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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 8136-8139 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.5635
Surrogate Markers for Antiangiogenic Therapy and Dose-Limiting Toxicities for Bevacizumab With Radiation and Chemotherapy: Continued Experience of a Phase I Trial in Rectal Cancer PatientsDepartment of Radiation Oncology, Duke University Medical Center, Durham, NC
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA
Department of Nuclear Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA To the Editor: Administration of bevacizumab (BV), a vascular endothelial growth factor (VEGF) specific antibody, has been tolerable to patients with an array of malignancies as reported in recent clinical trials involving this agent.1 According to the US Food and Drug Administration, the most common severe (National Cancer Institute CTC grade 3-4) adverse events in patients receiving BV were hypertension, diarrhea, asthenia, pain, and leukopenia. Although infrequent, serious adverse events of BV (arterial ischemic events, hemorrhage, wound healing delays, and bowel perforation) have comprised in aggregate a nontrivial percentage. We recently demonstrated that BV at a dose of 5 mg/kg was well tolerated by rectal cancer patients when combined with chemotherapy and radiation.2 We also reported that a single infusion of BV induces a significant decrease in tumor microvascular density (MVD). The decrease in MVD was associated with a decrease in interstitial fluid pressure (IFP) and an increase in pericyte coverage of tumor vessels, which was suggestive of a process of normalization of tumor vasculature.3,4 In preclinical studies, the induction of tumor vascular normalization by VEGF blockade reduces hypoxia, optimizes radiotherapy, and increases drug delivery.5-7 Whether these effects are similar at a higher BV dose is unknown. As a continuation of our dose-escalation phase I trial, two consecutive cohorts of three patients with locally advanced rectal carcinoma were to be enrolled and treated with BV (10 mg/kg, day 1), after concurrent administration of BV (on days 15, 29, 43) with fluorouracil chemotherapy (225 mg/m2 q24 hours: on days 15-52) and pelvic radiation therapy (50.4 Gy in 28 fractions: on days 15 to 52). Surgery was scheduled 7 to 9 weeks after completion of therapy. Functional, cellular, and molecular studies were performed before and after initial BV monotherapy. Following the National Cancer Insistute trial guidelines, we terminated the dose-escalation component of our study when two consecutive patients developed dose-limiting toxicities (DLT) of diarrhea and colitis during the combined treatment. Following recovery from toxicity, these patients were able to resume and complete radiation therapy and fluorouracil. Because of these DLT, only 5 patients were enrolled at the 10 mg/kg dose (Table 1). All the patients underwent surgery (four low anterior resections; one abdominoperineal resection). Of note, one patient experienced a pulmonary embolus day 1 postoperatively and recovered completely with anticoagulation. Another patient developed an ileostomy obstruction with stent related ileal perforation 10 days following resection requiring laparotomy and ileostomy revision. The systolic blood pressure of one patient transiently increased by 20 mmHg 12 days after the first injection of BV. In all patients, the levels of thyroid-stimulating hormone remained within normal range, and no increase in proteinuria was seen throughout the treatment, suggesting that BV did not adversely affect the kidney or thyroid function. In phase II and III clinical trials, the addition of a BV to chemotherapy did not significantly increase type 3 diarrhea in patients with metastatic colorectal cancer8,9 or non–small-cell lung cancer.10 It is possible that increasing the dose of BV neoadjuvant treatment may have induced the intestinal DLT by reducing the protective effect of VEGF against the intestinal damage induced by radiation combined with chemotherapy.11,12
Of interest, pathologic evaluation of the surgical specimens for staging13 following completion of all therapy in thepatients receiving 10 mg/kg BV showed two complete pathologic responses (Table 1), as compared to no complete pathologic response in the 5 mg/kg BV group (two patients with ypT3N2, two patients with ypT1N0, two patients with ypT2N0). These tumor responses were also detected on computed tomography (CT) and positron emission tomography scans after completion of chemo-radiation therapy (presurgery). Intriguingly, the complete responses were seen in the two patients experiencing DLT. Histological evaluation of the surgical specimens of the three other patients on 10 mg/kg BV showed ulceration and fibrosis with residual microscopic disease (consistent with Manard grade 3-4 features). The dose effect on efficacy remains unknown because of small patient numbers at the high-dose level. Some of the results of our correlative studies in patients treated with BV are summarized in Tables 2 and 3. Twelve days after the 10 mg/kg BV-dose MVD, blood flow analyzed by CT and IFP were reduced, but fluorodeoxyglucose uptake measured on positron emission tomography scans and permeability surface product (measured by CT, not shown) did not change. Thus, the effect of the 10 mg/kg BV-dose on the rectal carcinoma vasculature was consistent with our previous findings obtained with the 5 mg/kg BV-dose.2
We extended our previous studies to identify kinetic changes in tumor cell proliferation and apoptosis indices in response to VEGF blockade.5 Similar to the apoptosis induced by the inhibition of VEGF signaling in experimental tumors,14,15 we found a significant increase in tumor cell apoptosis at day 12 after BV administration (Table 2). Our findings show, for the first time that BV can increase tumor cell apoptosis in human tumors in situ. By down-regulating antiapoptotic proteins, BV may further sensitize tumor cells to the cytotoxic effects of chemotherapy and radiation.16 Surprisingly, BV did not significantly decrease the fraction of proliferating cell nuclear antigen–positive tumor cells; moreover, there was a clear tendency for increased proliferation in BV-treated patients (P = .06, Table 2). We hypothesize that this increase in proliferation of tumor cells reflects an improved tumor microenvironment (eg, decrease in tumor hypoxia) subsequent to vascular normalization concurrent with the reduction in vascularization. We also evaluated the changes in angiopoietin 2 (Ang-2) expression, a molecule which promotes the destabilization of blood vessels by inhibiting the recruitment of pericytes to blood vessels.17 At day 12 after BV, Ang2 expression decreased proportionally with the MVD, but the percentage of Ang-2-positive blood vessels remained high (90% to 100%). The persistence of Ang-2 expression may provide a target for tumor vascular normalization. The characterization of surrogate markers to evaluate the effects of antiangiogenic drugs is a critical facet of the development of targeted therapies. One 10 mg/kg BV infusion substantially reduced the percentage of viable circulating endothelial cells (CECs) at day 3 in three of five patients; these patients had high CEC counts at baseline. In contrast to patients on 5 mg/kg BV, low viable CEC counts were maintained at day 12 after first BV infusion in all five patients (Table 3). The kinetics of progenitor cells in circulation showed similar trends (not shown). These cells were detected at concentrations that were two orders of magnitude lower than those of viable CECs. The complexity of the progenitor population –resulting from similarities in surface marker expression among cell subsets –warrants further characterization for an appropriate interpretation of this marker. The decrease in blood concentration of viable CEC in patients on 10 mg/kg BV occurred at day 12 (which corresponds approximately to the half-life of BV in blood circulation) despite the significant increase in the levels of plasma VEGF and interestingly, also of plasma placental growth factor (PlGF, a ligand for VEGFR1; Tables 2 and 3). It will be critical to establish how much of the VEGF in the plasma represents free protein (unbound to BV) at day 12. We propose that the kinetics of CECs in the circulation in conjunction with the levels of VEGF family proteins in the plasma should be further evaluated as potential surrogate markers for the efficacy of VEGF blockade in humans.2 Furthermore, the elevated PlGF levels in plasma warrant exploration of anti-PlGF strategies. In summary, the 10 mg/kg BV dose combined with chemo-radiation therapy induced two complete responses in locally-advanced rectal cancer patients, but also induced DLT in these two patients. Correlative investigations supported our previous findings that bevacizumab has antivascular effects and normalizes the tumor vasculature. These issues as well as further validation of surrogate markers are explored in our ongoing phase II trial at the 5 mg/kg dose, determined as the maximum-tolerated dose for BV on the basis of current studies. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES 1. Ellis LM, Kirkpatrick P: Bevacizumab. Nat Rev Drug Discov 4:S8–S9, 2005[CrossRef] 2. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has anti-vascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline] 3. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nature Med 7:987-989, 2001[CrossRef][Medline]
4. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005
5. Tong RT, Boucher Y, Kozin SV, et al: Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64:3731-3736, 2004 6. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs tumor response to radiation. Cancer Cell 6:553-563, 2004[Medline] 7. Wildiers H, Guetens G, De Boeck G, et al: Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979-1986, 2003[CrossRef][Medline] 8. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004
9. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003
10. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004 11. Okunieff P, Mester M, Wang J, et al: In vivo radioprotective effects of angiogenic growth factors on the small bowel of C3H mice. Radiat Res 150:204-211, 1998[Medline]
12. Paris F, Fuks Z, Kang A, et al: Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293:293-297, 2001 13. Colon and Rectum, American Joint Commission on Cancer Cancer Staging Manual (ed 6th Edition). New York, Springer-Verlag, 2002, pp 121-130
14. Lee C, Heijn M, di Tomaso E, et al: Anti-vascular endothelial growth factor treatment augments tumor radiation Response under normoxic or hypoxic conditions. Cancer Res 60:5565-5570, 2000 15. Shaheen RM, Ahmad SA, Liu W, et al: Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85:584-589, 2001[CrossRef][Medline] 16. Pidgeon GP, Barr MP, Harmey JH, et al: Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer 85:273-278, 2001[CrossRef][Medline]
17. Maisonpierre PC, Suri C, Jones PF, et al: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55-60, 1997
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
