Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma

DOI 10.1007/s11060-010-0121-0 CLINICAL STUDY - PATIENT STUDY Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma Richard M. Zuniga Roy Torcuator Rajan Jain John Anderson Thomas Doyle Lonni Schultz Tom Mikkelsen Received: 2 July 2009 / Accepted: 25 January 2010 Ó Springer Science+Business Media, LLC. 2010 Abstract After withdrawal of bevacizumab in patients with recurrent high-grade glioma, we have observed a rapid tumour re-growth or rebound radiographic phenomenon with accelerated clinical decline. We retrospectively reviewed 11 patients treated at the Henry Ford Hermelin Brain Tumor Center with recurrent high-grade glioma who demonstrated a rebound progression pattern after the discontinuation of bevacizumab. The original tumour area-ofenhancement increased by a mean of 158%, when compared to the rebound magnetic resonance imaging. After rebound, no patients (0/8) showed a response to next-line treatments that did not include bevacizumab. The median survival of those re-treated with bevacizumab was 149 and 32 days for those who received other regimens. Abrupt discontinuation of bevacizumab after recurrence often leads to a dramatic rebound phenomenon and rapid clinical decline. Slow tapering of the bevacizumab dose after R. M. Zuniga (&) R. Torcuator T. Mikkelsen Henry Ford Health System, Hermelin Brain Tumor Center, 2799 W Grand Blvd, Detroit, MI 48202, USA e-mail: rickzunigaperu@hotmail.com R. Torcuator T. Mikkelsen Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA R. Jain Department of Neuroradiology, Henry Ford Health System, Detroit, MI, USA J. Anderson T. Doyle Department of Medical Oncology, Henry Ford Health System, Detroit, MI, USA L. Schultz Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI, USA tumour progression may prevent this from occurring and improve responsiveness to next-line therapies. Keywords Glioma Bevacizumab Rebound Recurrent glioma Glioblastoma Introduction High-grade gliomas are aggressive tumours with a poor prognosis even after treatment with standard post resection chemo-radiation. These tumours exhibit diffuse parenchymal infiltration and are highly angiogenic. The landmark clinical trial by Stupp et al., described a median survival of 14.6 months and a 2-year survival rate of 26% for those with glioblastoma multiforme (GBM) after undergoing surgical resection with subsequent external beam radiation therapy plus temozolomide as first line therapy [1]. Due to the highly infiltrative nature of these tumours, recurrence is essentially inevitable. After first-line treatment failure, historical data reports a dramatic decrease in overall survival (OS) to 25 weeks for GBM and 47 weeks for AA [2]. However, agents that target multiple signaling pathways and critical growth factors essential for tumour angiogenesis have become a major focus of interest in experimental clinical studies. Vascular endothelial growth factor (VEGF) is a potent growth factor produced by tumour and stromal cells that facilitates migration, proliferation and survival of endothelial cells making it essential in tumour angiogenesis [3]. VEGF is heavily overexpressed in high-grade gliomas and is directly correlated with tumour growth rate, metastatic potential and poor outcome [4 6]. Bevacizumab, an anti-vegf recombinant humanized monoclonal antibody, has been found to be active in other

solid tumours, such as breast, non-small cell lung and colorectal cancer, and renal cell cancer [7 10]. Over the past several years bevacizumab has been studied in highgrade gliomas with encouraging results. A number of reports have described an excellent improvement in radiographic response and clinical outcome in patients treated with bevacizumab and the cytotoxic agent, irinotecan, for recurrent high-grade gliomas [11 14]. Despite these encouraging results, the remarkable and rapid radiographic response seen on MRI does not appear to lead to a proportional improvement in survival and very few show any response at all to next-line therapy after bevacizumab failure [15]. As we gain more experience using this agent in highgrade gliomas, we also learn more about what occurs after treatment failure. Mancuso et al. conducted a laboratory research study with mice to address the reversibility of VEGF inhibition after cessation of anti-vegf therapy. It was noted that even after a 50 60% reduction of tumour vascularity, empty sleeves of basement membrane were left behind. By day 7 after drug withdrawal, tumours were fully re-vascularized, suggesting that these remaining empty sleeves of basement membrane and pericytes are responsible for this tumour revascularization. These basement membranes also serve as angiogenic growth factor storage sites and tracks for tumour vascular regrowth [16]. This rapid tumour re-growth has also been noted in some of our patients after treatment failure with bevacizumab. A dramatic rebound radiographic recurrence phenomenon has been observed that appears to lead to a rapid clinical decline. It has not been defined who is susceptible to this rebound effect and traditional radiographic criteria used to assess response are not good indicators of effective tumour control in patients treated with VEGF inhibitors [13, 14], and cannot predict who may present with this aggressive form of progression. These observations led us to conduct a retrospective review of selected patients with the objective of quantitatively describing this rebound phenomenon along with its clinical implications in terms of patient outcome and response to subsequent therapy regimens. Methods Patient selection We performed a retrospective search of the Henry Ford Hospital, Hermelin Brain Tumor Center database for all patients with recurrent high-grade glioma treated with bevacizumab-based regimens from 11/15/2005 to 12/31/2008 and found 53 patients. At the time of analysis, 40 patients had progressed while on bevacizumab and required discontinuation of the drug. We identified 11 patients within this group who presented with a rebound progression of disease (PD) pattern after the discontinuation of bevacizumab. All of the patients were required to have a minimum KPS score of 60%, normal kidney and adequate bone marrow function to be eligible for initial treatment with bevacizumab. Treatment Each patient was treated with bevacizumab plus irinotecan IV infusions given once every two weeks. The bevacizumab was administered at a dose of 10 mg/kg. The dosing for irinotecan was dependent on whether the patients were receiving enzyme-inducing anti-epileptic drugs (EIAED). If they were taking an EIAED, they received 340 mg/m 2 of irinotecan once every two weeks. If they were not taking EIAEDs they received 125 mg/m 2 of irinotecan every two weeks. Three treatment sessions constituted one-six-week cycle. After bevacizumab treatment failure, eight out of the 11 patients received next-line treatment regimens that did not include bevacizumab (erlotinib, imatinib, hydroxyurea, sirolimus, fractionated stereotactic radiotherapy and the clinical trial investigational drugs MLN-518 [tyrosine kinase inhibitor] and EM-1421). After the demonstration of rebound recurrence on MRI, the three remaining patients were re-started on bevacizumab-based regimens (i.e., one patient received irinotecan, one received carboplatin and one received alternate-dose temozolomide). MRI assessment The MRIs for all 11 patients were reviewed by the authors and a neuro-radiologist. All 11 patients had high quality and acceptable post-gadolinium T1 weighted and FLAIR MRI sequences. We quantitatively measured and compared the largest cross-sectional area of enhancement and of abnormal FLAIR signal seen on MRI at four different time points: (1) Prior to the initiation of bevacizumab; (2) after one cycle of bevacizumab; (3) at the time of bevacizumab failure, and (4) after discontinuation of the drug. Treatment failure and response was defined using the revised MacDonald criteria [17]. A new focus of enhancement outside of at least a 2-cm margin from the index lesion was defined as distant PD. An increase of over 25% of the largest cross-sectional area of enhancement of the index lesion constituted a local pattern of PD. Rebound PD was defined as an increase of at least 50% in the largest crosssectional area of enhancement on the rebound MRI compared to the one performed at the time of bevacizumab failure. The revised MacDonald criteria define complete response (CR) as complete resolution of all detectable areas of enhancement. Partial response (PR) is defined as at least

a 50% decrease in the largest cross-sectional tumour area. All others were labeled stable disease (SD). Measurements, endpoints, and statistical analysis All patients underwent serial interval MRIs with and without gadolinium contrast every 6 8 weeks after the discontinuation of bevacizumab. Our end points include the median patient OS after the rebound MRI as well as the radiographic response rate when started on next-line therapy. Treating clinicians at our institution reported end-point outcomes. We determined the rate of response in patients who were re-started on bevacizumab, as well as those who were started on a different salvage treatment regimen. The Kaplan Meier method was used for end-point estimation (Fig. 1). Results Patient population We reviewed 53 patients with recurrent high-grade glioma treated with bevacizumab-based regimens. At the time of analysis 11 (eight men and three women) out of the 40 patients who failed bevacizumab therapy because of tumor recurrence, demonstrated radiographic rebound PD after the discontinuation of bevacizumab. Of these 11 patients, eight had primary GBM, two had secondary GBM, and one had anaplastic oligodendroglioma. All had received at least one prior chemotherapy regimen before the administration of bevacizumab. The median age of our patient population was 56 years of age. The median baseline KPS score at the time of bevacizumab failure was 90%. The median KPS at the time of radiographic rebound was 60%. One of the patients rebounded on the first MRI after complete surgical resection of the area of enhancement seen at the time of bevacizumab failure. Patient characteristics are shown in Table 1. Response analysis We assessed radiographic response to next-line treatment after bevacizumab failure. Prior to beginning therapy with bevacizumab, the mean cross-sectional area of contrast enhancement and of abnormal FLAIR signal was 14.03 and 43.9 cm 2, respectively. All but one of the 11 patients demonstrated at least partial radiographic response (PR) after one cycle of bevacizumab therapy. From the time of bevacizumab failure to the subsequent rebound MRI the mean largest cross-sectional area of enhancement and increased FLAIR signal went from 18.53 to 36.24 cm 2 and 43.38 to 64.39 cm 2, respectively (Fig. 2). The mean interval between the MRI performed at the time of bevacizumab failure and the rebound MRI was 6.1 weeks (Table 2). Clinical outcomes included a median time to progression while on bevacizumab of 198.5 days. The median OS of patients who presented with rebound recurrence was 47.5 days. The seven patients who were not re-started on bevacizumab had an OS of 32 days, and those who were re-started on this anti-angiogenic drug had an OS of 149 days (Table 1). Of the three patients who were re-started on bevacizumab after the rebound MRI, two demonstrated partial Fig. 1 Kaplan Meier showing overall survival

Table 1 Demographic and Medical History Information (n = 11) Variable Age Mean (SD) 53.5 (11.3) Median (Range) 56 (37 to 72) Sex, N (%) Male 8 (72.7%) Female 3 (27.3%) Pathology, N (%) GBM 8 (72.7%) Anaplastic oligodendroglioma 1 (9.1%) Mixed anaplastic oligoastrocytoma, GBM 1 (9.1%) Oligodendroglioma, GBM 1 (9.1%) KPS at start of Avastin Median 90 Range 60 100 KPS at Rebound Median 60 Range 50 90 Survival after Rebound Median 7 weeks 95% confidence interval 4.3 26.6 weeks Overall Survival (OS) Median 10.8 months 95% confidence interval 7.7 16.2 months radiographic response and the other remained stable after one 8-week cycle. Only one out of the eight patients who were not re-started on bevacizumab had a stable first follow-up MRI. This patient received fractionated radiosurgery and one month of temozolomide as next-line therapy. Conclusions High-grade gliomas are very aggressive tumours with a poor prognosis even after treatment with standard post resection chemo-radiation [1]. Historically, data tells us that few respond to second-line therapy and prognosis is grim. However, the introduction of the anti-vegf humanized recombinant monoclonal antibody, bevacizumab, has provided remarkable response rates never seen before with previous therapy regimens. As bevacizumab use increases, we gain insight into radiographic patterns of response and progression as well as the changes observed after cessation of this anti-angiogenic drug [13, 16, 18]. To our knowledge, this is the first report describing a rebound radiographic phenomenon after the abrupt discontinuation of bevacizumab when used as therapy for recurrent high-grade glioma. However, this phenomenon has been described in patients treated with bevacizumab for other medical conditions. Matsumoto et al. reported rebound macular edema in those with retinal vein occlusion Fig. 2 Original tumor area seen on post-gd T1 weighted (a) and FLAIR MRI (e) sequences prior to initiating therapy with bevacizumab in a patient with recurrent high-grade glioma. Post-Gd T1 weighted (b) and FLAIR MRI (f) sequences that demonstrate partial response after 1 six-week cycle of treatment with bevacizumab. Post- Gd T1 weighted (c) and FLAIR MRI (g) sequences at the time of bevacizumab failure and subsequent cessation of bevacizumab therapy. Post-Gd T1 weighted (d) and FLAIR MRI (h) sequences at the time of rebound progression demonstrating a dramatic increase in area of enhancement and abnormal FLAIR signal 6 weeks after cessation of therapy with bevacizumab

Table 2 Descriptive statistics for time between MRIs, contrast and FLAIR measurements at each MRI and change in contrast and FLAIR measurements between MRIs Variable Mean S.D. Median Range Time Start of to after 1st cycle bevacizumab 8.1 weeks 3.6 8 weeks 4 17.9 weeks After 1st cycle of bevacizumab to progression 23.6 weeks 13.4 22.9 weeks 6 49.9 weeks Progression to rebound 6.1 weeks 2.5 6 weeks 3 10 weeks Contrast Start of bevacizumab 14.03 7.91 15.66 3.64 28.6 After 1st cycle of bevacizumab 8.97 6.23 8.40 1.08 17.60 Progression while on bevacizumab 18.53 13.14 18.02 0.36 44.95 Rebound 36.24 19.71 31.00 5.45 74.88 Change from start to after 1st cycle -5.06 4.57-3.44-14.84 0.55 Change from 1st cycle to progression 9.56 13.97 6.84-12.09 39.62 Change from progression to rebound 17.71 12.24 16.78 0.76 49.68 FLAIR Start of bevacizumab 43.39 25.93 43.43 11.60 84.70 After 1st cycle of bevacizumab 30.88 13.14 33.75 8.91 48.72 Progression while on bevacizumab 43.38 20.88 43.66 21.19 90.12 Rebound 64.39 24.61 55.30 29.45 101.12 Change from start to 1st cycle -12.50 17.64-7.23-49.03 6.10 Change from 1st cycle to progression 12.50 14.60 10.40-2.46 44.06 Change from progression to rebound 21.01 16.02 16.12 2.09 51.12 after bevacizumab cessation [19]. Cacheux et al. reported a tumour growth doubling time after bevacizumab interruption of 2 to 5 weeks in a small cohort of patients with metastatic colorectal cancer treated with FOLFOX6 or FOLFIRI chemotherapy in addition to bevacizumab [18]. Pre-clinical data reported by Mancuso et al., suggests that residual sleeves of basement membrane and pericytes after endothelial cell degeneration caused by bevacizumab treatment provide a scaffold for rapid tumour vascular re-growth [16]. Our data supports this effect as it shows a mean increase of 95.6% in the largest cross-sectional area of enhancement between the MRI at the time of bevacizumab failure and the rebound MRI. When compared to the original tumour size, the increase is 158%. The changes in increased FLAIR signal are not quite as dramatic. There is a mean increase of 48.4% between the abnormal FLAIR signal seen at the time of bevacizumab failure and the rebound MRI. These changes were observed at a median of 6 weeks after discontinuation of bevacizumab therapy. The major variations seen are primarily at a vascular level and the initial amount of improvement seen on contrastenhanced sequences does not necessarily represent a proportional degree of tumour burden control. Clinically, our review showed that this rebound phenomenon resulted in severe clinical decline with a median OS of 47.5 days. Our review also suggests that those who are not re-started on bevacizumab after the rebound MRI do very poorly with a median survival of 32 days. The median OS of those re-started on bevacizumab was markedly better at 149 days. Six out of the 11 total patients had a low functional status at the time of rebound enhancement seen on the MRI. Our review is limited by its retrospective nature along with a small number of selected patients. By using the MacDonald criteria our measurements may underestimate the degree of change between MRIs, as they only compare images on the same 2- dimensional plane and do not take into account the depth of the tumour burden. More sophisticated imaging techniques involving volumetric analysis are being used to more accurately determine tumour size [14, 20]. The purpose of this review is to describe this phenomenon and not to determine the frequency or to closely examine which patients are susceptible to this rebound effect. However, we must note that 11 out of the 40 patients (27.5%) that failed bevacizumab therapy demonstrated rebound PD. Also, 10 out of those 11 (91%) initially showed PR while on bevacizumab, which is higher than the response rates previously reported. This may indicate that the patients at a higher risk are those who have the best initial response. Nonetheless, our review highlights the importance of finding ways to prevent this rapid progression from occurring. One such manner may be to slowly taper the dose or increase the interval between treatment sessions with bevacizumab.

In conclusion, this analysis describes a rebound phenomenon that portends a dismal and rapid clinical decline. It also supports the observed lack of response to any subsequent therapies. However, all three of the patients in our study group who were re-started on bevacizumab therapy re-responded, which led to an improved OS. A larger controlled study should be performed to follow up on these preliminary results and support or nullify this hypothesis. References 1. Stupp R, Mason WP, van den Brent MJ, Weller M, Fischer B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer R, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Esenhauer E, Mirimanoff R (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987 996 2. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572 2578 3. Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl 3):11 16 4. Pradeep CR, Sunila ES, Kuttan G (2005) Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr Cancer Ther 4:315 321 5. Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanism of angiogenesis in gliomas. J Neurooncol 78:281 283 6. Poon RT-P, Fan S-T, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207 1225 7. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427 434 8. Hurwitz H, Fehrenbacker L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335 2342 9. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355:2542 2550 10. Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, Shenkier TN, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666 2676 11. Vredenburgh JJ, Desjardins A, Herndon JE, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253 1259 12. Cloughesy T, Prados M, Wen P, Mikkelsen T, Abrey LE, Schiff D, Yung WK, Maoxia Z, Dimery I, Friedman HS (2008) A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab alone or in combination with irinotecan on 6-month progression free survival in recurrent, treatment-refractory glioblastoma. J Clin Oncol, ASCO Annual meeting proceedings (Post-meeting edn), vol 26, no 15S (May 20 Suppl), 2010b 13. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, Schultz L, Mikkelsen T (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91:329 336 14. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779 787 15. Torcuator R, Zuniga RM, Doyle T, Anderson J, Mikkelsen T et al (2008) Salvage concurrent chemotherapy with bevacizumab for recurrent malignant gliomas previously treated with bevacizumab and irinotecan. Neuro-oncology 10(5):829. doi:10.1215/152285 17-2008-051 (abstract) 16. Mancuso MR, Davis R, Norberg SM, O Brien S, Sennino B, Nakahara T, Yao V, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe D, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610 2621 17. MacDonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277 1280 18. Cacheux W, Boisserie T, Staudacher L, Vignaux O, Dousset B, Soubrane O, Terris B, Mateus C, Chaussade S, Goldwasser F (2008) Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol 19:1651 1661 19. Matsumoto Y, Freund F, Peiretti E, Cooney MJ, Ferrara D, Yannuzzi LA (2007) Rebound macular edema following bevacizumab (avastin) therapy for retinal venous occlusive disease. Retina 27:426 431 20. Ananthnarayan S, Bahng J, Roring J, Nghiemphu P, Lai A, Cloughesy T, Pope W (2008) Time course of imaging changes of GBM during extended bevacizumab treatment. J Neuro-oncol 88:339 347