|Year : 2016 | Volume
| Issue : 3 | Page : 423-428
Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria
A Joshi1, A Ramaswamy1, V Noronha1, VM Patil1, A Chandrasekharan1, A Goel1, A Sahu1, N Sable2, A Agrawal3, S Menon4, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||24-Feb-2017|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Sorafenib is an established upfront treatment option for metastatic RCC (mRCC). There is no published literature regarding its performance in Indian Patients. We present an analysis of Sorafenib use in our institute and attempt to validate the Heng criteria as a prognostic score in these patients. MATERIALS AND METHODS: Patients who received Sorafenib as first line treatment for advanced RCC from June 2012 to December 2015 were prognosticated by Heng criteria and retrospectively analysed for baseline demographics, toxicity, response and outcomes. RESULTS: 82 patients (65 males, 17 females) with a median age of 57 years were included for final analysis. Median ECOG PS was 1, 95.2 % of the patients had Stage IV disease and clear cell was the predominant histology (79.4%). 23.2%, 42.7% and 34.1% of patients were classified as low, intermediate and high risk by Heng's criteria, respectively. Dose reduction was required in 24.4% of patients, while 14.6% required permanent cessation of Sorafenib due to intolerable or recurrent side effects. Common adverse events included HFS (68.2%), mucositis (35.3%), fatigue (35.3%), rash (32.9%) and hypertension (25.6%). Response rate observed was 18.2%, while clinical benefit rate was 57.2% in the 57 patients where response was evaluable. Median progression free survival was 7.75 months (5.45-10.05) and median overall survival (OS) was 12.18 months (9.61 – 14.76). Median OS was 19.6, 16.1 and 10.3 months respectively for low, intermediate and high risk patients by Heng criteria and the criteria was statistically discriminatory for the 3 groups for OS (p=0.045, chi-square test). CONCLUSION: Sorafenib is a viable upfront treatment option for metastatic RCC in Indian patients with acceptable PFS, although a high incidence of HFS, mucositis and rash is observed. The Heng score has discriminatory value in mRCC with Sorafenib and can be considered for routine use in the clinic.
Keywords: Heng criteria, Indian scenario, metastatic renal cell carcinoma, sorafenib
|How to cite this article:|
Joshi A, Ramaswamy A, Noronha V, Patil V, Chandrasekharan A, Goel A, Sahu A, Sable N, Agrawal A, Menon S, Prabhash K. Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria. Indian J Cancer 2016;53:423-8
|How to cite this URL:|
Joshi A, Ramaswamy A, Noronha V, Patil V, Chandrasekharan A, Goel A, Sahu A, Sable N, Agrawal A, Menon S, Prabhash K. Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria. Indian J Cancer [serial online] 2016 [cited 2017 Apr 30];53:423-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/423/200662
| » Introduction|| |
Sorafenib was one of the earliest tyrosine kinase inhibitors (TKIs) introduced and approved for the treatment of metastatic renal cell carcinoma (mRCC), based on the seminal TARGET trial. Since then, a number of targeted systemic therapies have entered clinical practice with an even larger number in advanced phases of clinical trials. Sorafenib has often been used as a comparator arm in studies used for the approval, and confirmatory trials of these newer systemic therapies,,,, whether as first line or in subsequent lines of therapy. Despite the progression-free survival (PFS) benefit shown by these drugs over sorafenib, these studies also confirm the efficacy of sorafenib as a valid, first-line option for the treatment of mRCC.
While a majority of the studies, including prospective trials and large-scale retrospective data, from the Western Hemisphere have shown PFS in the range of 5.5–8.2 months,,,,, there have been studies from Asia, albeit with smaller numbers, which have shown consistently higher PFS rates with sorafenib.,,, While a certain demographic and geographic profile predictive of responses to oral TKIs in lung cancers are known (Gefitinib in young, female, Asian, nonsmokers), such a phenomenon is not as yet known in renal cell carcinoma (RCC).
A majority of studies including prognostic indices for patients on treatment with TKIs use the MSKCC; a large study and another smaller study additionally validated both the MSKCC and Heng's score simultaneously, while hinting that the Heng's score may have a slightly better discriminatory ability., While the larger study by Heng et al. included a cohort of patients treated with sorafenib, it did not individually report the discriminatory performance of the Heng's score with sorafenib.
This study was done to evaluate the efficacy and safety of sorafenib in RCC in the Indian population as well as an attempted to validate the prognostic ability of the Heng's score with sorafenib. To the best of our knowledge, this is the first such study published from India regarding the performance of sorafenib as well as the first paper to individually report outcomes for patients treated with sorafenib and prognosticated by the Heng's criteria.
| » Materials and Methods|| |
This is a part of a prospective CTRI registered study designed to collect data for patients in a structured format and was approved by the Institutional Review Board and Ethics Committee for all patients diagnosed with RCC (IEC-79; CTRI Number – CTRI/2012/11/003147). Patients treated with sorafenib for advanced or mRCC between June 2012 and December 2015 were extracted from this database and analyzed. Previous treatment with another TKI meant exclusion from the study.
Baseline demographic details including comorbidities, sites of disease/metastases, PFS, and overall survival (OS) were evaluated. Patients were prognosticated (if all factors available) and the Heng's criteria calculated for all patients.
Requirement for dose reduction and recording of toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) was carried out. Response assessment to sorafenib was done every 2–4 months by clinical evaluation and radiology, either computed tomography scans or positron emission tomography scans. Where feasible, response was assessed by RECIST criteria. However, due to variation in centers where response assessment scans were conducted as well as variations in reporting, in places where RECIST criteria were not applied, responses were graded as complete response, partial response (PR), stable disease (SD), or progressive disease (PD) based on collusion between treating clinician and radiological reporting.
Response rates (RRs) were reported as percentages. PFS was calculated as the time between start of therapy and the date of progression, permanent cessation of sorafenib, loss to follow-up, or death from any cause (if disease had not progressed). OS was calculated as the time between the start of therapy and the date of death due to any cause. Median PFS and median OS were estimated using Kaplan–Meier method. Patients were stratified by Heng's criteria, and outcomes as per stratification were compared by log-rank test. Eastern Cooperative Oncology Group-Performance Status (ECOG PS) (0–1 vs. ≥2), number of metastatic sites (<2 and ≥2), nephrectomy status, and survival based on receiving second-line therapy were also evaluated as prognostic factors by log-rank test. SPSS statistical software version 20 was used for statistical input and analysis.
| » Results|| |
Baseline demographics [Table 1]
A total of 82 patients were started on Sorafenib during the prespecified time interval and were available for analysis. Baseline demographics are shown in [Table 1]. A majority were male (79.2%), median age was 57 (21–75) years, and median ECOG PS was 1. Hypertension (HTN), diabetes mellitus, and hypothyroidism at baseline were seen in 30.5%, 14.6%, and 22.9% of patients, respectively. A majority of patients were Stage IV (95.2), 46.3% had undergone nephrectomy, and none of the patients had received any prior interferon/interleukin therapy. Histology was available in 73 (89.2%) patients, with clear cell histology being the most common (79.4%), followed by papillary, chromophobe, sarcomatoid, and translocation associated in 13.6%, 2.7%, 2.7%, and 1.3% of patients, respectively. 45.1% of patients had metastases at >2 sites, with lungs being the sites of metastases (68.3%).
Based on Heng's score, 23.2%, 42.7%, and 34.1% of patients were classified as low risk, intermediate risk, and high risk, respectively.
Treatment details and adverse event profile [Table 2]
Sorafenib was started at standard doses of 400 mg twice per day in seventy patients (85.3%), at 400 mg once per day in ten patients (12.1%), and at 600 mg per day in two patients (2.4%), based on treating physician discretion.
The most common side effects were hand-foot-syndrome (68.2%), mucositis (35.3%), fatigue (35.3%), rash (32.9%), HTN (25.6%), proteinuria (20.6%), and hypothyroidism (15.9%). Patients with worsening of HTN and hypothyroidism, who required upscaling of previous medications as well as those with new onset of these adverse events were included in this category of toxicity assessment. Hematological adverse events were relatively less common, with only 4.8% patients having Grade 3 and Grade 4 anemia and neutropenia. Five patients (6.09%) had an episode of febrile neutropenia, potentially requiring admission and supportive care. Other rare side effects included renal insufficiency (3.65%), Grade 3/4 hyponatremia (7.3%), and symptomatic cardiac dysfunction (1.2%).
Twenty patients required dose reduction during the course of treatment with sorafenib due to various toxicities. Of these, 12 patients (14.6%) required permanent cessation of sorafenib due to recurrent/intolerable side effects. The reason for stoppage was due to a combination of side effects including recurrent Grade 3 HFS (7 patients), Grade 3/4 mucositis (6 patients), rash (2 patients), febrile neutropenia (1 patient), symptomatic cardiac dysfunction (1 patient), and grade 3/4 diarrhea (2 patients).
Response rates and survival data [Table 3]
|Table 3: Responses, survival outcomes, and prognostic factors with Sorafenib|
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Of the entire of cohort of 82 patients, 57 patients were available for response assessment. About 18.2% of patients had achieved a PR, whereas 39% of patients had SD for a clinical benefit rate of 57.2%. About 12.19% of patients had PD on 1st evaluation postsorafenib. Response assessment data were not available in ten patients, whereas sorafenib was stopped before response assessment in 9.7% of patients.
As of cutoff date for entry into analysis, with a median follow-up of 11.2 months (range 1–55 months), 27 patients (32.9%) were alive and on treatment, 55 patients (67.1%) had discontinued treatment due to PD, toxicity, loss to follow-up or death, and 34 patients (41.4%) had died. Twenty patients (24.3%) were offered second-line therapy and details are as per [Table 3].
The overall estimated median PFS across all risk groups in our study was 7.75 months (range 5.45–10.05). Patients stratified as low risk by Heng criteria did had a longer PFS than those with intermediate and high risk (14.4 months vs. 6.3 months vs. 6.3 months), but this was not statistically significant [P = 0.19, [Figure 1].
|Figure 1: Kaplan–Meier curve for progression-free survival as per Heng criteria|
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The overall estimated median OS across all risk groups in our study was 12.18 months (range 9.61–12.18). Patients stratified as low risk had a longer OS than those with intermediate and high risk (19.6 months vs. 16.1 months vs. 10.3 months), and the difference in median OS between the risk cohorts was statistically significant [P = 0.045, [Figure 2]. Other factors evaluated as prognostic factors including ECOG PS (0–1 vs. ≥2), number of metastatic sites, nephrectomy status, and survival based on receiving second-line therapy did not reach statistical significance (not shown).
| » Discussion|| |
Beginning with Bevacizumab, currently Food and Drug Administration-approved anti-vascular endothelial growth factor (VEGF) therapies and mTOR inhibitors for mRCC include sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus. Sorafenib is a recommended first-line option  for mRCC with data from two large expanded-access studies (NA-ARCCS and EU-ARCCS) and a third practice-based study (PREDICT) having confirmed its efficacy and safety in the nontrial real world population ,, in the long-term. Besides reliable long-term data, one of the major reasons for its increased use in a financially constrained population is the low cost of sorafenib generics in the Indian setting. Approximate monthly cost of generic sorafenib in India is US$60, compared to sunitinib (US$750) and pazopanib (US$400), which is beyond the reach of the majority of the Indian patient population.
While the TARGET trial set the benchmark for comparison for data on sorafenib, like all trial data, there was a systematic exclusion of patients who are commonly seen in clinical practice such as patients with brain metastases, high risk by MSKCC, nonclear cell histology, and ECOG PS >2. Such strict inclusion and exclusion criteria potentially make a direct translation of Phase III data to routine clinical practice, a nuanced decision. However, in the case of Sorafenib, data from expanded access programs and more importantly, a large 2599 patients nontrial data (PREDICT) have shown that sorafenib has efficacy that is seen in the clinic as well. Our study is a useful and important addition to the growing literature on sorafenib in RCC.
Patients in our study had a demographic and baseline profile that reflected the real world population seen in the PREDICT study (median age 57 vs. 60; presence of HTN 30.5% vs. 29.2; prevalence of diabetes mellitus 14.6% vs. 9.7%; nonclear cell histology 20.6% vs. 17%; ≥2 sites of metastases 45.1% vs. 47%). However, the proportion of patients with high-risk score was markedly more in our study (34.1% vs. 11%) although the PREDICT study used the MSKCC risk score. To note, the PREDICT study had no patients from the Indian subcontinent.
A majority of patients were started on standard dose (800 mg per day); however, 24.4% of patients required dose reduction, with 14.6% of these patients requiring permanent stoppage of treatment with sorafenib. As toxicity analysis has been captured based on documentation recorded at follow-up in view of this being a retrospective analysis, there is a greater stress on Grade 3 and Grade 4 toxicities than Grade 1/2, resulting in potential under-reporting of adverse events. The most common adverse events seen in our study were HFS, mucositis, fatigue, rash, and HTN. In a systematic review of the efficacy and side effects of sorafenib based on thirty studies reported by Fishman et al., they found that hand-foot-skin reaction, fatigue, rash or desquamation, diarrhea, and HTN were side effects seen in >20% of patients across trials, consistent with the profile seen in our study. However, HFS was seen in 68.2% of our patients, far higher than quoted in the larger data pools that we examined. The only other study, we could find with a comparable rate of HFS was a retrospective analysis of 256 patients from China, where the rate of HFS was 60.5%. Incidentally, there is early evidence to suggests that certain polymorphisms in VEGF receptor (VEGFR), specifically VEGF rs2010963, may predict for a higher prevalence of HFS, by altering VEGF expression by modulation of promoter activity in 5'-UTR region of VEGF. The high incidence of HFS in Indian patients with RCC receiving TKIs has also been documented by Krishna et al. in their study, where a Grade III HFS incidence of 51% was recorded with sunitinib. Whether this is due to polymorphisms in VEGFR or other factors need to be evaluated in Indian patients. Besides, the differences seen in the incidence of HFS, we also recorded a high incidence of Grade 3/4 hyponatremia (7.3%), which again is an adverse event less commonly reported although documented by Krishna et al. in their study with sunitinib. While further details regarding cause of this toxicity is unavailable, it delineates an adverse event potentially native to Indian patients and requires further study.
The disease control rate was seen in our study (57.2%) is lower than reported literature, but the median PFS (7.75 months) closely mirrors the survival data seen previously from Western literature, unlike the higher PFS data seen from Asian studies.,,, The median OS in our study also is lower that seen from Asian data as well as the TARGET study (17.8 months), but similar to the final results from the NA-ARCCS, which showed a median OS of 50 weeks. We contend that, besides potential differences in biology between different patient populations which require further research, the driving population in our study is patients who are high risk at baseline (34.1%) and have inherently poor outcomes with current treatment options. We could only come across one study from South Korea  which included 20% of high-risk patients in their study; however, they did not report OS for this subgroup separately. Besides, the study by Hudes et al. which established temsirolimus as the preferred option in poor risk mRCC, there is also some evidence to suggests that VEGFR-TKIs also work in this category of patients. A retrospective analysis of 88 poor risk mRCC patients by Lee et al., in which sunitinib/sorafenib was used showed a median time to progression of 5.0 months and median OS was 9.3 months. Our data on poor risk mRCC show comparable outcomes (median PFS - 6.3 months; median OS - 10.3 months) for poor risk mRCC.
Another possible reason for lower median OS in the entire cohort in this study is that we were able to expose only twenty patients (24.3%) of our patients to second-line treatment. It is well known that second-line therapy in patients progressing on first line TKIs adds an additional 12.5–14.8 months of OS to patients., While the addition of second-line therapy did increase median OS in our study (16.1 months vs. 10.6 months), this was not statistically significant (P = 0.192).
We used the Heng's score for prognostication in our study and even in this small cohort; we were able to validate its discriminative ability with respect to OS and risk groups (low vs. intermediate vs. high; 19.6 months vs. 16.1 months vs. 10.3 months; P = 0.045, Chi-square test). The Heng score is an easily computable value and studies such as ours can further its use in routine clinical practice. Other prognostic factors that we assessed (nephrectomy status, ECOG PS, and metastatic burden) did not yield significant differences between assessed groups, likely because of the small numbers in the study.
While our study is an indicator of the performance of sorafenib in routine clinical practice and has thrown up interesting facets with regard to its off-trial use and the use of Heng's criteria, certain caveats exist. A high lost to follow-up rate (25.7%), likely under-reporting of Grade 1 and Grade 2 toxicity and the subjective component in computing response rates because of variability in reporting, is lacunae in the present study although this is likely due to the inherent nature of a retrospective analysis.
| » Conclusion|| |
Sorafenib is a feasible, viable upfront treatment option for metastatic RCC in Indian patients with acceptable outcome. It appears to be well tolerated though the high incidence of HFS, skin rash and mucositis needs close monitoring and follow-up during follow-up. The Heng's score was validated as a discriminatory value in our study and can be considered for routine use in the clinic in Indian renal cell cancer patients.
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]