Current Cancer Therapy Reviews, 2010, 6, 13-18
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Clinical Update: Treatment of Glioblastoma Multiforme with Radiolabeled Antibodies that Target Tumor Necrosis Randy L. Jensen1, Joseph S. Shan3, Bruce D. Freimark2, Debra A. Harris2, Steven W. King2,3, Jennifer Lai3 and Missag H. Parseghian2,* 1
Huntsman Cancer Institute, Department of Neurological Surgery, University of Utah Medical Center, Salt Lake City, Utah, USA 2
Research & Development, Peregrine Pharmaceuticals Inc., Tustin, California, USA
3
Clinical Affairs, Peregrine Pharmaceuticals Inc., Tustin, California, USA Abstract: Glioblastoma multiforme (GBM) is one of the most intractable cancers in humans, and yet, in the past decade, incremental advances in the treatment of brain tumors have begun to suggest that effective therapies may be on the horizon. Here we review the latest treatments available to patients and focus on a promising radiotherapeutic strategy that employs the isotope 131Iodine conjugated to an antibody that binds the necrotic core found in all solid tumors. Historically, GBM patients who relapse have a median survival time of no more than 24 weeks; however, the Tumor Necrosis Therapy discussed here has already provided a good quality of life for several patients years beyond the historical median survival time. The cases of two long-term survivors are reviewed, and data are presented to show that initial post-treatment assessments of tumor progression actually turned out to be tumor necrosis and inflammation. Given the current lack of imaging modalities that can distinguish between tumor progression and pseudoprogression, these cases further highlight the challenges faced by physicians in differentiating disease progression or recurrence from necrosis.
Key Words: Convection enhanced delivery, malignant glioma, glioblastoma multiforme, radioimmunotherapy, local delivery, clinical trial. THE POOR PROGNOSIS OF GBM Glioblastoma multiforme (GBM) is the most common and most malignant primary tumor of the brain and is associated with one of the worst survival rates among all human cancers. The Central Brain Tumor Registry of the United States (CBTRUS) estimates that approximately 8,000 new cases of glioblastoma were diagnosed in 2004, with a oneyear survival of 29.6% [1]. Despite multimodal treatment with surgical resection, local radiotherapy, and systemic chemotherapy, the median survival time (MST) after diagnosis is just 12 months and has not improved over the past 20 years [2]. In GBM patients who relapse, the MST is 3 to 6 months despite aggressive treatment. Long-term survival of patients with GBM is rare, with the estimated survival rates for 1, 2, 3, and 5 years being 29.3%, 8.7%, 5.1%, and 3.3%, respectively [1]. This emphasizes the pressing need for new, more effective treatments for this disease. We describe new treatment modalities available with an emphasis on tumor necrosis therapy (TNT) and the long-term survival of patients who have undergone this therapy. PROMISING NEW TREATMENTS GBM is a highly infiltrative disease that usually recurs locally but can spread from its primary location into multiple regions of the brain. Surgery and stereotactic radiotherapy
*Address correspondence to this author at Peregrine Pharmaceuticals Inc., 14272 Franklin Avenue, Tustin, CA, USA; Tel: 1-714-508-6052; Fax: 1-714-838-6940; E-mail:
[email protected] 1573-3947/10 $55.00+.00
are initially effective against localized disease, but because of acquired resistance and the infiltrative nature of this tumor, additional therapies are needed. These problems are compounded by the need for systemically administered cytotoxic drugs to traverse the blood–brain barrier. Although the blood–brain barrier becomes partially disrupted in vessels within tumor masses, it remains intact in the normal vessels that nourish the diffuse infiltrating tumor cells that have separated from the main tumor mass. Also, the resistance of tumor cells to chemotherapeutic drugs and irradiation is increasingly a problem in relapsing tumors. Many new drugs and treatments are being explored, including cytotoxic chemotherapeutic drugs, growth factor signaling pathway inhibitors, anti-angiogenic agents, and immunotherapeutics (reviewed in [3]). The following new treatments stand out as producing promising clinical benefit: 1) Treatment with the hypoxia-activated alkylating agent temozolomide plus radiotherapy extends the MST of newly diagnosed GBM patients to 14.6 months as compared with 12.1 months for radiotherapy alone (P 1 Year
1.0 mCi
8
19
11
1 ( 9% )
1.5 mCi
8
14
5
0 ( 0% )
2.0 mCi
21
56
7
4 ( 57% )
2.5 mCi
19.5
82+
2
2 (100%)
3.0 mCi
13
13
3
0 ( 0%)
Temozolomide [39]
9
24
128
< 20% (est.)
Temozolomide data of patients treated at first relapse [39].
Table 2. Survival of GBM Patients Treated with Cotara Patient
Survival (Weeks)
Last Report
05-205
468+
11/16/09
05-207
459+
11/16/09
06-201
254+
8/17/04
02-213
186
N/A
02-205
71
N/A
06-202
69
N/A
12-202
56
N/A
proportional to the tumor size to achieve a standard irradiation dose per cm3 of tumor. To adjust for differences in tumor size, each patient underwent a preoperative magnetic resonance imaging (MRI) scan to determine the clinical target volume (CTV), which was defined as the baseline gadolinium-enhancing tumor volume, including nonenhancing areas of central necrosis. The remaining 6 patients in the phase I study then received doses of 1.0 or 1.5 mCi of Cotara per cm3 CTV. A dose of 1.5mCi/ cm3 was calculated to deliver 13,700 cGy to the CTV. The phase I data indicated that 1.0 and 1.5 mCi/cm3 could be delivered to patients safely and produced a tolerable radiation effect. The patient population was expanded into a phase II study in which patients with malignant glioma were to be given total doses of 1.0, 1.5, 2.0, 2.5, or 3.0 mCi of Cotara per cm3 of CTV in one or two infusions (Table 1). Adverse events were merged for the two studies. Treatment-emergent, drug-related adverse events that were ascribed by the investigators to the treatment included brain edema (16%), hemiparesis (14%), headache (14%), convulsion (6%), and aphasia (4%). Systemic adverse events were mild. The ‘therapeutic window’ was judged to be between 1.25 and 2.5 mCi/cm3 CTV of the actual dose administered. Tumors in patients receiving less than 1.25 mCi/cm3 had typically progressed by week 8 of the study, whereas patients receiving more than 2.5 mCi/cm3 experienced more toxicity. For 12 patients with recurrent GBM who were treated with between 1.25 and 2.5 mCi/cm3
CTV, the MST was 37.9 weeks. One patient had a PR, 6 had stable disease, and 4 had disease progression. CLINICAL UPDATE ON TREATMENT OF RECURRENT GBM WITH COTARA To illustrate the effectiveness of an approach that targets the histone/DNA complex in the necrotic core of a tumor, using a convection-enhanced delivery system, Table 2 lists the long-term survivors from the studies just described. Of these long-term survivors, two case studies are presented of patients treated at our institution. Case 1: Patient 05-205. A 42-year-old mother of nine with a past medical history of polycystic kidney disease, hypertension, obesity, and sleep apnea presented with headache, nausea, and vomiting in March of 2000. Her physical examination was essentially normal. Her family history was significant for a father with colon and prostate cancer and a paternal grandmother with melanoma. A computed tomography (CT) scan demonstrated an approximately 4-cm left temporal mass that enhanced in a ring-like fashion with contrast. An MRI scan was attempted; however, the patient's size and severe claustrophobia prevented completion of this study. She underwent a left temporal craniotomy for subtotal resection of her tumor, which pathologically was consistent with GBM. A postoperative MRI scan was obtained using a large-bore MRI device that demonstrated a small amount of residual disease. The patient was treated with postoperative radiation of 6000 cGy in 200 cGy fractions over 30 days. She was started on temozolomide adjuvant treatment and experienced minor difficulties with nausea and vomiting and some diarrhea. After two cycles of chemotherapy, an MRI scan demonstrated progression of her tumor. Despite reresection of her temporal lobe tumor, by October 2000 her tumor continued to progress, and she was enrolled in the Cotara trial. The patient underwent placement of two interstitial catheters into the recurrent tumor. She tolerated this well, as well as the subsequent infusion of study drug. She experienced only minor headaches during the follow-up period. At her 8-week MRI scan it appeared that there was a significant increase in the size of the enhancement of the treated tumor and therefore she was disqualified from continuing with the trial. Ten months after her original presentation she underwent another craniotomy and resection of the presumed tu-
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Jensen et al.
Fig. (1). Tracking patient 1 for 48 months after treatment with 131I-chTNT-1/B (Cotara). Representative axial (top row) and coronal (bottom row), T1-weighted, gadolinium-enhanced magnetic resonance images demonstrating tumor size over time.
Fig. (2). Hematoxylin and eosin stained histological sections demonstrating tumor necrosis after treatment with 131I-chTNT-1/B (Cotara). A. 4X, Pre Cotara demonstrating hypercellularity. B. 10X Pre Cotara demonstrating pseudopalisading and necrosis consistent with glioblastoma multiforme. C. 20X Pre Cotara demonstrating mitotic figures and hypercellularity. D. 4X Post Cotara demonstrating global necrosis. E. 10X same necrotic figures. F. 20X demonstrating thickened, hyalinized blood vessel walls consistent with radiation treated tumor vasculature.
mor recurrence and radiation necrosis. The pathological analysis was consistent with radiation necrosis without evidence of tumor (Figs. (1) and (2)). One week later she developed fever and drainage from her wound and underwent removal of an infected craniotomy bone flap and reconstruction of dura with a vascularized temporalis pedicle. She was treated with antibiotics and eventually her bone flap was replaced. She was followed with serial MRI until April 2001, when tumor progression suggested by increased enhance-
ment was found, and she was started on irinotecan (CPT-11) chemotherapy for over a year. She has had gradual regression of tumor abnormalities on her MRI scans over this time period. Since that time, her MRI scans have been stable, as have her neurological deficits of left hemiparesis and homonymous hemianopsia. Case 2: Patient 05-207. A 23-year-old man was diagnosed with GBM in December 1996 after a new onset of
Treatment of Glioblastoma Multiforme with Radiolabeled Antibodies
seizures. He underwent a stereotactic biopsy followed by radiation therapy and procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy. He had significant progression of this disease requiring a craniotomy in January 1997 and stereotactic radiotherapy in April 1997. He required two more craniotomies in December 1997 and March 1998. His disease remained stable until a surveillance MRI scan in early December 2000 indicated recurrence of the left temporal lobe tumor. This was confirmed by MR spectroscopy. The patient was referred to our institution and eventually enrolled in the Cotara trial. In early January 2001, he underwent an uncomplicated stereotactic placement of interstitial catheters. He tolerated the procedure as well as the subsequent CED treatment. His 8-week MRI demonstrated tumor progression suggested by increased enhancement and, per investigational protocol, he was deemed a treatment failure. He remained clinically stable, with the exception of difficulty controlling his seizures periodically and a stable right quadrant field cut. He has been followed with serial MRI scans without evidence of tumor progression. He has mild expressive aphasia and some cognitive slowing. Presently, he is physically active, lives independently, and is gainfully employed. DIFFERENTIATING TUMOR NECROSIS VERSUS TUMOR PROGRESSION The two cases described are enlightening in that both resulted in postoperational MRI scans that suggested tumor progression; however, the evidence indicates otherwise. There is an emerging body of literature on the topic of “pseudoprogresssion.” This was originally mentioned by Hoffman in 1979 [26] and more fully described by de Witt in 2004 [27] to describe early tumor bed enhancement for GBM tumors treated with radiation therapy with or without carmustine. The authors of these papers described enhancement on MRI in the immediate post-radiotherapy time frame that mimicked tumor progression but was later found to improve or remain stable on follow-up imaging. More recently, this was better defined in the era of the currently used temozolomide regimen [28]. This paper included surgically confirmed early necrosis without evidence of recurrent tumor after treatment with concurrent Temodar® and radiotherapy. This was further confirmed by an even larger patient series [29-31]. This phenomenon is not restricted only to conventional chemotherapy and radiation. Similar findings have been seen in the CED of nonradioactive agents to treat glioblastoma [32]. As reported by Parney et al. (2005), patients with recurrent malignant glioma underwent CED of human interleukin-13 conjugated to a truncated Pseudomonas exotoxin and, in a number of the MR images, physicians were challenged in their ability to discern a disease progression or recurrence from necrosis and inflammation. Some of the same mechanisms behind the development of post-treatment peritumoral enhancement after chemotherapy, radiation, and convection-enhanced therapies may be seen after Cotara treatment. In fact, both of the patients we describe were judged to have failed treatment but ultimately were proven to have stable disease. To our knowledge, to date, there is no modern imaging technique such as MR spectroscopy, perfusion or diffusion-weighted imaging, or positron emission
Current Cancer Therapy Reviews, 2010, Vol. 6, No. 1
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tomography that can be used to distinguish between tumor progression and pseudoprogression. Furthermore, it has been suggested, and we agree, that pseudoprogression may represent an exaggerated response to effective therapy and may lead to a nonindicated change in therapy or create a falsenegative response to subsequent therapy [33]. A patient may be subjected to additional treatments unnecessarily if false progression is determined; therefore, the importance of repeat scans or other additional procedures to confirm MR progression after CED treatment with Cotara is emphasized. CONCLUDING REMARKS Favorable prognostic factors for patients with GBM include young age, female, high Karnofsky performance status score, and small residual tumor after surgical debulking [2, 34, 35]. A summary of 281 long-term GBM survivors (>3 years) indicates a median age of 36.9 years [36]. Some have suggested the younger age for long-term survivors may be the result of 1) tumor type reclassification, particularly in older studies [37, 38], 2) earlier age of detection, and 3) aggressive treatment [2]. In comparison, the 4 Cotara patients listed in Table 2 who survived >3 years had a median age of 47 years. Although clinical trials of GBM patients with Cotara are ongoing, it is noteworthy that in the study of heavily pretreated patients with recurrent GBM discussed here, 14.3% (4/28) and 10.7% (3/28) treated with Cotara have survived >3 and >5 years from treatment, respectively, with two patients continuing to survive >9 years after therapy. This compares favorably with statistics suggesting a 3-year and 5year survival from initial diagnosis of 5.2% and 3.4%, respectively (see Table 23 in [1]). While ongoing trials have not reached these follow-up milestones yet, preliminary results are encouraging, with several patients already surviving over a year. Data from the range-finding studies indicate an optimum target radiation dose is achievable and, when administered by CED, should maximize the exposure of drug to tumor. The growing trend to treat GBM is to aggressively treat disease in a post-surgery, adjuvant setting with combination therapy. It is clear that those treating patients who have malignant gliomas need to be aware of imaging changes consistent with pseudoprogression. This may necessitate liberal use of follow-up and confirmatory imaging and surgical biopsy for histological diagnosis when indicated. Identification of patterns in a patient’s treatment history and disease biomarkers will become an important aspect to develop Cotara as a potential form of therapy. ACKNOWLEDGEMENT We thank Kristin Kraus, M.Sc., for editorial assistance in preparing the manuscript. REFERENCES [1]
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Accepted: June 19, 2009
