Recurrent Glioblastoma

Given the aggressive nature of glioblastoma, it is nearly a certainty that all patients will need to be evaluated for potential treatment of recurrent disease. There is currently no definitive standard of care for recurrent glioblastoma. Unlike in other solid tumors that have benefited from genomic or molecular profiling and targeted therapy, it is often the case that the recurrent tumor no longer reflects the index tumor. In the pre-bevacizumab era, the meidan overall survival was 30 weeks, and only 10 weeks for median progression-free survival. This chapter discusses the definition of recurrence and gives a further breakdown of the treatment options and surgical and nonsurgical management, with a review of pertinent studies that have led to a better understanding of treatment options for recurrent disease. Other chapters provide expert opinion on the role of antiangiogenic agents (see Chapter 10) and tumor treating fields (See Chapter 17) as they pertain to recurrent glioblastoma and are only briefly discussed here.

Defining recurrence

Before the decision to treat recurrent glioblastoma, it is essential to determine whether or not radiographic evidence of recurrent disease is secondary to glioblastoma progression or to radiographic pseudoprogression. In order to standardize the assessment of response to initial glioblastoma treatment, the MacDonald Criteria organized response based on 4 categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) ( Table 11.1 ).

Table 11.1

MacDonald versus Response Assessment in Neuro-Oncology (RANO) Criteria for response in malignant gliomas

MacDonald	RANO
CR
Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 wk	Disappearance of all enhancing measurable and nonmeasurable disease sustained for a minimum of 4 wk Stable or improved FLAIR/T2-weighted lesions
No new lesions	No new lesions
Stable or improved clinically	Stable or improved clinically
No corticosteroids	Patients cannot be receiving corticosteroids (physiologic replacement doses are acceptable)
PR
≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 wk	≥50% decrease (compared with baseline) in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for a minimum of 4 wk No progression of nonmeasurable disease
No new lesions	No new lesions
Stable or reduced corticosteroid dose	Stable or improved FLAIR/T2-weighted lesions
Stable or improved clinically	Stable or improved clinically Corticosteroid dosage at the time of the scan should be no greater than the dosage at the time of the baseline scan
SD
Does not qualify for CR, PR, or PD	Patient does not qualify for CR, PR, or progression Stable FLAIR/T2-weighted lesions on a corticosteroid dose no greater than at baseline
Stable clinically	Stable clinically
PD
≥25% increase in sum of the products of perpendicular diameters of enhancing lesions relative to best previous scan	≥25% increase in sum of the products of perpendicular diameters of all measurable enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response following the initiation of therapy, while on a stable or increasing dose of corticosteroids. Significant increase in FLAIR T2-weighted lesions compared with baseline or best response following initiation of therapy, not caused by comorbid events (eg, radiation therapy, ischemic injury, seizures, postoperative changes, other treatment effects), while on a stable or increasing dose of corticosteroids
Any new lesion	New lesions
Clinical deterioration	Clinical deterioration not attributable to any causes apart from the tumor (eg, seizures, medication side effects, complications of therapy, cerebrovascular events, or infection) or decreases in corticosteroid dose. Failure to return for evaluation owing to death or deteriorating condition. Clear progression of nonmeasurable disease

Abbreviation: FLAIR, fluid-attenuated inversion recovery.

From Roy S, Lahiri D, Maji T, et al. Recurrent glioblastoma: where we stand. South Asian J Cancer 2015;4:164; with permission.

These criteria were initially formulated in 1990, and relied on the enhancing pattern of the tumor, which did not address the effects of chemoradiotherapy and antiangiogenic agents on radiographic imaging. Several factors compound the difficulty in determining pseudoprogression from true progression and include post–radiation treatment effects that increase contrast enhancement and T2 hyperintensity over the first month, which may increase vascular probability, and the use of bevacizumab, which may conversely decrease contrast enhancement. To address this, the Response Assessment in Neuro-Oncology Working Group (RANO) devised criteria for determination of the first progression, which depend on the timing from the initial chemoradiotherapy treatment. In general, these criteria added more restrictive parameters for diagnosing progressive disease within 90 days of chemoradiotherapy completion as well as consideration to corticosteroid use and T2/fluid-attenuated inversion recovery sequencing assessment. At present, the RANO criteria are considered the most appropriate tools for evaluation of progression and response in glioblastoma. Advances in MRI diagnostic capabilities have also been used to differentiate pseudoprogression from true progression, although these tools are suggested for guidance and not definitive diagnosis. Recently, Galldiks and colleagues evaluated a group of 22 patients with glioblastoma with concern for new contrast-enhancing lesions or existing lesions showing increased enhancement on their routine MRI within first 4 months after completion of chemoradiotherapy and compared those findings with O-(2-(18)F-fluoroethyl)- l -tyrosine [(18)F-FET] PET scans done at the same time. In the 11 patients with available histopathologic confirmation, they found significantly lower compound uptake in those with necrosis or pseudoprogression than in those with confirmed tumor recurrence. Although this is promising, this study and others have determined that labeled uptake remains a diagnostic option.

Surgical intervention for recurrent disease

The decision to proceed with surgical intervention on a patient with recurrent glioblastoma is not always clear. However, existing within the current literature are multiple prognostic factors that can guide the course of treatment of recurrent disease. There are many studies that have individually examined consecutive patients and their outcomes following repeat resection. This chapter describes what the authors think is the most relevant literature in assisting clinicians (and patients) in the decision to proceed with surgery.

One of the most important studies advocating gross total resection of recurrent glioblastoma was performed in 2012 by Bloch and colleagues. A total of 107 patients were examined after repeat glioblastoma resection. Of that subset, 52 patients had an initial gross total resection, of whom 31 (60%) had gross resection at recurrence and a median survival of 20.4 months versus 18.4 months for patients with a subsequent subtotal resection. In patients who initially had a subtotal resection (55), 47% had gross total resection recurrence with a median survival of 19 months and 53% had a subtotal resection with a median survival of 15.9 months. These findings indicated that extensive initial resection was not necessarily correlated with survival for every presentation, but that gross total resection on recurrence was statistically associated with increased overall survival. In this study, as in several others, the Karnofsky Performance Scale (KPS) at the time of surgical intervention for recurrent disease was an independent predictor of survival. More recent studies have similarly found that low residual volume and increased extent of resection were consistent with longer overall survival and progression-free survival ( Fig. 11.1 ).

Studies that examine the overall survival for patients with current disease are sometimes intrinsically biased secondary to patient selection. For example, patients with a high KPS and noneloquent areas tend to be logical candidates for second, if not third or even fourth, resections of glioblastoma. For example, a study by Chaichana and colleagues found that the median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months. Although these patients were matched in a case-control evaluation, the specific tumor molecular heterogeneity was unable to be analyzed, and it may be more a reflection of underlying favorable molecular profiling than simply surgical intervention that allowed these impressive extensions of life. These special patients are more likely to be included in studies and trials that result in publication. It is rare for a very old patient with a low KPS and highly aggressive course to benefit from second-stage or third-stage craniotomies. There is a growing body of literature that indicates that although the ideal patient may be of younger age, elderly patients when properly selected may also benefit from surgical resection. Park and colleagues devised a validated scale to predict survival after recurrent surgery and their findings were as expected: patients with Karnofsky performance statuses greater than 80, tumor volume less than 50 cm ³, and lack of involvement in cortical brain structures were all significantly associated with better postoperative survival. This scale was updated in 2010 and added the presence of ependymal involvement to further stratify patients by likelihood of prognosis following surgical resection.

The use of carmustine wafers is discussed in detail elsewhere in this book (Chapter 16), but briefly these wafers were first approved by the US Food and Drug Administration (FDA) in the context of recurrent glioblastoma. This approval was based on a 1995 study of 222 patients with recurrent glioblastoma across 27 medical centers who underwent randomization to receive either carmustine wafers or placebo. The median survival of the 110 patients who received carmustine wafers was 31 weeks compared with 23 weeks for those who received placebo, and 6-month overall survival was 50% greater in those in the experimental group. In 2008, a 10-year institutional analysis at Johns Hopkins reviewed 122 patients who underwent craniotomy and Gliadel wafer implantation for recurrent glioblastoma with a median survival of 11.3 months, and 13% were alive at 2 years, with an increasing trend to survival linked to the use of Gliadel. The combination of Gliadel with other agents is challenging because of the exclusion of Gliadel wafers in many clinical trials evaluating novel agents, due in part to the confounding radiographic artifacts due to Gliadel. The complications noted by the Hopkins group were similar to a comparative cohort without wafers, and included cerebral edema, seizures, and wound infections. An advantage of the carmustine wafer is that it avoids the systemic toxicity (immunosuppression, bone marrow failure, gastrointestinal effects) of chemotherapy, as there is no detectable level of agent in the blood stream.

Chemotherapy and radiation for the treatment of recurrent glioblastoma

Chemotherapy

Since 1996 there have been almost 100 studies to establish the ideal treatment of recurrent glioblastoma ( Table 11.2 ). Most of these were phase I and II, single-arm studies with fewer than 50 patients in the experimental group. These studies examined chemotherapeutic, dietary, and mechanistic permutations that included, in chronologic order, tamoxifen, procarbazine, temozolomide, carboplatin, etoposide, RMP-7 (bradykinin anal-g, Cereport™), gefitinib, bis-chloroethylnitrosourea; carmustine (BCNU), irinotecan, temsirolimus, imatinib, hydroxyurea, tipifarnib, sirolimus, pioglitazone, rofecoxib, capecitabine, bevacizumab, cilengitide, erlotinib, vorinostat, everolimus, O-benzylguanine, sulfasalazine, cetuximab, cediranib, lapatinib, enzastaurin, lomustine, cintredekin, sorafenib, sagopilone, 6-Thioguanine (6-TG), capecitabine, celecoxib, bortezomib, lomustine, 1-2-chlorethyl-3-cyclohexyl-1-nitrosurea (CCNU), tumor treating fields, lonafarnib, sunitinib, ketogenic diet, temsirolimus, dasatinib, panobinostat, etirinotecan pegol, valparin, and afatinib. Despite these investigations, there still exists no clear standard of care for recurrent disease.

Table 11.2

Studies of novel agents for the treatment of recurrent glioblastoma

Investigators, Year	Study Design	Patients Per Arm (N)	Interventions	Prior Adjuvant Therapy	Radiographic Response (%)	PFS (mo)	Median OS (mo)
Couldwell et al, 1996	Phase II, single arm	20	Tamoxifen	RT + Chemo	CR or PR (20)	NA	7
Brandes et al, 1999	Phase II, single arm	28	Procarbazine + tamoxifen	RT + Chemo	CR (4), PR (25), SD (32), PD (39)	Median 3	7
Yung et al, 2000	Phase II, 2 randomized arms	112	TMZ	RT + Chemo	PR (5), SD (40)	6, 21%; median 4	4
Yung et al, 2000	Phase II, 2 randomized arms	138	Procarbazine	RT + Chemo	PR (5), SD (27)	6, 8%; median 2	2
Watanabe et al, 2002	Phase II, single arm	14	Carboplatin + etoposide	RT + Chemo	CR (0), PR (14), SD (43), PD (43)	Mean 4	9
Prados et al, 2003	Phase II, 2 randomized arms	40	RMP-7 + carboplatin	RT + Chemo	CR (0), PR (8)	Median 2	6
Prados et al, 2003	Phase II, 2 randomized arms	40	Placebo + carboplatin	RT + Chemo	CR (3), PR (10)	Median 2	5
Rich et al, 2004	Phase II, single arm	53	Gefitinib	RT + Chemo	CR (0), PR (0), SD (42), PD (58)	6, 13%	9
Brandes et al, 2004	Phase II, single arm	42	BCNU + irinotecan	RT + Chemo	CR (0), PR (21), SD (50), PD (29)	6, 17%; median 4	12
Prados et al, 2004	Phase II, single arm	38	BCNU + TMZ	RT + Chemo	CR (0), PR (6), SD (6), PD (88)	6, 38%; median 3	9
Chang et al, 2005	Phase II, single arm	43	Temsirolimus	RT at minimum	CR (0), PR (5), SD (47), PD (48)	6, 2%; median 2	NA
Dresemann, 2005	Phase II, single arm	30	Imatinib + hydroxyurea	RT + Chemo	CR or PR (20)	6, 32%; 24, 16%	5
Galanis et al, 2005	Phase II, single arm	65	Temsirolimus	RT + Chemo	CR or PR (0)	6, 8%; median 4	4
Reardon et al, 2005	Phase II, single arm	33	Imatinib + hydroxyurea	Chemo at minimum	CR (3), PR (6), SD (42), PD (48)	6, 27%; median 4	12
Cloughesy et al, 2006	Phase II, single arm	67	Tipifamib	RT at minimum	CR (0), PR (7)	6, 9%	NA
Reardon et al, 2006	Phase II, single arm	34	Gefitinib + sirolimus	RT + Chemo	CR (0), PR (5), SD (38), PD (47)	6, 23%	NA
Wen et al, 2006	Phase II, single arm	34	Imatinib	Not specified	PR (6)	6, 3%	NA
Hau et al, 2007	Phase II, single arm	14	Pioglitazone + rofecoxib + (capecitabine or TMZ)	RT + Chemo	CR (0), PR (20), SD (10), PD (70)	6, 20%	NA
Vredenburgh et al, 2007	Phase II, single arm	35	BEV + irinotecan	RT + Chemo	CR or PR (57)	6, 46%; median 6	10
Reardon et al, 2008	Phase II, 2 randomized arms	40	Cilengitide high dose	RT + Chemo	CR (0), PR (13)	6, 15%; median 2	10
Reardon et al, 2008	Phase II, 2 randomized arms	41	Cilengitide low dose	RT + Chemo	CR (0), PR (5)	6, 10%; median 2	7
de Groot et al, 2008	Phase II, single arm	44	Erlotinib + carboplatin	RT + Chemo	CR (0), PR (2), SD (47), PD (51)	6, 14%; median 2	7
Galanis et al, 2009	Phase II, single arm	66	Vorinostat	Not specified	CR or PR (3)	6, 17%; median 2	6
Kreisl et al, 2009	Phase II, single arm	22	Everolimus + gefitinib	Not specified	CR (0), PR (14), SD (36), PD (50)	6, 5%; median 3	6
Quinn et al, 2009	Phase II, single arm	52	O-benzylguanine + gliadel wafers	RT + Chemo	NA	NA	13
Reardon et al, 2009	Phase II, single arm	27	Etoposide + BEV	RT + Chemo	CR (4), PR (19), SD (70), PD (7)	6, 46%; median 5	12
Robe et al, 2009	Phase II, single arm	10	Sulfasalazine	RT + Chemo	CR (0), PR (0), SD (10), PD (90)	Median 1	2
Friedman et al, 2009	Phase II, 2 randomized arms	85	BEV	RT + Chemo	CR (1), PR (27)	6, 43%; median 4	9
Friedman et al, 2009	Phase II, 2 randomized arms	82	BEV + irinotecan	RT + Chemo	CR (2), PR (29)	6, 50%; median 6	9
van den Bent et al, 2009	Phase II, 2 randomized arms	54	Erlotinib	RT + Chemo	CR (0), PR (4), SD (17)	6, 11%	8
van den Bent et al, 2009	Phase II, 2 randomized arms	56	TMZ or carmustine (if failed TMZ)	RT + Chemo	CR (0), PR (10), SD (35)	6, 24%	7
Neyns et al, 2009	Phase II, single arm	55	Cetuximab	RT + Chemo	CR (0), PR (5), SD (31)	6, 7%; median 2	5
Reardon et al, 2009	Phase II, single arm	231	Imatinib + hydroxyurea	Not specified	CR or PR (8)	6, 11%; median 26	6
Batchelor et al, 2010	Phase II, single arm	31	Cediranib	RT + Chemo	PR (57), SD (31)	6, 26%	8
Raizer et al, 2010	Phase II, single arm	38	Erlotinib	RT + Chemo	CR (0), PR (0), SD (8), PD (92)	6, 3%; median 2	6
Reardon et al, 2010	Phase II, single arm	32	Sirolimus + erlotinib	RT + Chemo	CR (0), PR (0), SD (47), PD (53)	6, 3%; median 2	9
Yung et al, 2010	Phase II, single arm	48	Erlotinib	RT + Chemo	CR (2), PR (4), SD (16), PD (78)	6, 20%	9
Sathornsumetee et al, 2010	Phase II, single arm	25	BEV + erlotinib	RT + Chemo	CR (4), PR (46), SD (42), PD (8)	6, 29%; median 4	11
Thiessen et al, 2010	Phase II, single arm	17	Lapatinib	RT + Chemo	CR (0), PR (0), SD (25), PD (75)	NA	NA
Dresemann et al, 2010	Phase III, 2 randomized arms	120	Hydroxyurea	Not specified	CR or PR (1)	6, 7%	5
Dresemann et al, 2010	Phase III, 2 randomized arms	120	Imatinib + hydroxyurea	Not specified	CR or PR (2)	6, 5%	5
Wick et al, 2010	Phase III, 2 randomized arms	174	Enzastaurin	Not specified	NA	6, 11%; median 2	7
Wick et al, 2010	Phase III, 2 randomized arms	92	Lomustine	Not specified	NA	6, 19%; median 2	7
Kunwar et al, 2010	Phase III, 2 randomized arms	183	Cintredekin besudotox	RT + Chemo	NA	NA	9
Kunwar et al, 2010	Phase III, 2 randomized arms	93	Gliadel wafers	RT + Chemo	NA	NA	9
Perry et al, 2010	Phase II, single stratified arm. Stratified by prior TMZ failure timing	29	Dose-dense TMZ (progression before 6 cycles TMZ)	RT + Chemo	CR or PR (3), SD (24), PD (73)	6, 27%; median 4	27
		29	Dose-dense TMZ (progression after 6 cycles TMZ)	RT + Chemo	CR or PR (0), SD (8), PD (92)	6, 7%; median 2	15
		29	Dose-dense TMZ (progression after TMZ completion)	RT + Chemo	CR or PR (11), SD (26), PD (63)	6, 36%; median 4	29
Brada et al, 2010	Phase II, 3 randomized arms	224	PCV	RT alone	NA	Median 4	7
		112	5-d TMZ	RT alone	NA	Median 5	9
		111	21-d TMZ	RT alone	NA	Median 4	7
Reardon et al, 2011	Phase II, single arm	32	Sorafenib + TMZ	RT + Chemo	CR (0), PR (3), SD (47), PD (50)	6, 9%; median 6	10
Abacioglu et al, 2011	Phase II, single arm	25	Dose-dense TMZ	RT + Chemo	CR (0), PR (10), SD (50), PD (40)	6, 17%; median 3	7
Stupp et al, 2011	Phase II, single arm	38	Sagopilone	RT + Chemo	CR (0), PR (0), SD (25), PD (75)	6, 81%; median 2	8
Walbert et al, 2011	Phase II, single stratified arm	43	6-TG + capecitabine + celecoxib + (TMZ or lomustine)	RT + Chemo	CR (2), PR (9), SD (33), PD (56)	6, 14%; median 2	8
Reardon et al, 2011	Phase II, 2 randomized arms	10	Metronomic TMZ + BEV	RT + Chemo (BEV resistant)	CR (0), PR (0), SD (40), PD (60)	6, 0%; median 1	3
Reardon et al, 2011	Phase II, 2 randomized arms	13	Metronomic etoposide + BEV	RT + Chemo (BEV resistant)	CR (0), PR (0), SD (62), PD (31)	6, 10%; median 2	5
Friday et al, 2012	Phase II, single arm	37	Vorinostat + bortezomib	Not specified	NA	6, 0%; median 2	3
Gilbert et al, 2012	Phase II, single arm	30	Cilengitide + surgery	Not specified	NA	6, 12%; median 2	NA
Desjardins et al, 2012	Phase II, single arm	32	TMZ + BEV	RT + Chemo	CR (0), PR (28), SD (50), PD (22)	6, 19%; median 4	9
Franceschi et al, 2012	Phase II, single arm	26	CCNU + dasatinib	RT + Chemo	CR (0), PR (4), SD (25), PD (71)	6, 6%; median 1	6
Lee et al, 2012	Phase II, single arm	18	Sorafenib + temsirolimus	RT + Chemo	CR (0), PR (12)	6, 0%; median 2	NA
Pan et al, 2012	Phase II, single arm	16	Sunitinib	RT + Chemo	CR (0), PR (0), SD (31), PD (69)	6, 17%; median 1	13
Stupp et al, 2012	Phase III, 2 randomized arms	120	TTF	RT + Chemo	CR or PR 14	6, 21%; median 2	7
Stupp et al, 2012	Phase III, 2 randomized arms	117	Physician’s choice Chemo	RT + Chemo	CR or PR 10	6, 15%; median 2	6
Batchelor et al, 2013	Phase III, 3 randomized arms	131	Cediranib	RT + Chemo	CR (1), PR (14), SD (64), PD (9)	Median 3	8
		129	Cediranib + lomustine	RT + Chemo	CR (2), PR (16), SD (55), PD (16)	Median 4	9
		65	Lomustine + placebo	RT + Chemo	CR (0), PR (9), SD (41), PD (41)	Median 3	10
Yust-Katz et al, 2013	Phase IB, single arm	34	Lonafarnib + TMZ	RT + Chemo	CR (6), PR (18), SD (47), PD (29)	6, 38%; median 4	14
Peereboom et al, 2013	Phase II, single arm	56	Erlotinib + sorafenib	Not specified	CR (0), PR (5), SD (41), PD (45)	6, 14%; median 3	6
Zustovich et al, 2013	Phase II, single arm	43	Sorafenib + TMZ	RT + Chemo	CR (0), PR (12), SD (48), PD (48)	6, 26%; median 3	7
Norden et al, 2013	Phase II, single arm	58	Dose-dense TMZ	RT + Chemo	CR (0), PR (13), SD (35), PD (52)	6, 11%; median 2	12
Kreisl et al, 2013	Phase II, single stratified arm. Stratified by prior BEV failure	31	Sunitinib (BEV resistant)	RT + Chemo (± BEV)	CR or PR (0)	6, 0%	4.4
Kreisl et al, 2013		32	Sunitinib (BEV naive)	RT + Chemo (± BEV)	CR or PR (10)	6, 6%	9.4
Han et al, 2014	Phase II, single arm	40	Dose-dense TMZ	RT + Chemo	CR or PR (3)	6, 10%; median 2	5
Rieger et al, 2014	Phase II, single arm	20	Ketogenic diet	RT + Chemo	CR (0), PR (0), SD (8), PD (92)	Median 1	8
Wen et al, 2014	Phase II, single arm	43	Erlotinib + temsirolimus	RT + Chemo	CR (0), PR (0), SD (29), PD (71)	6, 13%; median 2	NA
Taal et al, 2014	Phase II, 3 randomized arms	50	BEV	RT + Chemo	CR or PR (38)	6, 16%; median 3	8
		46	Lomustine	RT + Chemo	CR or PR (5)	6, 13%; median 1	8
		52	BEV + lomustine	RT + Chemo	CR or PR (39)	6, 42%; median 4	12
Lassman et al, 2015	Phase II, single arm	50	Dasatinib	RT + Chemo	CR (0), PR (0), SD (24), PD (76)	6, 6%; median 2	8
Lee et al, 2015	Phase II, single arm	24	Panobinostat + BEV	RT + Chemo	CR (0), PR (29), SD (58), PD (12)	6, 30%; median 5	9
Nagpal et al, 2015	Phase II, single arm	20	Etirinotecan pegol	RT + Chemo (BEV resistant)	CR (0), PR (17)	6, 11%; median 2	5
Odia et al, 2015	Phase II, single arm	30	Bortezomib + tamoxifen	RT + Chemo	CR (0), PR (0), SD (0), PD (100)	6, 0%; median 1	4
Taylor et al, 2015	Phase II, single arm	11	Bosutinib	RT + Chemo	CR (0), PR (0), SD (25), PD (75)	6, 0%; median 2	12
Weller et al, 2015	Phase II, 2 randomized arms	52	Dose-intensified TMZ biweekly	RT + Chemo	CR (4), PR (4)	Median 2	10
Weller et al, 2015	Phase II, 2 randomized arms	53	Dose-intensified TMZ monthly	RT + Chemo	CR (8), PR (8)	Median 2	10
Robins et al, 2015	Phase II, 2 randomized arms. Stratified by BEV resistance	73	TMZ + veliparib 21-d, BEV naive	RT + Chemo	CR or PR (0)	Median 2	10
		73	TMZ + veliparib 5-d, BEV naive	RT + Chemo	CR or PR (4)	Median 2	11
		32	TMZ + veliparib 21-d, BEV resistant	RT + Chemo	CR or PR (5)	Median 2	5
		37	TMZ + veliparib 5-d, BEV resistant	RT + Chemo	CR or PR (0)	Median 2	5
Reardon et al, 2015	Phase II, 3 randomized arms	41	Afatinib	RT + Chemo	CR (0), PR (2), SD (34), PD (56)	3%; median 1	10
		39	Afatinib + TMZ	RT + Chemo	CR (3), PR (5), SD (36), PD (44)	6, 10%; median 2	8
		39	TMZ	RT + Chemo	CR (0), PR (10), SD (54), PD (33)	6, 23%; median 2	11