Correspondence
Lung-Cancer Staging with PET–CT
N Engl J Med 2009; 361:1606-1608October 15, 2009
- Article
To the Editor:
In their assessment of the usefulness of combined positron-emission tomography and computed tomography (PET–CT) in the preoperative staging of lung cancer, Fischer et al. (July 2 issue)1 provide no information on the interval between baseline staging and thoracotomy, nor on the use of neoadjuvant therapy. A prolonged delay between PET–CT and surgery may negate the diagnostic value of PET–CT and may be due to coexisting conditions that would themselves have a negative effect on survival. Although the PET–CT scans in the study were read by an experienced radiologist and a nuclear medicine specialist, it is unclear who interpreted the diagnostic CT scans and whether the final tumor–node–metastasis (TNM) stage was determined by the same investigators in all patients or whether the stage was decided locally. These factors are important for assessing the influence of observer bias on the study results.
1 ReferencesJohn F. Bruzzi, F.F.R.R.C.S.I.
Galway University Hospitals, Galway, Ireland1
Fischer B ,Lassen U ,Mortensen J , et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009;361:32-39
Full Text | Web of Science | Medline
To the Editor:
In the study reported on by Fischer et al., recurrence or death occurred in a remarkable proportion of the patients during the first year of follow-up, especially in the conventional-staging group. Did these patients undergo imaging for extrathoracic metastases?
Moreover, no information is given about incomplete resections, which are strong negative predictors of survival, even when additional therapy is provided. These resections are associated with high rates of local and distant recurrence.1
The definition of futile thoracotomy is controversial with regard to recurrence and death within 12 months. The results with respect to futile thoracotomies are the same in both groups if these patients are excluded.
1 ReferencesServet Bölükbas, M.D.
Dr. Horst Schmidt Klinik, Wiesbaden, Germany
servet_boeluekbas@web.de Sammy A. Baierlein, M.D.
St. Claraspital Basel, Basel, SwitzerlandJoachim Schirren, M.D.
Dr. Horst Schmidt Klinik, Wiesbaden, Germany1
Brundage MD ,Davies D ,Mackillop WJ . Prognostic factors in non-small cell lung cancer: a decade of progress. Chest 2002;122:1037-1057
CrossRef | Web of Science | Medline
To the Editor:
Fischer et al. conclude that the use of PET–CT reduced the number of futile thoracotomies, but since the frequency of futile thoracotomies was the primary end point of the study, it should be defined carefully. The criteria used in the definition of futile thoracotomies vary among several trials, and the definition remains controversial.1-3 In their previous article regarding endoscopic ultrasound-guided biopsy in lung-cancer staging,4 some of the authors in the current study defined futile thoracotomies as either exploratory thoracotomy without tumor resection or postoperative death from lung cancer or recurrent disease during follow-up. Why did the authors change the definition in the current study? Does PET–CT still reduce the number of futile thoracotomies with the use of the previous definition? Furthermore, the use of 12 months as a cutoff value in the interval to recurrence or death to define futile thoracotomies has not been widely validated.
4 ReferencesJung-Jyh Hung, M.D.
Cathay General Hospital, Taipei, Taiwan
bradley.hung@gmail. com Wen-Juei Jeng, M.D.
Chang Gung Memorial Hospital, Taipei, TaiwanJung-Sen Liu, M.D., Ph.D.
Cathay General Hospital, Taipei, Taiwan1
van Tinteren H ,Hoekstra OS ,Smit EF , et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002;359:1388-1393
CrossRef | Web of Science | Medline2
Viney RC ,Boyer MJ ,King MT , et al. Randomized controlled clinical trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 2004;22:2357-2362
CrossRef | Web of Science | Medline3
Canadian Lung Oncology Group
CrossRef | Web of Science | Medline4
Larsen SS ,Vilmann P ,Krasnik M , et al. Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: preliminary results from a randomised clinical trial. Lung Cancer 2005;49:377-385
CrossRef | Web of Science | Medline
To the Editor:
Fischer and colleagues detected previously unrecognized distant metastases in 9 of 87 patients who underwent PET–CT. However, the specificity of PET–CT is often below 90%. Standardized uptake values just above 2.5 have a specificity as low as 53%.1 A previous randomized trial that showed a decrease in futile thoracotomies asked for tissue confirmation of 18F-fluorodeoxyglucose (18F-FDG)–avid regions.2 Why was this not done in the study by Fischer et al.? The authors point out that mediastinoscopy was performed in 94% of the patients. Mediastinoscopy confirmed lymph-node metastases in 27 of 189 patients (14%), and endoscopic ultrasonography confirmed lymph-node metastases in 14 of 189 patients (7%). PET–CT is also used to avoid futile mediastinoscopies.3 The second edition of the guidelines of the American College of Chest Physicians does not require invasive staging for lymph nodes that are normal on PET–CT in patients with peripheral stage I disease.4 The PET–CT group included 30 patients with stage I disease. Would selective mediastinoscopy have spared most of these patients an unnecessary procedure?
4 ReferencesGoetz Kloecker, M.D., M.S.P.H.
Cahid Civelek, M.D.
Mohammad Janjua, M.D.
University of Louisville, Louisville, KY
goetzkloecker@yahoo.com 1
Nambu A ,Kato S ,Sato Y , et al. Relationship between maximum standardized uptake value (SUVmax) of lung cancer and lymph node metastasis on FDG-PET. Ann Nucl Med 2009;23:269-275
CrossRef | Web of Science | Medline2
van Tinteren H ,Hoekstra OS ,Smit EF , et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002;359:1388-1393
CrossRef | Web of Science | Medline3
Serra M ,Cirera L ,Rami-Porta R , et al. Routine positron emission tomography (PET) and selective mediastinoscopy is as good as routine mediastinoscopy to rule out N2 disease in non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24:Suppl:18S-18S
CrossRef4
Detterbeck FC ,Jantz MA ,Wallace M ,Vansteenkiste J ,Silvestri GA . Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:Suppl:202S-220S
CrossRef | Web of Science | Medline
To the Editor:
Fischer et al. report that at follow-up, 61% of patients in the PET–CT group and 51% in the control group had died (P=0.15). Of note, the trial was not powered to detect an effect on mortality. Assuming a 50% mortality rate at 2 years, at least 170 patients per group are needed to detect a 30% difference in relative risk (at a beta level of 0.2 and an alpha level of 0.05). However, this study with 91 patients in the control group and 98 patients in the intervention group had a power of 53 to 55%.
Using a two-by-two table, I computed a relative risk of 1.21 (95% confidence interval, 0.93 to 1.56); there appears to be a 21% increased risk of death at 2 years in the intervention group relative to the control group.
This risk should be further evaluated in an adequately powered study; the benefit of averting thoracotomies should not occur at the expense of increased mortality.
Waseem Sharieff, M.D., Ph.D.
Juravinski Cancer Centre, Hamilton, ON, Canada
doc.sharieff@utoronto. ca Author/Editor Response
Bruzzi stresses the importance of the interval between baseline staging and subsequent surgery. In our study, all patients were referred for mediastinoscopy before randomization. This referral ensured that PET–CT did not delay mediastinoscopy and subsequent surgery. A few patients who were randomly assigned to PET–CT did not undergo the procedure, which would have delayed subsequent procedures. These patients were included in our intention-to-treat analyses. Therefore, no difference between the two groups in the interval between baseline staging and surgery was observed. Neoadjuvant therapy before surgery was not allowed in this study. The primary CT scans were performed and read at the referring departments, according to predefined protocols for CT based on consensus by the Danish Society of Radiologists; this ensured that all enrolled patients had comparable inclusion criteria.
In response to Bölükbas et al.: CT scans showed the thorax and upper abdominal organs; only if there were specific symptoms was further imaging of the extrathoracic area performed. The final TNM stages were decided by the referring investigators (specialists in pulmonary medicine) on the basis of all available data.
We agree with Bölükbas et al. and Hung et al. that the definition of futile thoracotomy is controversial. We chose the same criteria as those used in the PET in Lung Cancer Staging study.1 Even if the definition comprises only exploratory thoracotomy, death, or recurrence during follow-up, PET–CT still significantly reduced the frequency of futile thoracotomies (P<0.01). Follow-up data were retrieved from the national database and medical records from all relevant hospitals. As noted by Bölükbas et al., incomplete resection is a strong negative predictive factor. Incomplete resection occurred with similar frequency (5%) in the two groups of the trial.
In response to Kloecker et al.: conventional staging procedures were based on recommendations from the Danish Lung Cancer Group in 2001.2 This system was recognized as the best standard, and all areas of increased uptake of 18F-FDG were evaluated by biopsy or other imaging techniques at the discretion of the referring clinician. In 2002, when the present study was initiated, the data provided by Serra et al.3 were not available, and to simplify our study it was decided to perform mediastinoscopy as a part of the standard staging procedure in all patients. We agree that selective mediastinoscopy could have spared patients with stage I disease an unnecessary procedure. However, the high frequency of mediastinoscopy in our study strengthens the result, since the conventional workup was the same among all clinical stages.
Our study was powered to assess futile thoracotomies and not to evaluate mortality. Hence, we agree with Sharieff that a larger study is warranted to ensure that the benefit of averting thoracotomies does not occur at the expense of increased mortality.
3 ReferencesBarbara Malene Fischer, Ph.D.
Odense University Hospital, Odense, Denmark
bjerregaard.fischer@gmail. com Ulrik Lassen, Ph.D.
Jann Mortensen, Dr.Med.Sci.
Copenhagen University Hospital, Copenhagen, Denmark1
van Tinteren H ,Hoekstra OS ,Smit EF , et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002;359:1388-1393
CrossRef | Web of Science | Medline2
Lung cancer — diagnosis and therapy. Aarhus, Denmark: Danish Lung Cancer Group, 2001. (In Danish.)
3
Serra M ,Cirera L ,Rami-Porta R , et al. Routine positron emission tomography (PET) and selective mediastinoscopy is as good as routine mediastinoscopy to rule out N2 disease in non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24:Suppl:18S-18S
CrossRef
