This analysis involved three Phase III, multicentre, open-label, fixed sequence paired studies that compared the efficacy and safety of Gd-DOTA using each patient as his/her own control. The studies evaluated: cerebral and spinal tumours (Study 1), abdominal and pelvic lesions (Study 2), and hepatic lesions (Study 3). At each centre, the study commenced after approval from the relevant Ethics Committee. Each patient provided written informed consent.

The primary objective of the analysis was to determine the intrinsic diagnostic performance of Gd-DOTA-enhanced MRI compared with non-enhanced MRI in the characterization of tumoral lesions, using histology or a corroborative diagnosis as the gold standard.

Two independent, off-site MR experts blinded to the patient's identity, clinical conditions, and histology or corroborative diagnosis, were required to read three MRI modalities: the unenhanced MRI or ‘pre-injection’ MRI; the Gd-DOTA-enhanced MRI or ‘post-injection’ MRI (post-injection images only); the ‘paired’ or ‘pre+post’-injection MRI (unenhanced and Gd-DOTA-enhanced images had to be read jointly). These were read in a random order.

The histology was read on site by a reader who was blinded to the off-site MRI readers’ findings. MR images were also read on site; the on-site reading was unblinded to clinical conditions, but was performed without any information about the gold standard results. The readers were radiologists with a minimum of ten years experience. The centres used different equipment to perform the MRI examinations (Philips, GE or Siemens, 1 or 1.5T).

Patients could be male or female and had to be at least 18 years of age. All patients were scheduled to undergo a contrast-enhanced MRI examination to specify diagnosis or for follow-up of pre-existing lesions and were expected/scheduled to undergo either a biopsy or surgery of the lesion(s) detected. Female patients were required to be using effective contraception or to be surgically sterilised or post-menopausal (amenorrhea for at least 12 months).

Specific inclusion criteria for patients in the three individual studies were:

patients presenting or suspected of having a minimum of one cerebral or spinal tumour(s) and a maximum of three lesions detected during previous CT or MRI examination performed within 3 weeks of study MRI examination

patients suspected of having at least one complex and solid pancreatic or pelvic or renal or adrenal lesion as depicted during previous sonographic or helical CT examination performed within 3 weeks before inclusion

patients suspected of having a maximum of three complex or solid hepatic focal lesions, measuring at least 2 cm in diameter in at least one plane, depicted during previous sonographic examination performed within 2 weeks before MRI examination.

Exclusion criteria included a contraindication to MRI (such as pacemaker, aneurysm clip or severe claustrophobia), pregnancy, lactation, and known allergy to gadolinium chelates. Patients were also excluded if they were participating in another trial involving an investigational drug or if they had received a gadolinium complex within 2 days, or iron oxide nanoparticules within 7 days before the study MRI examination.

Specific exclusion criteria for patients included in the cerebral and spinal tumours study, and hepatic lesions study were: non-tumoral cerebral disease, such as diffuse pathology (e.g. multiple sclerosis, Alzheimer’s disease), or a liver cyst as unique lesion.

Patients who satisfied all eligibility requirements underwent an unenhanced MRI examination followed immediately by a Gd-DOTA-enhanced MRI. Gd DOTA was administered as a single dose of 0.1 mmoL/kg (0.2 mL/kg) by intravenous bolus. MRI procedures were performed under similar conditions according to the imaging laboratory's standard practice. The patient then underwent surgery and histological analysis within
1 month, or for liver tumours only, a corroborative diagnosis within 6 months after the
Gd-DOTA-enhanced MRI. The stages and timings common to each of the three studies are summarized in Figure 1.

Figure 1

Figure 1. Key events and timings common to the three study schedules.

The following sequences were performed according to anatomical investigation site.

1. Cerebral and spinal tumours:

Before Gd-DOTA administration: T1 weighted Spin Echo, T2 weighted fast spin echo (FSE) and fluid attenuation inversion recovery (FLAIR).

After Gd-DOTA administration: T1 weighted Spin Echo.

2. Abdominal and pelvic lesions:

Before Gd-DOTA administration: T1 GE, T2 FSE, and Fat suppressed T1 GE.

After Gd-DOTA administration: dynamic T1 GE (at 30, 60 and 90 seconds), T1 GE (at 180 and 300 seconds), and fat suppressed T1 GE.

3. Hepatic lesions:

Before Gd-DOTA administration: T1 weighted breath hold gradient echo (GE) and T2 weighted FSE.

After Gd-DOTA administration: T1 weighted breath hold GE was acquired at 20 seconds (arterial phase), 1 minute (venous phase) and from 5 to 10 minutes (delayed phase).

The off-site readers described each identified lesion in terms of location and morphology, including margin delineation, shape and appearance (homogenous/ heterogeneous). Each lesion was then characterized by the readers as ‘benign’, ‘malignant’ or ‘non assessable’. The images were also read on site.

Technical failures of either MRI procedure were considered as diagnostic errors (non evaluable patients) relative to the gold standard procedure. The number of technical failures for each MRI procedure and the paired differences (Gd-Dota enhanced MRI minus gold standard, unenhanced MRI minus gold standard, Gd-Dota enhanced MRI minus unenhanced MRI) were calculated and compared.

For each lesion, the reader had to assess the delineation quality using a 5-point scale: 1 = uncertain border between tumour and tissue that is not tumour; 2 = poorly defined border between tumour and tissue that is not tumour; 3 = fairly defined border between tumour and tissue that is not tumour; 4 = well defined border between tumour and tissue that is not tumour; 5 = very well defined border between tumour and tissue that is not tumour.

For each lesion, the reader had to assess the diagnostic confidence using a 5-point scale: 1 = nil; 2 = poor; 3 = moderate; 4 = high; 5 = excellent. For the purpose of this analysis, only “high” and “excellent” diagnostic confidence scores have been considered.

The patients’ diagnostic classifications (in terms of the agreement between the findings of the MRI procedures and those of the gold standard procedure) are summarized in Table 1. These classifications were True Positive (TP), True Negative (TN), False Negative (FN), and False Positive (FP).

Figure 2

Table 1. Patient’s diagnostic classification in terms of the relationship of the MRI procedures to the gold standard procedure

The diagnostic performance was assessed by accuracy, sensitivity, specificity and positive and negative predictive values. These diagnostic efficacy variables were derived from matching reader evaluations resulting from both MRI and gold standard examinations. These variables were also evaluated at lesion level to investigate whether the matching of the diagnosis at this level might offer potential benefits for patient management. The matching of diagnosis at lesion level may offer a more rigorous investigation than the matching at patient level because two patient diagnoses could match even if the evaluation at the lesion level does not fit between MRI procedures.

For off-site readings, intra-reader repetition on MRI results (lesions) was summarized for Reader 1 and Reader 2. Inter-reader repetition on MRI results (lesions) was also summarized for Reader 1 and Reader 2 within each MRI modality (pre-injection (unenhanced) and post-injection and pre+post).

The following safety variables were reported in each of the three studies: quantity of Gd-DOTA injected; number of adverse events; number of patients experiencing at least one adverse event; number of patients treated for an adverse events; withdrawals and withdrawals due to adverse event; frequencies of each response category (intensity, outcome, pre-existence, and relationship); any changes in vital signs for up to 72 hours after the Gd-DOTA injection; and pain or discomfort at injection site.

Three pooled patient populations were considered in this analysis. The all-included-patients population comprised all patients enrolled in the study who had signed the informed consent. The evaluable safety population included all patients who received at least one injection of Gd-DOTA regardless of the quantity. The evaluable efficacy population included all patients who had valid diagnostic assessments for the gold standard procedure and at least one of the two MRI procedures (Gd-DOTA-enhanced or unenhanced MRI examinations).

Two analyses were conducted on the evaluable efficacy population: a primary analysis involving assessable and all non-assessable (technical failures) MRI procedures (when paired with an assessable MRI procedure they were considered as diagnostic errors (FP, FN) and were taken into account in this primary analysis); a secondary analysis excluding these non-assessable MRI procedures (technical failures) when paired with an assessable MRI procedure.

All efficacy analyses were conducted on the evaluable population at patient-level and at lesion-level. Only off-site results were considered in primary analysis, the secondary analysis took into account on-site data.

All outputs were produced using SAS version 9.01 or a later version (SAS Institute – Cary, NC). Descriptive statistics were used for the demographic characteristics. Pre- and post-contrast MRIs were compared using McNemar's test for the differences in accuracy, sensitivity and specificity. Statistical tests were two-sided and performed using a 5% level of significance.

Intra-reader and inter-reader agreements were both assessed using a Kappa test. Interpretation guideline for Kappa values is as follows: <0.20 poor agreement; 0.21–0.40 fair agreement; 0.41–0.60 moderate agreement; 0.61–0.80 good agreement; 0.81–1.00 very good agreement.

Technical failures

Technical failure rates were significantly greater for unenhanced images with both groups of readers (p<0.0001). Though the incidence of technical failures was higher for on-site readings than those made off-site and the difference between pre and post enhancement was greater on-site, with differences being seven times more frequent in pre than in pre+post injection modalities (Table 3).

Figure 4

Table 3. Measures of diagnostic performance at patient level, with technical failures included.

Lesion delineation quality

Delineation quality (percentage of lesion borders that were assessed as “well” or “very well” defined) was significantly superior on contrast-enhanced MRI modalities compared with unenhanced images, irrespective of whether readings were made off-site or on-site (Figure 2).

Figure 5

Figure 2. Lesion delineation quality: percentage of lesion borders that were “well” or “very well” defined. Graph A shows results of off-site readings. Graph B shows results of on-site readings.

Missing data at lesion level were excluded from this analysis for off-site (pre: N=47 patients, post-reading: N=10, pre+post reading: N=9), and on-site readings (pre-reading: N=92 patients, post-reading: N=18). There was no ‘pre+post’ MRI modality assessment on site.

Diagnostic confidence assessment

Diagnostic confidence (percentage of lesions for which diagnostic confidence was assessed as “high” or “excellent”) was significantly superior on contrast-enhanced MRI modalities compared with unenhanced images, irrespective of whether readings were made off-site or on-site (Figure 3). Missing data at lesion level were excluded.

Figure 6

Figure 3. Diagnostic confidence: percentage of lesion for which diagnostic confidence was assessed “high” or “excellent”. Graph A shows results of off-site readings. Graph B shows results of on-site readings.

The image clarity and confidence in delineation before and after Gd-DOTA administration is shown in the brain (Figures 4 and 5), the liver (Figure 6) and the kidney (Figure 7).

Figure 7

Figure 4. A 54-year-old woman. Same slices acquired before (a) and after (b) Gd-DOTA administration. The left parietal lesion is more well-defined and more easily assessable after Gd-DOTA administration.

Figure 8

Figure 5. A 81-year-old man. Same slices acquired before (a) and after (b) Gd-DOTA administration. Glioblastoma is more well-defined and more easily assessable after Gd-DOTA administration.

Figure 9

Figure 6. A 46-year-old woman. Same slices acquired before (a) and after (b) Gd-DOTA administration. The liver lesion is more well-defined and more easily assessable after Gd-DOTA administration.

Figure 10

Figure 7. A 87-year-old man. Same slices acquired before (a) and after (b) Gd-DOTA administration. The right kidney lesion is more well-defined and more easily assessable after Gd-DOTA administration.

Diagnostic performance at patient level

Diagnostic performance at lesion level

When off-site and on-site readings were evaluated at lesion level, the findings were similar to those seen at patient level. When non-assessable data (technical failures) were taken into account, all parameters of diagnostic performance (accuracy, sensitivity, specificity, PPV, NPV) of contrast-enhanced MRI modalities were statistically significantly higher than for unenhanced MRI (Table 4). However, when technical failures were excluded globally all diagnostic performance parameters were higher for Gd-DOTA-enhanced MRI than for the unenhanced MRI without statistical differences between MRI modalities.

Figure 11

Table 4. Measures of diagnostic performance at lesion level, with technical failures included.

Intra- and inter-reader agreement

The safety population comprised 379 patients who received an injection of Gd-DOTA. No new safety issue related to Gd-DOTA was identified during the course of the three trials. Thirty-seven patients experienced at least one adverse event (9.8%), representing a total of 53 adverse events. The most common adverse events were nausea, vomiting and pain. These were of mild or moderate intensity and had favourable resolution without treatment. Eighteen adverse events were reported as serious and, according to the Investigators, all were linked to the patient’s poor general condition and could not be attributed to the contrast agent administration.