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Co-occurring adverse events enable early prediction of progression-free survival in metastatic renal cell carcinoma patients treated with sunitinib: a hypothesis-generating study

Abstract

Aims and background

Clinical practice shows significant differences in treatment outcomes and toxicity of sunitinib across patients. This retrospective study assessed early predictive markers for progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) treated with sunitinib in the first-line setting.

Methods

We evaluated 28 patients with stage IV clear cell RCC (with good or intermediate MSKCC risk prognosis) treated at the Department of Oncology, University Hospital, Cracow between 2008 and 2013. Data included demographic profiles, adverse events during first cycle of therapy, treatment delays, and treatment outcomes. Sunitinib was administered on a standard schedule (50 mg/day, 4 weeks on, 2 weeks off). PFS values were estimated with the Kaplan-Meier method and compared using the log-rank test; we identified independent PFS predictors using multiple Cox regression models.

Results

PFS was significantly longer in patients who experienced at least 1 adverse event after the first cycle of sunitinib (median 17.6 months vs. 5.6; p = 0.006). Hypertension and hand-foot syndrome were significantly correlated with longer PFS (29.3 vs. 6.0 months; p = 0.002, and not reached vs. 9.8 months; p = 0.002, respectively). We observed a similar (though not significant) tendency for neutropenia (17.5 vs. 8.4 months; p = 0.055). In multiple Cox regression, hypertension was the only individual independent predictor of PFS, but the co-occurrence of any 2 or 3 sunitinib-induced adverse events also predicted longer survival.

Conclusions

Although small, our study suggests that hypertension and hand-foot syndrome predict longer PFS in patients with clear cell RCC treated with sunitinib. The co-occurrence of 2 or more side effects seems also a significant predictor of longer survival. Larger studies are warranted to confirm the correlation between co-occurring side effects and PFS.

Tumori 2015; 101(5): 555 - 559

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000342

Authors

Jakub Kucharz, Paulina Dumnicka, Marek Kuzniewski, Beata Kusnierz-Cabala, Roman Maria Herman, Krzysztof Krzemieniecki

Article History

Disclosures

Financial support: The study was funded by the Jagiellonian University Medical College.
Conflict of interest: JK is a member of Pfizer’s advisory board and received support for travel/accommodation at meetings. KK is a member of Pfizer’s advisory board and received support for travel/accommodation at meetings. PD, MK, BKC and RMH declare no conflict of interest.

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Introduction

Sorafenib and sunitinib, the antiangiogenic agents recently introduced in the treatment of advanced renal cell carcinoma (RCC), have significantly improved treatment outcomes. However, these agents are also associated with adverse events that were previously uncommon in systemic treatment. These include cutaneous, vascular and mucosal toxicities, such as hand-foot syndrome (HFS), skin rash or hypertension (1), and endocrine toxicities such as hypothyroidism (2). These adverse effects seem to be directly related to the mechanisms of action of these drugs, i.e., inhibition of multiple signaling pathways.

Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that acts on vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRα and PDGFRβ), stem cell factor receptor (Kit), Fms-like tyrosine kinase 3 (Flt-3), and colony-stimulating factor-1 receptor (CSF-1R) (3). Sunitinib is recommended in the ESMO guidelines for the treatment of patients with metastatic clear cell RCC (mRCC) who are of low or intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (4).

In a phase III clinical trial by Motzer et al (5), treatment of mRCC patients with sunitinib resulted in a significantly higher response rate (31% versus 6%) and longer progression-free survival (PFS; 11.0 months versus 5.0 months) compared to interferon alpha. Also, the sunitinib safety profile has been confirmed in a real-world setting; however, clinical practice shows significant differences in treatment outcomes and sunitinib toxicity across patients (6). The most common adverse events associated with sunitinib are hypertension, hypothyroidism, HFS, and myelosuppression. Their occurrence can be taken to indicate sunitinib activity in the body (7). Previous studies have shown correlations between the occurrence of sunitinib side effects and treatment outcomes including overall survival (OS), PFS, and objective response rate (ORR), but most of these studies assessed only individual clinical or laboratory parameters in heterogeneous patient samples where some patients had nephrectomy and others did not, where different lines of treatment were applied, and patients belonged to various MSKCC and Heng risk groups (including poor risk) (8-9-10-11).

The aim of this study was to assess whether the early occurrence of individual or clustered sunitinib-induced adverse events (taking place during the first cycle of therapy) predicted PFS in a homogeneous group of patients with clear cell mRCC. We also sought to determine whether the number of co-occurring sunitinib side effects was a significant predictor of PFS.

Materials and methods

Patient selection and therapeutic procedure

This was a retrospective study of 28 patients treated at the Department of Oncology at the University Hospital in Cracow, Poland between 2008 and 2013, and selected according to the following inclusion criteria: diagnosis of clear cell mRCC, application of sunitinib as first-line treatment for mRCC, prior nephrectomy (total or nephron-sparing surgery), and good or intermediate MSKCC risk prognosis. All patients received sunitinib on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off).

We received permission to conduct this study from the Jagiellonian University Bioethics Committee (permission number KBET/45/B/2013).

Data collection and evaluation criteria

Our data set consisted of patient demographics, adverse events, treatment delays, and treatment outcomes. Performance scores were evaluated with the ECOG scale. Data on objective adverse events included hypertension, HFS, hypothyroidism, and neutropenia that had occurred by the end of the first cycle of therapy and were documented in patients’ evaluations on day 43. Blood pressure (BP) was measured during hospital visits, and patients were also asked to monitor their BP at home. Patients with office systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg, home SBP ≥135 mmHg and/or home DPB ≥85 mmHg, as well as those who had pre-existing medication-controlled arterial hypertension and required additional antihypertensive medication during treatment were classified as having developed sunitinib-induced hypertension. The aforementioned criteria comply with the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines (12). Adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (13). Clinical and laboratory evaluation was performed every 4 to 6 weeks and included physical examination and blood tests. Response to therapy was evaluated every 12 weeks using the RECIST 1.1 criteria.

Statistical analysis

Nominal variables are summarized as the number of patients (percentage of the group) to which they apply, and continuous variables are given as medians (lower/upper quartile). We calculated PFS values taking as the start date the beginning of sunitinib treatment and as the end date disease progression or death, estimated them using the Kaplan-Meier method, and compared them by means of the log-rank test. We identified independent PFS predictors using multiple Cox proportional hazards models and reported hazard ratios (HR) with 95% confidence intervals (95% CI).

Results

Table I summarizes the characteristics of the study group (n = 28) at the start of sunitinib treatment. During the study period, progression was observed in 21 patients (75%) while 7 patients were still in treatment at the end of the study. Median PFS was 11.2 months (lower/upper quartile 5.6/29.4 months).

Study group demographics at the beginning of sunitinib treatment. All patients had clear cell histology and all started sunitinib as first-line treatment with the initial dose of 50 mg per day

Clear cell mRCC patients (N = 28)
mRCC = metastatic renal cell carcinoma; ECOG = Eastern Cooperative Oncology Group; MSKCC = Memorial Sloan Kettering Cancer Center.
Age, years 65 (58/69)
Male sex, N (%) 19 (68)
Fuhrman:
 grade 1-2, N (%) 10 (36)
 grade 3-4, N (%) 18 (64)
Time from diagnosis to systemic treatment <1 year, N (%) 15 (54)
ECOG performance score:
 0, N (%) 13 (46)
 1, N (%) 14 (50)
 2, N (%) 1 (4)
MSKCC prognosis:
 favorable, N (%) 8 (29)
 intermediate, N (%) 20 (71)
Prior nephrectomy (partial or total) 28 (100)
Metastases:
 no metastases 5 (18)
 lung, N (%) 17 (61)
 liver, N (%) 11 (39)
 bone, N (%) 6 (21)
 1 site, N (%) 15 (54)
 2 or more sites, N (%) 8 (29)

The sunitinib side effects observed during the first treatment cycle included hypertension, hypothyroidism, neutropenia, and HFS (Tab. II). Eight patients (29%) exhibited no side effects after the first treatment cycle, and 10 (36%) experienced individual side effects: 4 had neutropenia, 1 had hypothyroidism, and 5 had hypertension. The remaining 10 patients (36%) experienced 2 or more co-occurring side effects (6 patients had 2 side effects, and 4 had 3 side effects).

Sunitinib-induced adverse events observed by the end of the first treatment cycle

Adverse event N (%)
Hypertension 14 (50)
Neutropenia 12 (43)
Hand-foot syndrome 6 (21)
Hypothyroidism 2 (7)
At least one adverse event 20 (71)

PFS was significantly longer in patients who had experienced at least 1 adverse event by the end of the first treatment cycle (median 17.6 months, lower quartile 9.8 months vs. 5.6, lower/upper quartile 2.8/8.4 months; p = 0.006). Hypertension and HFS were significantly correlated with longer PFS (Fig. 1a and 1b). Additionally, we observed a similar but not significant tendency for neutropenia (Fig. 1c). Multiple Cox regression revealed hypertension to be the only individual independent PFS predictor (Tab. III, model 1). However, when adverse events other than hypertension were analyzed as a cluster, we found them to be independently associated with PFS (Tab. III, model 2). The co-occurrence of any 2 or more adverse events was positively correlated with longer PFS (Fig. 1d; Tab. III, model 3). The longest PFS times were observed in patients suffering from 3 simultaneous side effects (range 12.2-47.6 months; lower PFS quartile 29.0 months, PFS median was not reached). This group, however, included only 4 patients.

Kaplan-Meier curves showing PFS in patients with sunitinib adverse events after the first cycle of treatment (dashed lines) and those with no early side effects (solid lines). Early-onset hypertension (a) and HFS (b) were positively correlated with longer PFS rates, and the same tendency was observed for neutropenia (c). Co-occurring side effects (d) predicted longer PFS. HFS = hand-foot syndrome; PFS = progression-free survival; p in log-rank test

Multiple Cox regression models to predict progression in mRCC patients treated with sunitinib

Predictor variables Unadjusted MSKCC adjusted
HR (95%CI) P value HR (95%CI) P value
mRCC = metastatic renal cell carcinoma; Memorial Sloan Kettering Cancer Center; HR = hazard ratio; CI = confidence interval.
Model 1 Hypertension 0.25 (0.08-0.77) 0.016 0.27 (0.08-0.94) 0.039
Neutropenia 0.46 (0.18-1.19) 0.1 0.45 (0.17-1.18) 0.1
Hand-foot syndrome 0.32 (0.06-1.60) 0.2 0.31 (0.06-1.59) 0.2
Model 2 Hypertension 0.19 (0.07-0.56) 0.003 0.22 (0.06-0.74) 0.015
Other adverse events 0.38 (0.15-0.95) 0.039 0.37 (0.15-0.95) 0.038
Model 3 No adverse events Reference group - Reference group -
Single adverse event 0.30 (0.10-0.89) 0.029 0.38 (0.12-1.21) 0.1
Multiple adverse events 0.10 (0.03-0.38) <0.001 0.12 (0.03-0.44) 0.002

Discussion

Although limited by the small number of patients, our study suggests that the occurrence of hypertension and HFS by the end of the first cycle of sunitinib therapy is a significant predictor of longer PFS in patients with clear cell mRCC. Hypertension was a significant predictor of PFS in multiple regression analysis, and this finding is consistent with the sunitinib literature (14).

To the best of our knowledge, the present study is the first to evaluate the correlation between the number of sunitinib-induced adverse events and treatment outcomes. We found statistically significant PFS differences between 3 groups of patients: those who experienced no side effects during the first cycle of treatment, those who experienced a single side effect, and those who experienced multiple co-occurring side effects (with medians of 5.6, 11.2, and 29.3 months, respectively).

Rixe et al (14) found a correlation between some adverse effects and ORR in 40 patients treated with sunitinib (50 mg/day, 4 weeks on, 2 weeks off) in second-line treatment, after cytokine failures. Patients who experienced stomatitis, tiredness, hypertension, testicular erythema, or hair depigmentation had significantly higher response rates, but the correlation between the number of occurring adverse events and treatment outcomes was not tested. Multivariate analysis revealed that second-degree or greater arterial hypertension was an independent predictor of better treatment outcomes (OR 2.33, 95% CI, 1.69-3.22; p = 0.009).

In our sample, 50% of patients experienced hypertension. In Rini et al’s (10) meta-analysis of sunitinib-treated patients, 58% had an elevated SBP and 48% had an elevated DBP after the first cycle of therapy; increased BP values were positively correlated with longer PFS and OS, and better ORR. It is important to note, however, that most patients included in this study received sunitinib as second-line treatment (after cytokines). In contrast, Bono et al (9) evaluated 64 mRCC patients who received various schedules of sunitinib (50 mg/day, 4 weeks on, 2 weeks off [33%], or continuous dosages of 37.5 mg/day [42%] or 25 mg/day [25%]). Fifty-two percent of these patients received sunitinib as second- or further-line treatment. The study noted the onset of hypertension or exacerbation of medication-controlled pre-existing hypertension in 38% of patients, and both types of hypertension were independent predictive markers for longer PFS and OS times. However, the threshold BP values used to recognize hypertension (>150/100 mmHg) were higher than those in our study. We defined hypertension according to the current (2013) ESH/ESC definition i.e., as office BP ≥140/90 mmHg, in which case antihypertensive treatment is recommended in most patients. It should be noted that the guidelines define optimal (<120/80 mmHg), normal (120-129/80-84 mmHg) and high-normal BP (130-139/85-89 mmHg). However, pharmacological treatment is recommended in patients with BP ≥140/90 mmHg, and in those older than 60 years with BP ≥150/90 mmHg. Moreover, the tresholds for initiating pharmacological treatment as well as the treatment goals have changed considerably over the years, which may explain some differences between studies.

HFS occurred in 21% of the patients in our sample. The relationship between medication-induced adverse events affecting the skin and treatment outcomes in mRCC patients receiving TKIs (sunitinib or sorafenib) were also examined by Poprach et al (15). They found HFS in 6.1% of patients in their sample, and there was a significant positive correlation between the occurrence of HFS and longer PFS and OS times. Some of the patients in this study had received interferon alpha immunotherapy prior to the TKI treatment cycle, and a subset of the sample differed from our sample in terms of clinical and pathological profiles. Finally, Michaelson et al (16) observed any grade HFS in 23% of 1,186 sunitinib-treated patients with mRCC (n = 770) or gastrointestinal stromal tumors (n = 416) who received sunitinib on various schedules (50 mg/day, 4 weeks on, 2 weeks off; 50 mg/day 2 weeks on, 1 week off, or 37.5 mg continuous daily dosing). HFS occurrence in the mRCC patients in this sample was a strong predictor of higher ORR, and longer PFS and OS (ORR 66.5% vs. 31.8%; PFS 14.3 vs. 8.3 months; OS 38.3 vs. 18.9 months, p<0.0001). In mulvariate analysis, HFS remained a significant predictor of longer PFS and OS in mRCC patients. Consequently, Nakano et al (17) observed a similar association of HFS occurrence and PFS among mRCC patients treated with another TKI, sorafenib. In patients with HFS, median PFS was longer (4.6 months vs. 1.5 months; p = 0.002) and the best tumor response was better (mean -16.7% vs. -17.9%; p<0.001). In multivariate analysis, HFS was the only significant predictor of PFS.

We did not evaluate hypothyroidism because it was observed in only 2 patients after the first cycle of treatment. It typically occurs later (on average, between 12 and 50 weeks after starting sunitinib treatment) (2). It is important to remember, however, that previous studies have documented correlations between the in-treatment onset of hypothyroidism and PFS (18) and ORR (19).

Concluding, the major limitation of our study is the small sample size; it must therefore be regarded as hypothesis generating and should be validated in future larger studies. However, our results suggest that the adverse events we evaluated may be considered an effective marker of sunitinib exposure and effectiveness. The correlation between sunitinib-induced adverse events and treatment outcomes provides an argument in favor of maintaining adequately effective sunitinib dosages even in patients with multiple but acceptable toxicities, while incorporating supportive care (such as antihypertensive drugs or proper skin care) to reduce the side effects. Such strategy may enable optimal sunitinib treatment results. It is also important to explain the significance of adverse events to patients treated with sunitinib as this might increase compliance.

Disclosures

Financial support: The study was funded by the Jagiellonian University Medical College.
Conflict of interest: JK is a member of Pfizer’s advisory board and received support for travel/accommodation at meetings. KK is a member of Pfizer’s advisory board and received support for travel/accommodation at meetings. PD, MK, BKC and RMH declare no conflict of interest.
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Authors

Affiliations

  • Department of Oncology, University Hospital in Cracow, Cracow - Poland
  • Department of Experimental and Clinical Surgery, Jagiellonian University Medical College, Cracow - Poland
  • Department of Medical Diagnostics, Jagiellonian University Medical College, Cracow - Poland
  • Department of Nephrology, Jagiellonian University Medical College, Cracow - Poland
  • Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Cracow - Poland
  • Department of Oncology, Jagiellonian University Medical College, Cracow - Poland

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