Wai-Lup Wong

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer

BACKGROUNDnThe role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate.nnnMETHODSnIn this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival.nnnRESULTSnFrom 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately

To PET or not to PET? That is the question. Staging in anal cancer

2,190 in U.S. dollars) per person over the duration of the trial.nnnCONCLUSIONSnSurvival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum

BACKGROUNDnAnal cancer is a rare tumour accounting for ∼2% of all colorectal cancers between 1997 and 2000 in the UK. Staging is still dominated by DRE (digital rectal examination), computed tomography (CT) and magnetic resonance imaging (MRI) imaging. The role of PET as a definitive modality is still emerging and there are relatively few adequate studies in the literature.nnnMETHODSnWe looked at patients treated radically for anal cancer at Mount Vernon Cancer Centre (UK) between 2009 and 2010. Eighty-eight patients underwent treatment according to data-based coding records of which 46 had positron emission tomography (PET)/CT scans. Notes were unavailable for three patients. We compared staging following conventional modalities (DRE, MRI and CT) and PET/CT scans for these 43 patients.nnnRESULTSnIn 18 patients, the PET/CT stage differed from MRI. PET/CT altered the stage in 42% of patients but changes in subsequent management were not implemented.nnnCONCLUSIONSnOur data show that PET/CT does alter staging in a significant number of cases although it did not lead to change in management under the current guidelines. Furthermore, there is agreement that PET/CT shows greater sensitivity for detection of lymph nodes and our study has demonstrated a distinct trend towards upstaging of anal cancer with PET/CT.BACKGROUNDnAnal cancer is a rare tumour accounting for ∼2% of all colorectal cancers between 1997 and 2000 in the UK. Staging is still dominated by DRE (digital rectal examination), computed tomography (CT) and magnetic resonance imaging (MRI) imaging. The role of PET as a definitive modality is still emerging and there are relatively few adequate studies in the literature.nnnMETHODSnWe looked at patients treated radically for anal cancer at Mount Vernon Cancer Centre (UK) between 2009 and 2010. Eighty-eight patients underwent treatment according to data-based coding records of which 46 had positron emission tomography (PET)/CT scans. Notes were unavailable for three patients. We compared staging following conventional modalities (DRE, MRI and CT) and PET/CT scans for these 43 patients.nnnRESULTSnIn 18 patients, the PET/CT stage differed from MRI. PET/CT altered the stage in 42% of patients but changes in subsequent management were not implemented.nnnCONCLUSIONSnOur data show that PET/CT does alter staging in a significant number of cases although it did not lead to change in management under the current guidelines. Furthermore, there is agreement that PET/CT shows greater sensitivity for detection of lymph nodes and our study has demonstrated a distinct trend towards upstaging of anal cancer with PET/CT.

PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality 18fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer

BackgroundIn locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease.Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection.Methods/designThis is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4–12xa0cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acidu2009+u2009flurourcilu2009+u2009oxaliplatin (FOLFOX)u2009+u2009bevacizumab (BVZ) or FOLFOXu2009+u2009irinotecan (FOLFOXIRI)u2009+u2009BVZ, given in 2 weekly cycles for up to 6xa0cycles prior to TME. Patients stop treatment if they fail to respond after 3xa0cycles (defined asu2009≥u200930xa0% decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT).The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy.DiscussionIn LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial.Trial registrationClinical trial identifier BACCHUS: NCT01650428

PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer

BACKGROUNDnPancreatic cancer diagnosis and staging can be difficult in 10-20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer.nnnOBJECTIVEnTo determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer.nnnDESIGNnA multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy.nnnPARTICIPANTSnPatients with suspected pancreatic malignancy.nnnINTERVENTIONSnAll patients to undergo PET/CT following standard diagnostic work-up.nnnMAIN OUTCOME MEASURESnThe primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours.nnnRESULTSnBetween 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUVmax.) for a pancreatic cancer diagnosis was 7.5. PET/CT demonstrated a significant improvement in relative sensitivity (pu2009=u20090.01) and specificity (pu2009=u20090.023) compared with MDCT. Incremental likelihood ratios demonstrated that PET/CT significantly improved diagnostic accuracy in all scenarios (pu2009<u20090.0002). PET/CT correctly changed the staging of pancreatic cancer in 56 patients (pu2009=u20090.001). PET/CT influenced management in 250 (45%) patients. PET/CT stopped resection in 58 (20%) patients who were due to have surgery. The benefit of PET/CT was limited in patients with chronic pancreatitis or other pancreatic tumours. PET/CT was associated with a gain in quality-adjusted life-years of 0.0157 (95% confidence interval -0.0101 to 0.0430). In the base-case model PET/CT was seen to dominate MDCT alone and is thus highly likely to be cost-effective for the UK NHS. PET/CT was seen to be most cost-effective for the subgroup of patients with suspected pancreatic cancer who were thought to be resectable.nnnCONCLUSIONnPET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer.nnnSTUDY REGISTRATIONnCurrent Controlled Trials ISRCTN73852054 and UKCRN 8166.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment programme.

Can combined 18F-FDG-PET and dynamic contrast-enhanced MRI predict behavior of desmoid tumors in patients with familial adenomatous polyposis?

BACKGROUNDnPlanned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial.nnnOBJECTIVESnTo determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting.nnnDESIGNnA pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1u2009:u20091 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Coxs proportional hazards model.nnnSETTINGSnThirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK.nnnPARTICIPANTSnPatients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited.nnnINTERVENTIONnPatients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage.nnnRESULTSnIn total, 564 patients were recruited (ND arm, nu2009=u2009282; and surveillance arm, nu2009=u2009282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (pu2009=u20090.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon.nnnLIMITATIONSnPragmatic randomised controlled trial with a 36-month median follow-up.nnnCONCLUSIONSnPET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice.nnnFUTURE WORKnPET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work.nnnTRIAL REGISTRATIONnCurrent Controlled Trials ISRCTN13735240.nnnFUNDINGnThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.

Management of Advanced Head and Neck Cancer

BACKGROUND: Desmoid tumors associated with familial adenomatous polyposis show variable behavior; about 10% grow relentlessly, resulting in severe morbidity or mortality. Investigations that could identify the minority of desmoid tumors that behave aggressively would allow these tumors to be treated early and spare the majority of patients who have more benign disease from unnecessary intervention. OBJECTIVE: The aim of this study was to investigate whether imaging the tumor metabolic-vascular phenotype by modern methods predicts growth. DESIGN: This is a prospective case series study. SETTINGS: The study was conducted at a tertiary center specializing in familial adenomatous polyposis and desmoid disease. PATIENTS: Nine patients with familial adenomatous polyposis (4 male, mean age 39 years) with desmoid tumor underwent 18F-FDG-PET and dynamic contrast-enhanced MRI. Standard MRI was repeated a year later to assess tumor growth. MAIN OUTCOME MEASURES: The primary outcome measured was the correlation between 18F-FDG-PET and dynamic contrast-enhanced MRI parameters and subsequent desmoid growth. RESULTS: Failed intravenous access precluded dynamic contrast-enhanced MRI in 1 female patient. Thirteen desmoid tumors (4 intra-abdominal, 2 extra-abdominal, 7 abdominal wall; mean area, 68 cm2) were analyzed in the remaining 8 patients. Two patients died before follow-up MRI. Five tumors decreased in size, 3 increased in size, and 3 remained stable after a year. Significant correlation (Spearman rank correlation, significance at 5%) existed between maximum standardized uptake value and kep (r = −0.56, p = 0.04), but not with other vascular parameters (Ktrans (r = −0.47, p = 0.09); ve (r = −0.11, p = 0.72); integrated area under the gadolinium-time curve at 60 seconds (r = −0.47, p = 0.10)). There was no significant difference in the maximum standardized uptake value or dynamic contrast-enhanced MRI parameters (Ktrans, ve, kep, integrated area under the gadolinium-time curve at 60 seconds) between the tumors that grew or decreased in size or between the tumor sites. However, vascular metabolic ratio (maximum standardized uptake value/Ktrans) was significantly different for tumor site (p = 0.001) and size (p = 0.001, 1-way ANOVA). LIMITATIONS: This investigation is limited because of its exploratory nature and small patient numbers. CONCLUSIONS: Although not predictive for tumor behavior, some correlations existed between dynamic contrast-enhanced MRI and 18F-FDG-PET parameters. Vascular metabolic ratio may provide further information on tumor behavior; however, this needs to be evaluated with further larger studies.

Influence of N-butylscopolamine on SUV in FDG PET of the bowel.

n engl j med 375;5 nejm.org August 4, 2016 491 Appendix of our article, available at NEJM.org). In addition to treatment group, histologic findings emerged as an independent variable with regard to both progression-free survival and overall survival. Extent of resection dropped out during the stepwise selection process for both. Consequently, it is unlikely that either variable confounded the results. Since radiation therapy can cause neurocognitive decline, the appropriate time to initiate chemotherapy plus radiotherapy or radiotherapy remains controversial. Patients in the RTOG 9802 trial were randomly assigned to begin radiotherapy alone or chemotherapy plus radiotherapy within 4 weeks after surgery. The trial was not designed to address the question of timing of radiotherapy. Neurocognitive end points from the trial were reported previously and showed no worsening of mean Mini–Mental State Examination scores in either treatment group up to 5 years after the initiation of treatment.1 These data do not address less severe or more delayed neurocognitive decline. In the randomized groups, 48% of the patients underwent biopsy only. Low-grade gliomas are characterized by low cellularity, which results in small amounts of available tissue. The two studies2,3 cited by Touat et al. enrolled patients with tumors with anaplastic oligodendroglial elements rather than those with lower-grade oligodendroglial or astrocytic tumors (as were enrolled in the RTOG 9802 trial). In addition, when the trial began 18 years ago, institutional processes for collecting and submitting tumor tissue were less well developed than they are today. As a consequence, we had insufficient data for this report to address the effect of chemotherapy plus radiotherapy in patients with IDH1/2 wild-type low-grade gliomas. Efforts are under way to obtain tissues to increase the predictive power of future correlative analyses from the RTOG 9802 trial. We remind Knisely and Schulder that 63% of the patients with tumors that were tested had tumoral IDH1 R132H mutations. In this subgroup, survival was longer among patients who received chemotherapy plus radiotherapy than among those who received radiotherapy alone (hazard ratio, 0.42; P = 0.02). There is clear evidence to support treatment recommendations on the basis of current molecular classification for the majority of patients with low-grade glioma. Given the results of the RTOG 9402 and EORTC 26951 trials,2,3 it is reasonable to expect a benefit with PCV in patients with either low-grade or anaplastic gliomas containing other tumoral IDH1/2 mutations and little reason to expect a benefit in those with IDH1/2 wild-type tumors.

BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC)

ObjectivesPeristalsis can lead to confusing FDG PET bowel uptake artefacts and potential for recording inaccurate mean standardised uptake value (SUV) measurements in PET-CT scans. Accordingly, we investigate the influence of different SUV normalisations on FDG PET uptake of the bowel and assess which one(s) have least dependence on body size factors in patients with and without the introduction of the anti-peristalsis agent N-butylscopolamine (Buscopan).MethodsThis study consisted of 92 prospective oncology patients, each having a whole body 18F-FDG PET scan. Correlations were investigated between height, weight, glucose, body mass index (bmi), lean body mass (lbm) and body surface area (bsa) with maximum and mean SUV recorded for bowel normalised to weight (SUVw), lbm (SUVlbm), bsa (SUVbsa) and blood glucose corrected versions (SUVwg, SUVlbmg, SUVbsag).ResultsStandardised uptake value normalisations were significantly different between control and Buscopan groups with less variability experienced within individual SUV normalisations by the administration of Buscopan. Mean SUV normalisations accounted for 80% of correlations in the control group and 100% in the Buscopan group. Further, >86% of all correlations across both groups were dominated by mean SUV normalisations of which, about 69% were accounted for by SUVbsa and SUVbsag.ConclusionsWe recommend avoiding mean SUVbsa and individual glucose normalisations especially, mean SUVbsag as these dominated albeit relatively weak correlations with body size factors in control and Buscopan groups. Mean and maximum SUVw and SUVlbm were shown to be independent of any body size parameters investigated in both groups and therefore considered suitable for monitoring FDG PET uptake in the normal bowel for our patient cohort.

Sequential FDG-PET scanning in the assessment of response to neoadjuvant chemotherapy in operable esophageal cancer

Background Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). Methods/design This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on “T” and “N” downstaging were calculated. Findings Twenty patients aged 18–75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%–85%). Interpretation The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.