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Keywords:

  • renal cell carcinoma;
  • sunitinib;
  • brain;
  • metastases;
  • expanded access program

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open-label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP.

METHODS:

Previously treated and treatment-naive metastatic RCC patients ≥18 years received sunitinib 50 mg orally, once daily, on Schedule 4/2. Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, consisting of all patients who received ≥1 dose of sunitinib.

RESULTS:

As of December 2007, 4564 patients had enrolled in 52 countries. Of these enrollees, 4371 were included in the modified ITT population, of whom 321 (7%) had baseline brain metastases and had received a median of 3 treatment cycles (range 1-25). Reasons for their discontinuation included lack of efficacy (32%) and adverse events (8%). The most common grade 3-4 treatment-related adverse events were fatigue and asthenia (both 7%), thrombocytopenia (6%), and neutropenia (5%), the incidence of which were comparable to that for the overall EAP population. Of 213 evaluable patients, 26 (12%) had an objective response. Median progression-free survival and overall survival were 5.6 months (95% CI, 5.2-6.1) and 9.2 months (95% CI, 7.8-10.9), respectively.

CONCLUSIONS:

In patients with brain metastases from RCC, the safety profile of sunitinib was comparable to that in the general metastatic RCC population, and sunitinib showed evidence of antitumor activity. Cancer 2011. © 2010 American Cancer Society.

The treatment paradigm of advanced renal cell carcinoma (RCC) has been transformed by the regulatory approval of 6 new agents in 4 years. This is in contrast to the prior 2 decades when there were no new medication approvals for this indication. New targeted therapies—namely, angiogenesis inhibitors and mammalian target of rapamycin inhibitors—have shown superior response rates as well as progression-free survival (PFS) and overall survival (OS), compared with that of the previous era of cytokine therapy. Sunitinib malate (SUTENT, Pfizer Inc., New York, NY) is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and other RTKs with direct antitumor and antiangiogenic activity.1-5 It is currently approved worldwide for first- and second-line treatment of advanced RCC.

Sunitinib demonstrated single-agent activity in 2 phase II trials of patients with cytokine-refractory metastatic RCC,6, 7 which led to the design and conduct of a randomized, phase III trial of sunitinib compared with interferon-alfa (IFN-α) in 750 treatment-naïve patients with metastatic RCC.8 Sunitinib showed superior efficacy over IFN-α, with an investigator-assessed objective response rate (ORR) of 37% vs 9% (P < .001) and median PFS of 11 months vs 4 months, respectively (P < .001), establishing sunitinib as a reference standard of care. In addition, median OS with sunitinib was greater than 2 years (26.4 months) compared with 21.8 months with IFN-α (hazard ratio [HR] = 0.821, 95% CI, 0.673-1.001; P = .051).

Recently, Gore et al (2009) reported results from an open-label, expanded access program (EAP) with sunitinib for more than 4500 patients with metastatic RCC from 52 countries.9 This trial enrolled patients who were ineligible for sunitinib clinical trials (eg, those with brain metastasis, poor functional status, or the elderly) and were from countries where regulatory approval had not yet been granted. The authors found that, in this broader population of patients with metastatic RCC, the safety profile of sunitinib was manageable and efficacy results were encouraging, particularly in subgroups not typically enrolled in clinical trials.

One such subgroup is the 10%-20% of patients with metastatic RCC who have brain metastases10, 11 who have a life expectancy of approximately 4 to 6 months without systemic therapy.12 In general, RCC patients with brain metastasis typically experience a poorer outcome after medical intervention than patients presenting with other sites of metastases. For example, in a retrospective analysis by Kavolius et al (1998)13 of 94 RCC patients with a solitary metastasis surgical resection of a lung metastasis (n = 50 patients) was associated with a significant 3-fold increase in 5-year survival rate over surgical resection of a brain metastasis (n = 11; 54% vs 18%, respectively; P < .05).

Surgical resection of brain metastases has been associated with a median OS of 12.6 months; however, this survival benefit decreases to as low as 7.6 months and 3.0 months in patients with multiple brain metastases and cerebellar metastases, respectively.14

In addition, RCC is often considered a radioresistant malignancy, with radiotherapy typically reserved for palliation of bone disease. Median survival after radiotherapy of brain metastases has been only 3 to 4 months,15 with no additional benefit gained from radiotherapy after surgical resection.14 Stereotactic radiosurgery in highly selected populations with either a good performance score or a limited number of brain metastases (eg, ≤5 metastases) has been associated with 1- and 3-year survival rates of 40% and 16%, respectively.16, 17

RCC patients with brain metastasis were excluded from the sunitinib regulatory phase III trial18; however, anecdotal case reports of patients with brain metastases experiencing antitumor activity while on sunitinib have been observed.19-21 In addition, such activity is not unexpected or surprising because animal studies have shown that both sunitinib and its active metabolite penetrate the central nervous system (although there is rapid clearance and no apparent accumulation).22

This report describes the clinical safety and efficacy observed in patients with brain metastases who received sunitinib treatment as part of the global metastatic RCC EAP.9

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patients

This is an ongoing, international, open-label EAP of sunitinib in patients with metastatic RCC, which has completed accrual from 246 centers in 52 countries, as previously reported.9 The first patient was enrolled in June 2005 and the last patient in December 2007. The study population comprises patients ≥18 years with histologically confirmed metastatic RCC (of all histological subtypes) and includes both previously treated and treatment-naïve RCC patients with adequate organ function. Additional eligibility criteria, including the potential to derive clinical benefit from sunitinib treatment as judged by the investigator, were previously reported.9

The EAP was approved by the institutional review board (IRB) or independent ethics committee (IEC) at each participating center and conducted according to the International Conference on Harmonization Good Clinical Practice guidelines. All patients gave written informed consent.

Study Design and Treatment

Sunitinib capsules were provided by Pfizer Inc. and orally self-administered at a starting dose of 50 mg once daily, without regard to meals, in repeated 6-week cycles of 4 weeks on treatment, followed by 2 weeks off (Schedule 4/2). Dose reductions to 37.5 mg/day and then to 25 mg/day were permitted on the basis of individual patient tolerability. All patients began treatment on Schedule 4/2, but could be placed on a daily continuous dose upon dose reduction at the investigator's discretion. Patients received sunitinib until disease progression, unacceptable toxicity, or consent withdrawal. Palliative radiotherapy to specific sites of disease was permitted (except to target lesions), per the protocol, if considered medically necessary by the treating physician. In such cases, sunitinib was interrupted during palliative radiotherapy, stopping one day before and resuming treatment one day after.

Study Assessments

The primary objective was to provide access to sunitinib for patients who were ineligible for participation in sunitinib clinical trials, but who had the potential of deriving clinical benefit as judged by the investigator. Secondary objectives included assessment of safety and efficacy parameters ORR, PFS, and OS.

Disease assessment and physical examination were done at screening, where safety and tolerability (using National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 3.0), concomitant medication use, biochemistry, and hematology were also assessed.

Collection of safety data was outlined in the protocol, with toxicity assessed on days 1, 14, and 28 of cycle 1, and on days 1 and 28 of subsequent cycles. Adverse events were graded according to NCI CTCAE, version 3.0, and the association between adverse events and sunitinib therapy was assessed by the investigator.

No specific schedule or type of tumor assessments were mandated in the protocol. Instead, tumor assessments were done per local standard pattern of care for RCC, and data on response, PFS, and OS were collected where possible. ORR was defined as the number of complete and partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST).23 PFS was defined as the time from start of therapy to disease progression or death from any cause. OS was defined as the time from start of therapy to death from any cause (with survival times censored at last follow-up for patients remaining alive).

Statistical Evaluation

Consistent with the nature of expanded-access trials, sample size was not predetermined, no inferential analyses were planned, and no hypotheses were tested. Safety and efficacy data were analyzed for all patients receiving at least 1 dose of sunitinib (a modified intention-to-treat population) by the data cutoff date. ORR was calculated with the corresponding 95% 2-sided CI, using standard methods of binomial distribution. Estimates of median PFS and OS were derived using the Kaplan-Meier method, and 95% CI was calculated with standard methods for a fixed-sample, single-stage design. All statistical analysis was done using SAS version 9.1.1.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patients

A total of 4564 advanced RCC patients had been enrolled as of December 2007. Data for safety, treatment duration, tumor response, and survival were available for 4371 patients as of March 2008, the time of data cutoff. Brain metastases were present at baseline in 321 of these patients, and it is these patients that are described in this report.

The baseline characteristics of patients with brain metastases were comparable to that of the overall EAP population (Table 1): most patients had clear-cell histology (92%), the majority had undergone prior nephrectomy (88%), and few had received prior antiangiogenic therapy (12%).

Table 1. Baseline Characteristics in Patients With Brain Metastases and in the Overall Expanded Access Program (EAP) Population (Modified Intention-to-Treat Population)
CharacteristicsPatients With Brain Metastases n=321Patients Without Brain Metastases n=4042Overall EAP Population9 n=4371
  • Missing data (patients with brain metastases, without brain metastases, all patients): brain metastases status (NA, NA, 8); sex (n=1, 1, 9); ECOG PS (n=7, 85, 94); histology (n=1, 16, 25); prior nephrectomy status (n=11, 184, 203); prior cytokine therapy (n=2, 6, 16); prior antiangiogenic therapy (n=2, 0, 0). ECOG PS indicates Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan-Kettering Cancer Center.

  • a

    Risk factors are ECOG PS ≥2, low hemoglobin, and high calcium. For patients without prior cytokine treatment, additional risk factors were raised lactate dehydrogenase and time-to-use of interferon α of <1 year.23, 24 Patients with prior cytokine treatment were classified as favorable, intermediate, or poor if 0, 1, or >1 risk factors were present, respectively.24 Patients without prior cytokine treatment were classified as favorable, intermediate, or poor if 0, 1-2, or >2 risk factors were present, respectively.25 Note: Risk factor data in patients with brain metastases were only available for patients with prior cytokine treatment.

Median age, yrs (range)58 (21-81)60 (19-89)59 (19-89)
Male, n (%)237 (74)2988 (74)3225 (74)
ECOG PS, n (%)a
 0100 (31)1721 (43)1823 (42)
 1138 (43)1730 (43)1872 (43)
 257 (18)446 (11)503 (12)
 317 (5)56 (1)73 (2)
 42 (1)4 (<1)6 (<1)
Histology, n (%)a
 Clear cell295 (92)3468 (86)3758 (86)
 Other25 (8)558 (14)588 (13)
Prior nephrectomy, n (%)284 (88)3589 (89)3873 (89)
No. of metastatic sites, n (%)
 0041 (1)49 (1)
 17 (2)826 (20)833 (19)
 ≥2314 (98)3175 (79)3489 (80)
Site of metastasis, n (%)
 Lungs276 (86)3063 (76)3339 (76)
 Lymph nodes168 (52)2073 (51)2241 (51)
 Bone132 (41)1392 (34)1524 (35)
 Liver96 (30)1073 (27)1169 (27)
 Brain321 (100)0321 (7)
Prior therapy, n (%)
 Antiangiogenic39 (12)213 (5)238 (5)
 Cytokines238 (74)2736 (68)2974 (68)
Risk factors, n (%)a
 Favorable72 (22)1025 (25)1594 (36)
 Intermediate103 (32)1141 (28)1930 (44)
 Poor41 (13)294 (7)375 (9)
 Missing22 (7)276 (7)472 (11)

Treatment

The median number of treatment cycles in patients with brain metastases was 3 (range, 1-25), whereas the overall EAP population (4371 patients) received a median of 5 cycles (range, 1-25).9 The median durations of follow-up for patients with brain metastases and the overall EAP population were 7.3 months (range, <1-26.0) and 11.6 months (range, <1-28.0),9 respectively.

In patients with brain metastases, sunitinib doses were reduced from 50 mg/day to 37.5 mg/day in 85 patients (26%), with additional reductions to 25 mg/day in 32 patients (10%). (Two additional patients were assigned to and received 37.5 mg/day as a starting dose.) Further reduction to 12.5 mg/day, although not allowed in the protocol, occurred in 3 patients (1%). Comparative dose reductions in the overall EAP population to 37.5 mg/day occurred in 1446 patients (33%), with further reductions to 25 mg/day in 586 patients (13%) and to 12.5 mg/day in 18 patients (<1%).9 The mean relative dose intensity was similar between the two groups: 93% (SD 20) in patients with brain metastases and 95% (SD 25) in the overall EAP population.9

Fifty-two patients with brain metastases remained on study as of March 2008, whereas 229 patients (71%) had discontinued treatment. Reasons for discontinuation of therapy in patients with brain metastases and the overall EAP population9 included lack of efficacy (32% vs 27%, respectively), death (16% vs 17%), adverse events (both 8%), consent withdrawal (both 6%), lost to follow-up (both 2%), protocol violation (1% vs <1%), and other/missing (7% vs 14%).

Safety

In patients with brain metastases, the most commonly reported treatment-related nonhematological adverse events were diarrhea (34%), fatigue (32%), nausea (29%), and mucosal inflammation (27%), most of which were of grade 1/2 severity (Table 2). The most common grade 3/4 treatment-related nonhematological adverse events were fatigue (7%), asthenia (7%), and hand-foot syndrome (4%). The most common grade 3/4 hematological adverse events included thrombocytopenia (6%), neutropenia (5%), and anemia (4%).

Table 2. Treatment-Related Adverse Events That Occurred in at Least 10% of Patients With Brain Metastases (N=321)
 No. of Patients (%)
 Grade 1/2aGrade 3/4Totalb
  • a

    There was 1 patient with grade 1/2 treatment-related cerebral hemorrhage.

  • b

    A total of 7 patients with brain metastases (2%) had grade 5 treatment-related adverse events, including cardiac failure (n=1), hematemesis (n=1), hematochezia (n=1), asthenia (n=1), retroperitoneal abscess (n=1), urosepsis (n=1), and disease progression (n=1).

Nonhematological
 Diarrhea102 (32)8 (2)110 (34)
 Fatigue80 (25)23 (7)103 (32)
 Nausea86 (27)7 (2)93 (29)
 Mucosal inflammation78 (24)7 (2)85 (27)
 Anorexia68 (21)8 (2)76 (24)
 Vomiting67 (21)10 (3)77 (24)
 Dysgeusia70 (22)1 (0.3)71 (22)
 Stomatitis65 (20)6 (2)71 (22)
 Asthenia44 (14)21 (7)66 (21)
 Hand-foot syndrome42 (13)12 (4)54 (17)
 Hypertension42 (13)11 (3)53 (17)
 Rash45 (14)2 (1)47 (15)
 Constipation35 (11)035 (11)
 Dyspepsia34 (11)034 (11)
 Epistaxis33 (10)1 (0.3)34 (11)
 Yellow skin32 (10)032 (10)
 Skin discoloration31 (10)031 (10)
Hematological
 Thrombocytopenia38 (12)19 (6)57 (18)
 Neutropenia29 (9)16 (5)45 (14)
 Anemia30 (9)13 (4)43 (13)

There were no observed differences in toxicity in patients with brain metastases and the overall EAP population, with the overall incidence of any-grade treatment-related adverse events occurring in 92% of patients, regardless of the presence of brain metastases. Moreover, the incidence of grade 3/4 treatment-related adverse events in patients with brain metastases was comparable, if not lower, to that of the overall EAP population (Fig. 1).

thumbnail image

Figure 1. Most common grade 3/4 treatment-related adverse events in patients with brain metastases (n = 321) and the overall expanded access program (EAP) population (N = 4371; modified intention-to-treat population).

Download figure to PowerPoint

One patient with brain metastases experienced a treatment-related cerebral hemorrhage, which was mild in severity (grade 1/2). Three patients experienced treatment-related convulsions, 2 patients with grade 1/2 severity and 1 patient with grade 3/4 severity. One patient had grade 1/2 treatment-related partial seizure. The decision to assign treatment-related causality to convulsions and seizures was made exclusively by the investigator(s).

Treatment-related hypothyroidism was reported in 10 patients (3%), 8 of whom reported symptoms of grade 1/2 severity. In comparison, 6% of patients within the overall EAP population had treatment-related hypothyroidism,9 although routine testing of thyroid function was not required so incidence may have been higher. Twelve patients with brain metastases suffered treatment-related cardiac disorders (4%), of whom one patient had grade 3/4 congestive cardiac failure and one had grade 5 cardiac failure.

Sixty-five patients (20%) with brain metastases died on study (or within 28 days of their last dose) and 128 (40%) died during follow-up; 522 (12%) in the overall EAP population died on study and 1379 (32%) died during follow-up.9

Efficacy

Of 321 patients with brain metastases, 213 (66%) were evaluable for tumor response. One patient had a complete response and 25 (12%) had a partial response for an ORR of 12% (Table 3), compared with an ORR of 17% in the overall population.9 Of the 213 evaluable patients, 111 (52%) were reported to have had stable disease for at least 3 months, resulting in a clinical benefit rate of 64%.

Table 3. Tumor Response According to RECIST and Clinical Benefit in Patients With Brain Metastases and in the Overall Expanded Access Program (EAP) Population (Evaluable Patients Only)
 No. of Patients (%)
Patients With Brain Metastases n=213Patients Without Brain Metastases n=3251Overall EAP Population9 n=3464
  • RECIST indicates response evaluation criteria in solid tumors.

  • a

    Clinical benefit=objective response+stable disease ≥ 3 months.

Objective response26 (12)577 (18)603 (17)
 Complete responders1 (<1)33 (1)34 (1)
 Partial responders25 (12)544 (17)569 (16)
Stable disease ≥3 months111 (52)1918 (59)2029 (59)
Progressive disease or stable disease <3 months76 (36)756 (23)832 (24)
Clinical benefita137 (64)2495 (77)2632 (76)

Median PFS in patients with brain metastases was 5.6 months (95% CI, 5.2-6.1; Table 4; Fig. 2), whereas median PFS was 10.9 months (95% CI, 10.3-11.2) in the overall EAP population.9 Similarly, median OS was 9.2 months (95% CI, 7.8-10.9) in patients with brain metastases (Table 4; Fig. 2), compared with 18.4 months (95% CI, 17.4-19.2) in the overall EAP population.9 Median PFS and OS were similar, regardless of prior cytokine treatment status in those patients with brain metastases reported here (Table 4). This lack of impact of prior cytokine therapy on efficacy was also observed in the overall EAP population.9

thumbnail image

Figure 2. Kaplan-Meier estimates of (A) progression-free survival (PFS); (B) overall survival (OS) for patients with brain metastases* and the overall expanded access program (EAP) population.9 *No. at risk provided for patients with brain metastases only.

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Table 4. Summary of Median Progression-Free Survival (PFS) and Overall Survival (OS) in Patients With Brain Metastases and in the Overall Expanded Access Program (EAP) Population (Evaluable Patients Only)
 Patients With Brain Metastases (n=320)Patients Without Brain Metastases (n=4029)Overall EAP Population9 (n=4349)
All Patients n=320Prior Cytokine Treatment n=237No Prior Cytokine Treatment n=81All Patients n=4029Prior Cytokine Treatment n=2726No prior Cytokine Treatment n=1289All Patients n=4349Prior Cytokine Treatment n=2963No Prior Cytokine Treatment n=1370
  1. CI indicates confidence interval.

Median PFS, mo (95% CI)5.6 (5.2-6.1)5.6 (5.1-6.5)5.3 (4.1-6.8)11.1 (10.8-11.6)11.1 (10.6-11.7)11.3 (10.5-13.2)10.9 (10.3-11.2)10.8 (9.9-11.1)11.1 (9.9-12.4)
Median OS, mo (95% CI)9.2 (7.8-10.9)9.0 (7.5-10.9)8.7 (7.6-16.1)19.1 (18.2-19.7)19.2 (18.0-20.1)18.2 (17.3-20.4)18.4 (17.4-19.2)18.4 (17.2-19.3)18.1 (17.1-19.7)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

The analysis reported here provides evidence that the safety profile for sunitinib in patients with brain metastases is comparable to that of the general metastatic RCC population, a finding that Gore and colleagues have previously reported.9 In addition, the tolerability of sunitinib in patients with brain metastasis was similar to that reported in the prior phase II/III trials and registration program, in which well-defined, selected patient populations were enrolled.6-8

Specific toxicity concerns for RCC patients with brain metastasis, including cerebral hemorrhage, hypertension-related cerebral complications such as seizures, and reversible posterior leukoencephalopathy syndrome, appear to be unfounded in this trial. Notably, only 1 patient with brain metastases experienced treatment-related grade 1/2 cerebral hemorrhage. In addition, 4 patients experienced treatment-related convulsions, only one of which was of grade 3/4 severity.

Similar rates of dose modification and discontinuation because of adverse events, when compared with the overall EAP population, provide additional evidence that sunitinib therapy is well tolerated in this subpopulation. However, because of the nature of expanded access trials, these data must be interpreted with caution because some omissions in data reporting may have occurred. It should also be noted that the protocol specified that patients were to receive sunitinib until disease progression; however, some patients received treatment after progression, which could have confounded the results.

The degree of clinical benefit observed with sunitinib in this trial in patients with brain metastases from RCC was less than that reported with sunitinib in prior studies,6-8 which was expected. The median OS of 9.2 months observed with sunitinib in this trial, however, compares favorably with historical survival data for untreated RCC patients with brain metastases (ie, a life expectancy of 4 to 6 months12). In addition, the ORR of 12% was considerably higher than the ORR of 4% recently reported for sorafenib in patients with metastatic RCC and brain metastases in an expanded-access study.26 This may have important implications, as sorafenib treatment itself has been shown to reduce the occurrence of brain metastases.27

This report is supportive of sunitinib having clinical activity in patients with brain metastases from RCC. However, because assessment of response was not mandated in the protocol (an acknowledged limitation in this trial9), the reporting of response may have been inconsistent and, thus, may have negatively biased our efficacy reporting. Furthermore, response in cerebral tumors with angiogenesis inhibitors can be difficult to assess, and brain-specific tumor response measures were not used in this trial. Taken together, these factors may have impacted the ORR reported here for this subset of patients. In addition, no data are available regarding the number of patients who had prior irradiation of brain metastases or who received palliative radiotherapy while on the study. Therefore, further investigation is warranted.

RCC patients with brain metastases have limited treatment options. The encouraging efficacy and tolerability data shown in this report demonstrate that RTK inhibitors may have a role to play, along with surgery, radiotherapy, or palliative therapy. Sunitinib can be safely administered to these patients and offers them a viable treatment alternative. Therefore, further prospective investigation of the activity of sunitinib in patients with brain metastases from RCC is warranted. For example, an ongoing multicenter phase II trial in France is assessing ORR in the brain after sunitinib treatment in RCC patients with previously untreated or recurrent brain metastases after radiotherapy or surgery.28 Currently, there are several prospective trials of sunitinib in patients with gliomas, meningiomas, and also the rare genetic syndrome von Hippel-Lindau disease (in which patients are prone to RCC and cerebellar hemangioblastomas). Sunitinib is also being investigated in prospective trials of patients with metastatic brain tumors from several other primary tumor sites, such as metastatic lung cancer.29 Preliminary results of these prospective trials have been reported, but detailed results are awaited. In addition, sunitinib is being investigated in combination with radiation therapy for patients with primary and metastatic malignancies of the central nervous system.30

In conclusion, sunitinib therapy in metastatic brain disease from RCC is an additional treatment option in patients whose previous treatment armamentarium was severely limited. However, use of sunitinib in metastatic RCC patients with brain metastases may require future prospective randomized trials.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

M. E. Gore reported receiving honoraria for speaker bureaus and advisory boards from Pfizer, Roche, Novartis, Bayer, and GlaxoSmithKline. S. Hariharan, A. Nieto, and J. Yuan are full-time employees of Pfizer. C. Porta reported receiving speaker honoraria and consultant fees from Pfizer Oncology, Bayer Schering Pharma, Hoffman-La Roche, Novartis Pharma, GlaxoSmithKline, and Wyeth Pharmaceuticals, and research grants from Bayer Schering Pharma and Novartis Pharma. S. Bracarda reported receiving consultant fees from Bayer, Pfizer, Roche, Wyeth Pharmaceuticals, Novartis, and GlaxoSmithKline, and speaker honoraria from Novartis. R. Hawkins reported receiving research funding for unrelated products and advisory fees from Pfizer. G. A. Bjarnason and S-H. Lee have reported no potential conflicts of interest. S. Oudard reported receiving speaker honoraria from Pfizer, Wyeth Pharmaceuticals, and Novartis. G. Carteni reported receiving consultant fees and/or speaker honoraria from Bayer Schering Pharma, Pfizer Oncology, Hoffman-La Roche, Wyeth Pharmaceuticals, Novartis Pharma, and Sanofi-Aventis. C. Szczylik reported receiving advisory fees from Pfizer, Bayer, GlaxoSmithKline, and Wyeth Pharmaceuticals.

This study (clinicaltrials.gov NCT00130897) was supported by funding from Pfizer Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
  • 1
    Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007; 25: 884-896.
  • 2
    Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003; 2: 471-478.
  • 3
    O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003; 101: 3597-3605.
  • 4
    O'Farrell AM, Foran JM, Fiedler W, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003; 9: 5465-5476.
  • 5
    Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003; 9: 327-337.
  • 6
    Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006; 24: 16-24.
  • 7
    Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006; 295: 2516-2524.
  • 8
    Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27: 3584-3590.
  • 9
    Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncology. 2009; 10: 757-763.
  • 10
    Posner JB, Chernik NL. Intracranial metastases from systemic cancer. Adv Neurol. 1978; 19: 579-592.
  • 11
    Saitoh H. Distant metastasis of renal adenocarcinoma. Cancer. 1981; 48: 1487-1491.
  • 12
    Culine S, Bekradda M, Kramar A, Rey A, Escudier B, Droz JP. Prognostic factors for survival in patients with brain metastases from renal cell carcinoma. Cancer. 1998; 83: 2548-2553.
  • 13
    Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998; 16: 2261-2266.
  • 14
    Wronski M, Arbit E, Russo P, Galicich JH. Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology. 1996; 47: 187-193.
  • 15
    Wronski M, Maor MH, Davis BJ, Sawaya R, Levin VA. External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys. 1997; 37: 753-759.
  • 16
    Chang EL, Selek U, Hassenbusch SJ 3rd, et al. Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery. 2005; 56: 936-945; discussion 936-945.
  • 17
    Samlowski WE, Majer M, Boucher KM, Shrieve AF, Dechet C, Jensen RL, Shrieve DC. Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery. Cancer. 2008; 113: 2539-2548.
  • 18
    SUTENT (sunitinib malate) prescribing information. Available at: http://www.sutent.com Accessed November 16, 2009.
  • 19
    Medioni J, Cojocarasu O, Belcaceres JL, Halimi P, Oudard S. Complete cerebral response with sunitinib for metastatic renal cell carcinoma. Ann Oncol. 2007; 18: 1282-1283.
  • 20
    Negrier S. Case Report 3. Sunitinib malate in patients with cerebellar metastases. Eur J Cancer. 2007; 5(suppl): 32-34.
  • 21
    Helgason HH, Mallo HA, Droogendijk H, Haanen JG, van der Veldt AA, van den Eertwegh AJ, Boven E. Brain metastases in patients with renal cell cancer receiving new targeted treatment. J Clin Oncol. 2008; 26: 152-154.
  • 22
    Patyna S, Peng J. Distribution of sunitinib and its active metabolite in brain and spinal cord tissue following oral or intravenous administration in rodents and monkeys. Eur J Cancer. 2006; 4: 21.
  • 23
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000; 92: 205-216.
  • 24
    Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004; 22: 454-463.
  • 25
    Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002; 20: 289-296.
  • 26
    Henderson CA, Bukowski RM, Stadler WM, et al. The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Subset analysis of patients (pts) with brain metastases (BM). J Clin Oncol. 2007; 25(suppl 18s). Abstract 15506.
  • 27
    Massard C, Zonierek J, Gross-Goupil M, Fizazi K, Szczylik C, Escudier B. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol. 2010; 21: 1027-1031.
  • 28
    Sunitinib in treating patients with kidney cancer that has spread to the brain, 12/09 update. Available at: http://clinicaltrials.gov/ct2/show/NCT00814021
  • 29
    Novello S, Abrey LE, Grossi F, Camps C, Mazieres J, Selaru P, Patyna S, Torigoe Y, Chao R, Scagliotti G. Administration of sunitinib to patients with non-small cell lung cancer and irradiated brain metastases: a phase II trial. J Clin Oncol. 2009; 27(suppl 15s). Abstract 8077.
  • 30
    Wuthrick EJ, Curran WJ, Werner-Wasik M, et al. A phase I trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies. J Clin Oncol. 2008; 26 ( May 20 suppl). Abstract 2053.