Anti-angiogenic strategies are incorporated as treatment for many oncologic diseases, and studies to further optimize their use are ongoing. Despite hundreds of clinical trials, we still do not have a complete understanding of why some patients fail to respond to VEGF Signaling Pathway (VSP) inhibitors and other patients, despite initially responding to treatment, later progress on VSP therapy. We have learned through trial and error that bevacizumab is most effective when combined with other agents (e.g. cytotoxic chemotherapy). Most surprising is that despite higher single-agent activity with VEGFR TKI agents (compared to bevacizumab alone), trials reported to date combining VEGFR TKI agents with cytotoxic chemotherapy have not shown the same promise. Phase III trials of carboplatin/paclitaxel with or without sorafenib in both advanced melanoma(34
) and NSCLC,(35
) gemcitabine with or without axitinib in pancreatic cancer,(36
) and sunitinib with or without FOLFIRI in mCRC(37
) have all failed to show an improvement in the primary endpoint with the addition of a VEGFR TKI. Furthermore, patients with squamous histology in the NSCLC trial appeared to have increased
mortality on the sorafenib-chemotherapy arm compared with the placebo-chemotherapy arm.
It was postulated by Teicher in 1996 that combined administration of anti-angiogenic and cytotoxic therapies would yield maximal benefit, because such combinations would destroy two separate compartments of tumors – cancer cells and endothelial cells.(38
) This hypothesis was supported by the clinical data showing that bevacizumab treatment resulted in a significant increase of 5 months in overall survival in patients with metastatic colorectal cancer, when given in combination with standard chemotherapy,(4
) whereas as a single agent, it produced only modest objective responses.(2
) Jain in 2001 also proposed that judicious application of anti-angiogenic agents can normalize the abnormal tumor vasculature, resulting in more efficient delivery of drugs and oxygen to the targeted cancer cells, and therefore enhancing the effectiveness of chemotherapy and radiation.(39
) However, excessive vascular regression may be counterproductive as it compromises drug and oxygen delivery.
A normalization window
, or a period during which the blood vessels become normalized, is the theoretically optimal time when the addition of chemotherapy or radiotherapy to anti-angiogenic therapy should yield the best therapeutic outcome.(40
) A novel study using dynamic-contrast enhance magnetic resonance imaging (DCE-MRI) showed improved tumor perfusion, indicating normalization of blood vessels, in a murine RCC model after 3 days of sunitinib administration, but not after 1 day of sunitinib administration; mice were subsequently treated with weekly gemcitabine.(41
) This study suggests that chemotherapy combination with anti-angiogenic therapy may be optimized through the use of functional imaging. Understanding how VEGFR TKI therapy may antagonize cytotoxic chemotherapy was another important goal during the analysis of our study, as ongoing trials combining newer VEGFR TKIs with chemotherapy continue.
Here we show that nearly all patients with advanced solid malignancies have some initial reduction in tumor proliferation as measured by FLT PET/CT after 4 weeks of sunitinib treatment. This reduction was more apparent on the 4/2 schedule versus 2/1 schedule, and more significant for the FLT PET SUVmax then SUVmean, which is likely due to a greater duration of sunitinib exposure. Nevertheless, in both schedules, during the brief treatment break patients experienced a relative increase in FLT uptake consistent with an increase in tumor proliferation during the treatment withdrawal period. This finding supports our hypothesis and was seen in both the patients with renal cell cancer as well as other solid malignancies. Because of the longer exposure to sunitinib and longer treatment break, we would have predicted that the 4/2 schedule would have a larger “withdrawal flare,” but this was not the case. This may simply be due to the low number of patients assessed; however, a complex relationship between the clinical flare, sunitinib PK, and circulating VEGF could also be playing a role. We are addressing this question in currently on-going trials using a VEGFR TKI with a shorter half-life (e.g. NCT00859118).
During sunitinib exposure, it was observed that most (but not all) patients had some decline in SUV (). Looking at the individual patients (dotted lines), one can begin to appreciate the differences in response. Possible categories include those patients that experience no change or a small increase in SUV (proliferation) while on sunitinib but still experience a sunitinib withdrawal flare where SUV greatly increases; individuals where an initial decline in SUV is seen during sunitinib exposure but during withdrawal have an increase in proliferation; and individuals where no apparent change in SUV is seen during/after sunitinib treatment. In an attempt to link these observations with clinical outcomes (challenging given heterogeneous disease population and low numbers of patients), we conducted an exploratory analysis to evaluate the association between changes in SUV and the CB. As shown in , changes in SUV parameters suggest that those with lack of clinical benefit have a larger proliferative flare. Looking at the individual patient data (dotted lines), one can appreciate that initial steep declines in SUV during sunitinib treatment do not always correlate with clinical benefit. Our explanation for these findings is that sunitinib has both anti-angiogenic and anti-tumor activity in most solid tumors as evidenced by a decrease in FLT PET uptake in most patients. Treatment leads to increased physiological hypoxia, which results in a compensatory increase in proangiogenic factors, resulting in angiogenic escape. Thus, the greater ability of the host (patient) to compensate for treatment-induced hypoxia, the more likely that the patient will experience early sunitinib treatment failure. On the other hand, if the host cannot robustly compensate for treatment-induced hypoxia, then angiogenic escape is less likely to occur. The implications of this are enormous: this may provide a rationale to test anti-angiogenic combinations in order to ameliorate this compensatory response and personalize treatment by appropriate dosing schedule.
Our data suggests that the sunitinib withdrawal flare correlates with shorter duration of clinical benefit, and that the largest contributor on univariate and multivariate analysis to drive the flare is plasma VEGF ligand level. It has been observed that baseline VEGF levels gradually increase with chronic sunitinib exposure.(42
) While this may be an explanation for eventual treatment failure, the obvious implication is that we do have agents that can target VEGF ligand (e.g. bevacizumab). While studies testing the concurrent combination of sunitinib with bevacizumab have raised concerns regarding overlapping toxicities,(43
) suggestions of increased antitumor activity were seen. This raises the question of whether a “sequential” approach can be used to minimize overlapping toxicity and prolong benefit. Our current data has resulted in an ongoing study titled a “Phase I Study of Sequential Sunitinib and Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Advance Solid Malignancies” (NCT01243359) testing sequential
sunitinib with bevacizumab. Sunitinib is administered on the standard 4/2 schedule, with low-dose bevacizumab given on day 29 (at start of the 2 week treatment withdrawal) to suppress flare and cycles repeated every 6 weeks. FLT PET/CT imaging is being planned to see if the addition of low-dose bevacizumab will suppress the proliferative flare during sunitinib withdrawal.
One question that might be raised is whether the change in FLT PET uptake we observe is a reflection of tumor proliferation or simply vascular effect (e.g., decreased perfusion in tumor results in decreased tracer delivery resulting in lower FLT uptake). In order to address this question, we performed dynamic FLT PET/CT imaging. Using compartmental modeling (intravascular, extravascular, intracellular), one can calculate Ki
, which reflects the proliferative rate when corrected for K1
, which represents the vascular permeability/perfusion (45
). In summary, the FLT PET SUV and FLT PET Ki
trends were the same, indicating that FLT PET SUV analysis does adequately represent proliferative activity, which is consistent with both clinical and anatomic imaging observations.
In summary, we have shown that during sunitinib treatment on both the 4/2 and 2/1 schedules there are statistically significant increases in median sunitinib concentrations and median serum VEGF levels, and a median decrease in cellular proliferation as measured by SUVmean and SUVmax. Change in VEGF during sunitinib treatment predicted change in SUVmean during sunitinib withdrawal, which fits with the biologically plausible hypothesis that the rise in VEGF ligand during treatment may drive tumor flare during the withdrawal period. Finally, there was a suggestion of a more brisk proliferative flare in non-responders compared to responders. This suggests that patients with a robust compensatory response to treatment-induced hypoxia (e.g. large flare) might develop early treatment failure as a result.