Pseudoprogression after glioma therapy: a comprehensive review

Figures & data

Figure 1. Pseudoprogression example.

Sequential contrast-enhanced T1 MRI following radiation plus temozolomide for high-grade glioma are demonstrated. 4 months after completion of chemoradiation, the patient was noted to have progressive contrast enhancement surrounding the resection cavity concerning for tumor recurrence. Temozolomide was continued to complete a 6-month adjuvant course, and imaging findings subsequently improved. The patient now remains without evidence of recurrent disease 3 years postchemoradiation.

Figure 2. Spectrum of imaging findings, in the absence of recurrent disease, following adjuvant radiation treatment for high-grade glioma.

Table 1. Rates of pseudoprogression in studies of radiotherapy plus temozolomide.

Study (year)	Patients (n)	Time of early-response assessment	Portion with early progression	Pseudoprogression as a % of those with early progression	Overall rate of pseudoprogression	Ref.
Chamberlain et al. (2007)	51	6 months	26/51 (51%)	7/15 (47%)^†	7/40 (18%)	[28]
Taal et al. (2008)	68	1 month	31/68 (46%)	15/31 (48%	15/68 (22%)	[30]
Brandes et al. (2008)	103	1 month	50/103 (52%)	32/50 (64%)	32/103 (31%)	[46]
Chaskis et al. (2008)	54	6 months	25/54 (46%)	3/12 (12%)^†	3/54 (6%)	[32]
Clarke et al. (2009)	85	2–4 weeks	35/85 (41%)	10/27 (37%)^†	10/77 (13%)	[33]
Fabi et al. (2009)	12	2 months	4/12 (33%)	2/4 (50%)	2/12 (17%)	[34]
Peca et al. (2009)	50	6 months	15/50 (30%)	4/15 (27%)	4/50 (8%)	[11]
Roldán et al. (2009)	43	4–6 weeks	25/43 (58%)	10/20 (50%)^†	10/38 (26%)	[41]
Gerstner et al. (2009)	45	2–4 weeks	24/45 (53%)	13/24 (54%)	13/45 (29%)	[35]
Sanghera et al. (2010)	104	2–months	27/104 (26%)	7/22 (32%)^†	7/99 (7%)	[42]
Tsien et al. (2010)	27	3 months	14/27 (52%)	6/14 (43%)	6/27 (22%)	[43]
Yaman et al. (2010)	67	6 months	17/67 (25%)	4/17 (24%)	4/67 (6%)	[44]
Gunjur et al. (2011)	68	1 month	41/68 (60%)	14/41 (34%)	14/68 (21%)	[36]
Kang et al. (2011)	35	1 month	18/35 (51%)	8/18 (44%)	8/35 (23%)	[37]
Kong et al. (2011)	90	2 months	59/90 (66%)	26/59 (44%)	26/90 (29%)	[38]
Young et al. (2011)	321	2–4 weeks	205/321 (64%)	30/93 (32%)^†	NA^‡	[45]
Park et al. (2011)	48	4 weeks	25/48 (52%)	11/25 (44%)	11/48 (23%)	[39]
Pouleau et al. (2012)	63	2 months	33/63 (52%)	7/33 (21%)	7/63 (11%)	[40]
Totals	1334	Range: 2 weeks–6 months	674/1334 = 50.5% (range: 25–66%)	209/520 = 40.2% (range: 12–54%)	179/984 = 18.2% (range: 6–31%)

^†Excludes patients for whom determination of pseudoprogression is unknown (including those initiated on chemotherapy at radiographic progression).

^‡112 patients, all with worsened initial imaging, were excluded from analysis rendering this determination incomplete.NA: Not available.

Table 2. Median survival (in months) in patients with high-grade glioma undergoing adjuvant radiotherapy with concurrent temozolomide, as assessed by early radiographic findings and subsequent determination of pseudoprogression.

Study (year)	Patients (n)	Median survivals, by radiographic responses (months)				Ref.
		Overall cohort	Pseudoprogression	True early progression	Stable or improved
Brandes et al. (2008)	103	20.7	38.0^†‡	10.2	20.2	[46]
Roldán et al. (2009)	43	13.7	14.5^†	9.1	17.2	[41]
Gerstner et al. (2009)	45	NA	24.4	15.9		[35]
Sanghera et al. (2010)	104	13.0	28.7^†	8.3	15.5	[42]
Gunjur et al. (2011)	68	11.6	27.4^†	10.4	13.0	[36]
Kang et al. (2011)	35	25.2	NR^†	10.8	25.6	[37]
Kong et al. (2011)	90	16.9	21.7	13.5	29.3	[38]
Young et al. (2011)	209	NA	14.5	10.5	15.2^†	[45]

^†Median survival statistically higher than those with early progressive disease.

^‡Median survival statistically higher than those with stable/improved findings.

NA: Not available; NR: Not reached.

Table 3. Overview of imaging techniques utilized for discriminating between early progressive disease and pseudoprogression.

Imaging method	Supporting studies	Patterns associated with ePD (compared with PsP)	Strengths	Limitations
Conventional MR	[45,48]	Corpus callosum involvement, subependymal enhancement	Widely available	Poor ability to differentiate ePD vs PsP
Diffusion-weighted MRI	[49,50,52]	Lower mean ADC values and ADC ratios	Can characterize tissues and pathologic processes at the microscopic level	ADC depends on sampling method – confounded by necrosis, vascularity
MR perfusion	[38,43,53–62]	Higher rCBV in areas of enhancement	Studies have correlated rCBV values to tissue-confirmed diagnoses [53] and survival [59]	Vascular leak problematic, requires correction; rCBV value cutoffs vary by technique, institution
Proton MR spectroscopic imaging	[63–70]	Higher Cho/Cr and Cho/NAA ratios	Very high reported rates of diagnostic accuracy	May struggle to differentiate tissue when mixed tumor and necrosis are present; long scan time required
FDG-PET	[71–73]	Considerable overlap	Widely available	High background signal; unacceptably low sensitivity and specificity
C-Met-PET	[58,78–80]	SUVs tend to be higher for ePD than necrosis	Lower background activity than FDG-PET	Short half-life limiting availability; may be less effective than diffusion-weighted MRI [58]
Other novel PET tracers	FET-PET [81,82], FDOPA-PET [84], ^13N-NH3 PET [76]		Early investigational stages for these tracers

ADC: Apparent diffusion coefficient; Cho: Choline; Cr: Creatinine; C-Met: ¹¹C-methionine; ePD: Early progressive disease; FDOPA: ¹⁸F-labeled dopamine; FDG: ¹⁸F-labeled fluorodeoxyglucose; NAA: N-acetylaspartate; PsP: Pseudoprogression; rCBV: Relative cerebral blood volume; SUV: Standardized uptake value.

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