initially 800 mg once a day and then to de-escalate if there is either Grade 3 or 4 hematological and nonhematological toxicities like transaminitis. In the course of this retrospective study, as experience was gained in terms of tolerance, the protocol shifted to 400 mg once daily and then to escalate every 2 weeks by 200 mg, only if the tolerance is good. This study was reviewed and approved by the institutional review board of Tata Memorial Hospital, Mumbai. The study was registered with Clinical Trial Registry of India (CTRI) (CTRI/2018/01/011112).
Statistical analysis was performed using the SPSS version 21 (SPSS Inc., Chicago, IL, USA). Standard descriptive and analytical methods were used to describe the patient population and their baseline characteristics. Overall survival (OS) was defined as the time from initiation of the pazopanib to the date of death or last follow-up. Progression-free survival (PFS) was defined as the time from initiation of the pazopanib to the date of documented disease progression or death from any cause. Kaplan-Meier estimates were used to analyze time-to-event variables, and 95% confidence intervals (CIs) were computed for time-to-event medians. Toxicity was defined as per the CTCAE Version 4.0.
| » Results|| |
A total of 72 consecutive patients were included in this study. The patient characteristics are shown in [Table 1]. The median age at presentation was 47 (21–75) years. One-third of them had comorbidities (diabetes, hypertension). Most common histology was leiomyosarcoma (28%), synovial sarcoma (22%) followed by unspecified high-grade spindle cell sarcoma (18%), alveolar soft part sarcoma (14%), etc. High-grade sarcoma was predominant (67%) followed by intermediate grade (26%). Among primary sites, extremities (53%) were commonest followed by retroperitoneum (19%) and trunk (17%), etc. Lung was the most common (83%) site of metastases at presentation followed by bones (17%).
Treatment prior to pazopanib
The treatment received prior to the start of pazopanib is listed in [Table 2]. Of the total patients, 52 (77%) had definitive surgery and remaining only had biopsy, 30 (52%) received curative radiotherapy (adjuvant/neo-adjuvant), and 8 (13%) received palliative radiotherapy. Twenty-one patients (29%) had received prior adjuvant chemotherapy. On progression, 56% received at least one line of palliative chemotherapy and 18% did not ever receive chemotherapy due to poor performance status (PS-3 or 4), extremes of age, and patient refusal for intravenous chemotherapy, Palliative chemotherapy was doxorubicin-ifosfamide (45%), gemcitabine-docetaxel (35%), and 2 or more lines (10%). One patient with alveolar soft part sarcoma had received interferon alpha 2a. Median lines of therapies before pazopanib were 2 (range1–2). The median duration from the time of diagnosis to the start of pazopanib was 12 (1–120) months.
Treatment with pazopanib
[Table 3] summarizes the details of treatment with pazopanib. Majority of patients were Eastern cooperative oncology group (ECOG) PS1. The initial dose was kept as 400 mg once daily in view of tolerance concerns, especially after being previously treated extensively. Dose was increased to 600 mg once daily and then to 800 mg once daily as per the tolerance assessed subsequently after every 2–4 weeks. The median dose that was tolerated was 600 mg (range 200–800) per day. The patients were seen every month for clinical assessment with periodical imaging for response at 3 months and lab reports for toxicity assessment. Imaging studies were done earlier only if there was strong clinical suspicion of progression.
Patient tolerance to lower doses of pazopanib was excellent and, hence, dose escalation was done for majority of them. There was increase in toxicities noted at higher doses. Complete toxicity profile was available for 54 patients at the time of study. There were no Grade 4 toxicities. Grade II/III adverse effects are shown in [Table 4]. Hand-foot syndrome (HFS) was seen in 28% patients of which majority were of grade 2. Diarrhea was seen in 20% patients followed by fatigue (17%), which again were mainly grade 2. Other adverse events seen were hypertension (17%), hypothyroidism (15%), liver dysfunction (10%), mucositis (7%), anemia 6%, etc. Thirteen patients (32%) required dose reduction of pazopanib due to poor tolerance. In 5 patients (12%), pazopanib was stopped permanently due to grade 3 toxicities predominantly liver dysfunction. None of these patients had liver metastases.
Radiological assessment by means of computed tomography (CT) scan imaging was advised at every 3-month interval and response as per response evaluation criteria in solid tumors (RECIST) 1.1 was done. Among 50 evaluable patients, there were 12/50 (24%) partial responses (PR), 25/50 (50%) stable disease (SD), and 15/50 (30%) progressive disease (PD). Clinical benefit rate as measured by sum of PR and SD was, thus, 74%.
Overall survival and progression-free survival
The median follow-up duration was 18 months (2–40 months). The median progression-free survival was 5 months (95% CI: 3.3–6.6) and median OS was 12 months (95% CI: 6.8–17.1).
This data is depicted in [Figure 1] and [Figure 2].
|Figure 1: Overall survival (OS) as per Kaplan-Meier estimation, CI= Confidence interval, Cum = cumulative|
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|Figure 2: Progression-free survival (PFS) as per Kaplan-Meier estimation, CI= Confidence interval, Cum = cumulative|
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| » Discussion|| |
To our knowledge, our study reports the largest data on use of pazopanib in Indian patients with advanced soft tissue sarcoma after failing previous lines of chemotherapy and provides the efficacy and toxicity data in Indian patients.
The pivotal study by Van der Graaf et al. had showed improvement in PFS (defined as the time from start of pazopanib to clinical or radiological progression) in patients receiving pazopanib compared with those receiving placebo (Hazard ratio (HR): 0.35, 95% CI: 0.26–0.48; P < 0.001). The median PFS was 4.6 months for patient receiving pazopanib and 1.6 months for patients receiving placebo. In our study, PFS was 5 (3.3–6.6) months, which was comparable to the international data, albeit in a smaller cohort. Our median OS (12 months) is also comparable to the PALETTE trial (12.5 months) and Japanese post marketing surveillance study (11.2 months). Notably, in another retrospective Indian study with 33 patients, the median PFS was 5 months, which is comparable; however, their OS is higher (18 months), which could be effect of small sample artefact and also a one-third of the patients received pazopanib in first line. Another possibility of proportionately high good biology disease with lower grades (the information not available in the article) as response rates was lower (6%) with high survival.
Kasper et al. analyzed the long-term responders and survivors of PALETTE trial and found that 36% and 34% of all STS patients who received pazopanib had long PFS and/or OS, respectively. Of these long-term survivors, 3.5% of patient remained progression free with pazopanib for more than 2 years. Normal hemoglobin, low/intermediate grade histology, and good PS were identified as important prognostic factors related to sustained response. The PS of majority patients in our study was 1, 26% had intermediate grade, and also baseline median hemoglobin level was 11.8 g/dL. These factors may have contributed to PFS seen in our study. The estimated progression-free survival in our study population is 15% at 2 years.
Pazopanib has shown activity against most of the nonadipocytic STS subtypes, especially leiomyosarcoma and synovial sarcoma as demonstrated in the PALETTE study. Our study had only 50% patients with these subtypes but still pazopanib showed good efficacy results. There were 14% patients of alveolar soft part sarcoma. The best radiological response seen in PALETTE trial was SD (67%), PR (6%), and PD (23%). Our study had corresponding SD in 50%, PR in 24%, and PD in 30% patients. Majority of responses were SD, which is known in case of targeted agents like pazopanib.
Major side effects were grade 2 and included HFS, diarrhea, fatigue, hypertension, liver dysfunction, and hypothyroidism. They were managed with supportive measures like antihypertensive, urea-based skin creams, antidiarrheals, etc. The incidence of Grade 3 Hyperbilirubinemia and/or transaminitis was 10%, and the drug was stopped permanently in these patients. There were considerable adverse effects on the standard dose of 800 mg and nearly one-third of patients on 800 mg required dose reduction. Few patients on 600 mg also required dose reduction. In total, nearly 40% of the study population required dose reduction. Consequently, median dose in this study was 600 mg (200–800). The adverse effects seen in our study are similar to the PALETTE trial.
Yoo et al., in his study with 43 patients of Korean descent, found that pazopanib demonstrated acceptable antitumor activity in the Asian patients who had been heavily pretreated for sarcoma, with seemingly more favorable results in the patients with leiomyosarcoma, MPNST, MFH/UPS. Most of the patients in that trial were of poor performance status and were heavily pretreated. Most of the patients recruited in PALETTE study were Caucasian and only 24% had Asian ancestry. Our patients in the study had mostly of good PS and also only 9% patients had prior more than 2 lines of chemotherapy. Still in our patients, the tolerated dose of 600 mg is lower than the recommended dose 800 mg once daily.
The exact reason for this is not known. However, there are differences in tolerance and outcomes when same anticancer therapy is given to different populations due to pharmacogenomic differences. Based on our initial experience, we now start all patients with 400 mg once daily and then do stepwise 2 weekly increments to 600 mg once daily and further to 800 mg if well tolerated. In case of grade 3 adverse effects apart from transaminitis, similar strategy for dose decrement is employed. In the other Indian study, 70% patients received 400 mg dose, 18% 600 mg, and 12% 800 mg due to toxicity, which supports our findings.
The significance of identifying molecular targets and the use of TKI like pazopanib either alone or with combination of chemotherapy for better results cannot be overemphasized. The intensification of doxorubicin and ifosfamide by Judson et al. failed to show any benefit of such approach in palliation of advanced STS. The use of pazopanib in neoadjuvant setting also is being tried with aim to identify specific biomarkers and also to assess metabolic response. Regorafenib also has shown to have an important clinical antitumor effect in nonadipocytic soft tissue sarcomas, improving progression-free survival from 1 month with placebo to 4 months in a phase II study. pazopanib with gemcitabine versus pazopanib has shown better PFS rate at 3 months and overall PFS, especially in liposarcoma.
Limitations of this study include the retrospective nature and small patient number. The small sample size precludes any attempt to analyze influence of histological types on the outcome though majority of our patients had tumors of nonadipocytic histology. However, still, this is the largest real-world data from India about the use of pazopanib in advanced soft tissue sarcoma and helps us in deriving inferences about feasibility. Recent studies on pharmacokinetics of Aurora A Kinase inhibitor Alisertib has showed achievement of similar exposures in Asian patients who were administered 40% lower dose compared to the Western population. As per our study findings, similar pharmacokinetic variations may exist for pazopanib too and further studies are warranted. This will have important implications in clinic.
| » Conclusion|| |
Pazopanib showed promising efficacy with acceptable toxicity profile in Indian patients and can be considered as an important option for patients with prior treated nonadipocytic M-STS. Larger studies/clinical trials on optimum dosing of pazopanib and pharmacogenomic variations are indicated to confirm the novel dose requirement found in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]