¹⁸F-fluorodeoxyglucose positron-emission tomography-computed tomography to diagnose recurrent cancer

Participants

Patients with a history of cancer presenting with a clinical suspicion of recurrence in which conventional imaging (e.g., X-ray, ultrasound, CT, MRI and nuclear medicine bone scan) was non-diagnostic were eligible. Decisions about eligibility were made locally by the treating physicians: to be eligible for entry into the study, there needed to be a clinical suspicion of recurrent cancer. Clinical suspicion was often based on a constellation of symptoms, signs and blood tests. Then conventional imaging tests would have been performed and read by expert radiologists. If the treating physician was still uncertain about the diagnosis of recurrence, the patient was eligible for enrolment. Sometimes patients with previous malignancies are followed with regular surveillance after surgery, for example, CT scans for non-small-cell lung (NSCL) cancer or colorectal cancer. Occasionally, a new abnormality would appear on the CT scan, which was considered too small or nonspecific to be diagnostic for recurrence. These patients were also eligible. Eligible cancer types were NSCL, breast, head and neck (not thyroid), ovarian, oesophageal or lymphoma (Hodgkin's or non-Hodgkin's). Patients were excluded if: they were <18 years of age, had an established diagnosis of recurrent cancer, had undergone ¹⁸F-FDG PET-CT in the 6 months prior to registration, were unable to lie supine for ¹⁸F-FDG PET-CT, were pregnant or lactating, had significant medical problems making the patient unfit for further cancer therapy or were unable to give informed consent. Patients were recruited from four regional cancer centres in Ontario. The study was approved by the Ontario Cancer Research Ethics Board and patients provided written informed consent. The study was registered with ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00686465","term_id":"NCT00686465"}}NCT00686465).

Procedures

At enrolment, baseline clinical data were collected and, before the ¹⁸F-FDG PET-CT scan was performed, the treating physician was required to indicate their intended management had ¹⁸F-FDG PET-CT not been available (clinical follow-up, additional imaging after a period of time, tissue biopsy or treatment for recurrence).

Subjects then underwent ¹⁸F-FDG PET-CT. After ¹⁸F-FDG PET-CT, treating physicians were asked to indicate their management plan after considering the ¹⁸F-FDG PET-CT findings. The study protocol left decisions about management after ¹⁸F-FDG PET-CT to the discretion of the treating physician and the patient.

Subjects underwent a follow-up visit at 3 months post-registration to record data about further testing, biopsies, and treatments since registration. The principal aim of the follow-up visit was to confirm whether the physician's post-¹⁸F-FDG PET-CT management plan had been carried out.

¹⁸F-FDG PET-CT imaging

¹⁸F-FDG PET-CT scanners had to meet specified performance criteria and underwent quality control evaluation on each day imaging was performed. The ¹⁸F-FDG PET-CT scanners, with full-ring bismuth germanate detectors, were: a Discovery ST 64 (General Electric, Waukesha, WI, USA) in London, Ontario, Canada, a Biograph Duo (CTI/Siemens, Knoxville, TN, USA) at Princess Margaret Hospital, a Biograph 16 (Siemens, Knoxville, TN, USA) at St Joseph's Healthcare Hamilton and a 64 slice Gemini TF with lutetium-yttrium orthosilicate detectors (Philips Electronics NV, Eindhoven, Netherlands) in Thunder Bay. To ensure consistent exam quality across all sites, studies were performed using the NEMA NU2-2001 phantom (Data Spectrum Corporation, Hillsborough, NC, USA) to verify calibration inaccuracy, to verify reconstructed image resolution <10 mm full width half maximum and to qualify reconstruction methods at each site. Acquisition protocols were developed at each site to meet a minimum patient noise equivalent counts of >30 Mcounts per m (±10%). Compliance was assured by monthly monitoring and quarterly review by a Quality Assurance Subcommittee. Quality assurance procedures included independent second reading by a nuclear medicine physician of a randomly selected subset of 12 ¹⁸F-FDG PET-CT scans.

¹⁸F-FDG PET-CT was performed after a 6-hour fast; blood glucose was required to be <10 mmol l⁻¹ prior to i.v. administration of ¹⁸F-FDG (5 MBq kg⁻¹, not exceeding 550 MBq). PET acquisition was preceded by a low-dose CT, and a whole body ¹⁸F-FDG PET-CT scan in supine position was obtained from the base of the skull to the upper half of both femurs. The examination was interpreted by the nuclear medicine physician with knowledge of the clinical history and access to correlative imaging.

Outcomes

The primary outcome was change in planned management after ¹⁸F-FDG PET-CT. We further defined a major change in planned management as a change from a pre-¹⁸F-FDG PET-CT plan, which did not include treatment to a post-¹⁸F-FDG PET-CT plan which did include treatment. The primary outcome was adjudicated using all available source documents (e.g., clinic notes and imaging reports). Adjudicators also used all available source documents to assess whether, at the 3-month follow-up: (i) planned management was carried out; (ii) further testing or procedures were avoided because of ¹⁸F-FDG PET-CT findings and (iii) ¹⁸F-FDG PET-CT led to further testing or interventions that were unnecessary. Adjudication was conducted independently and in duplicate by two experienced oncologists (KIP and ISD) not otherwise involved in the conduct of the study. For subjects who terminated the study early, adjudicators used all information available at the time of withdrawal.

Impact of ¹⁸F-FDG PET-CT on planned management

Planned management was changed after ¹⁸F-FDG PET-CT in 52 subjects (53%, 95% CI, 42–63%); this was a major change in intended management for 38 subjects (38%, 95% CI, 29–49%) and a minor change for 14 subjects (14%, 95% CI, 8–23%) (Table 2). Chance-corrected inter-observer agreement between the adjudicated assessment and the treating physician's assessment of whether ¹⁸F-FDG PET-CT changed planned management was high (κ 0.80, 95% CI, 0.68–0.91).

Had ¹⁸F-FDG PET-CT not been available, the most common management plan would have been to schedule repeat imaging after waiting a period of time (57 subjects): either as soon as possible (n=8), within 1 month (n=5), in 3 months (n=41), in 6 months (n=2) or in 9 months (n=1). The next most common management plan, had ¹⁸F-FDG PET-CT not been available, was to either pursue a tissue biopsy (28 subjects) or to re-evaluate the patient in clinical follow-up (11 subjects), the latter typically in 3 months (n=10). The most frequent change in planned management after ¹⁸F-FDG PET-CT was to initiate treatment, rather than pursue additional imaging (Figure 2; Table 3). Of the 38 subjects who had a major change in intended management (i.e., plan changed to treatment after ¹⁸F-FDG PET-CT), the plan was to provide palliative treatment in 26 and potentially curative salvage treatment in 12.

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Figure 2

Relation of findings on PET-CT to changes in planned management.

Relation of findings on ¹⁸F-FDG PET-CT to changes in planned management and biopsy results

Of the 38 subjects whose management plan changed to treatment after ¹⁸F-FDG PET-CT, most had findings on ¹⁸F-FDG PET-CT imaging that was positive for recurrent cancer (37 subjects); the 1 remaining subject had indeterminate findings on ¹⁸F-FDG PET-CT (Figure 2).

Overall, findings of recurrent cancer on ¹⁸F-FDG PET-CT were associated with appreciable changes in planned management (Figure 2). In the 57 subjects whose pre-PET management plan was for repeat imaging after a period of time, ¹⁸F-FDG PET-CT was positive for recurrent cancer in 35, negative in 12 and indeterminate in 10 subjects. Positive findings on ¹⁸F-FDG PET-CT typically led to changes in planned management. Plans were changed for most of the 35 subjects with positive findings on ¹⁸F-FDG PET-CT to either initiate treatment (23 subjects) or to pursue tissue biopsy (8 subjects). In contrast, planned management was largely unchanged after ¹⁸F-FDG PET-CT for the 22 subjects with negative or indeterminate findings. In the eight subjects with a post-PET plan to pursue tissue biopsy: four had a biopsy positive for malignancy, one had a biopsy negative for malignancy, two declined a biopsy and one ultimately did not receive a biopsy because the surgical consultant felt recurrence was unlikely based on all available clinical information.

In the 28 subjects whose pre-PET management plan was for tissue biopsy, ¹⁸F-FDG PET-CT was positive for recurrent cancer in 22, negative in 2 and indeterminate in 4 subjects. Management plans for the 22 subjects with positive findings on ¹⁸F-FDG PET-CT changed to initiate treatment in 10 cases. For 11 other subjects with positive findings on ¹⁸F-FDG PET-CT, the plan after ¹⁸F-FDG PET-CT was unchanged: all 11 subjects went on to receive a biopsy and in all cases results were positive for malignancy.

In the 11 subjects whose pre-PET management plan was clinical follow-up after a period of time, ¹⁸F-FDG PET-CT was positive for recurrent cancer in 5, negative in 5 and indeterminate in 1. Management plans for the five subjects with positive findings on ¹⁸F-FDG PET-CT changed to initiate treatment (four subjects) or to pursue tissue biopsy (one subject). The latter subject ultimately did not receive a biopsy because the lesion was too small to biopsy and the subject declined wedge resection.

We would like to thank the patients who participated in this clinical research study; referring physicians, nuclear medicine physicians, and research staff at the local sites for recruiting patients and collecting study data; and staff at the Ontario Clinical Oncology Group for assisting with study and data management. Preliminary findings of this study were first presented in abstract form at the American Society of Clinical Oncology (ASCO) Annual meeting on 4 June 2012 in Chicago, USA.