For patients undergoing workup for known or suspected lung cancer, what is the optimal timing of PET/CT? Before or after tissue biopsy confirmation?

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Introduction

The use of PET/CT scanning in the diagnostic and staging workup for lung cancer varies according to local availability and practice. International guidelines vary in their detailed recommendations but generally include PET/CT in diagnostic and staging algorithms for lung cancer. [1][2][3][4] International guidelines for evaluation of pulmonary nodules also include PET/CT in the diagnostic workup.[5][6] However, this guideline will focus on the role and optimal timing of PET/CT in the evaluation of patients with more than a pulmonary nodule, where lung cancer has been either confirmed on tissue biopsy or where lung cancer is suspected and where the clinical effort underway aims to confirm this suspicion and to correctly ascertain the disease stage. This guideline restricts its recommendations to the use of PET/CT in the diagnosis and work up of non-small cell lung cancer (NSCLC). The term PET/CT refers to FDG-PET/CT throughout.

Approach taken to content development

The development of the content addressing this question was based on a non-systematic approach to the literature. There is a relative lack of papers that specifically address the question of optimal timing of PET/CT in the diagnosis and workup of lung cancer. This guideline has therefore explored available international recommendations as well as, appropriate papers that address aspects of the question and has combined these findings with practical clinical expertise.

Current evidence

Ideally, guideline recommendations on this question would draw upon high-level evidence that specifically investigated the best timing for PET/CT in the work up of NSCLC. However, extensive literature searches have not identified such evidence so a combination of published recommendations and clinical expertise inform this content.

Even though this section of the guidelines will focus particularly on PET/CT for workup of lung cancer, there exists some overlap with the use of PET/CT for the assessment of pulmonary nodules. Two publications give relatively clear recommendations for the use of PET/CT in the evaluation of pulmonary nodules where lung cancer is suspected.[5][6] Both papers concentrate on evaluation of pulmonary nodules per se, but pertinent recommendations for lesions suspicious for malignancy are summarized in Table 1. Levels of evidence are given where available.


Table 1. Summarised recommendations for PET/CT in the evaluation of pulmonary nodules suspicious for lung cancer

Gould 2013 Callister 2015
PET/CT is recommended for solid, indeterminate nodules >8mm with low-moderate pre-test probability of malignancy (estimated by clinical judgement or by using a validated model. (Grade 2C)*


PET/CT is not recommended to characterize nodules with a high pre-test probability of malignancy. (Grade 2C) (Although it is reasonable to use PET/CT for pre-treatment staging in such cases).**


PET/CT has high sensitivity (95%) and specificity (82%) for malignancy in pulmonary nodules compared with other imaging modalities. [7]


Negative PET/CT scan does not reliably exclude malignancy.


No data exist to compare integrated PET/CT with PET/CT combined with dedicated CT imaging.


The pre-test probability of malignancy influences interpretation of PET/CT, with high-risk individuals at risk of false-negative results, and low-risk individuals at risk of false-positive results. (Grade D)


Combined clinical and PET/CT information results in best diagnostic accuracy.


PET/CT is most efficacious in nodules with low-moderate pre-test probability of malignancy.


PET/CT is the preferred investigation for evaluation of pulmonary nodules as no other imaging modality is superior and PET/CT is widely available.


PET/CT should be offered to patients with a >10% risk of malignancy (according to the Brock model***).[8][9][10] (Grade B)


PET/CT should be used for staging if resection is considered.


*Where factors contributing to a pre-test likelihood of malignancy include age, smoking history, extra-thoracic cancer diagnosis > 5 years prior, size of lesion, spiculation and upper lobe location.
**In practice this would be a common point at which PET/CT would be used, whatever the intent of the clinician.
***The Brock model comprises four smoking variables (smoking intensity, smoking duration, quit time in former smokers, and current smoking status [current versus former]) and seven non-smoking variables (age, race/ethnicity, socioeconomic circumstance estimated by education level, body mass index, personal history of cancer, chronic obstructive pulmonary disease, family history of lung cancer).

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PET/CT for staging of known or suspected NSCLC

The other significant use of PET/CT is for non-invasive staging of NSCLC. Again, little data exist to inform us on optimal timing. However, recommendations from published guidelines are summarized in Table 2. Levels of evidence are given where available.

Table 2. Summarised recommendations for PET/CT from published lung cancer guidelines (with key references included)

NICE 2011 Silvestri 2013 SIGN 2014 NCCN 2016
Offer PET/CT as a first test for patients with low to intermediate probability of mediastinal malignancy potentially suitable for curative treatment.


Every cancer network should have rapid access to PET/CT.


PET/CT is appropriate to confirm the presence of isolated distant metastases/synchronous tumours in patients considered for curative treatment.


Consider research into the use of MRI and PET/CT in routine brain imaging prior to treatment with curative intent.

In patients with clinical (and CT) early stage disease considered for curative intent treatment, PET/CT is recommended to evaluate for metastases (except the brain). (Grade 1B)


PET/CT has multiple purposes in lung cancer workup including diagnostic accuracy, guiding biopsy and staging.


In patients with lower risk of metastatic disease (such as clinical stage IA peripheral tumours) PET/CT may not be indicated (possible false positive rates for metastases).[11]

After FDG PET/CT scanning of solitary lung lesions pathological confirmation of results is still required. (Grade C) [12]


All patients considered for radical treatment should have a staging FDG PET/CT scan before treatment. (Grade B) [13][2][14][15][16]


For adrenal metastases, negative PET/CT reliably excludes metastases (Grade B); after positive PET/CT tissue confirmation usually required unless metastatic disease is extensive. (Grade B) [17]

PET/CT imaging is frequently best performed before biopsy. (Grade 2A)


PET/CT is recommended for pre-treatment evaluation for all stages of disease. (Grade 2A)


PET/CT can play a role in evaluation and more accurate staging of NSCLC. [2][14]


PET/CT is even more sensitive and is therefore recommended by NCCN.[18][19][16][20]


The presence of post-obstructive pneumonitis means that the size of mediastinal lymph nodes has no correlation with tumour involvement. [21]


The use of PET/CT for staging of early stage disease avoids inappropriate surgical resection. [22]


PET/CT positive nodes generally require pathological confirmation. [2][23]


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Evidence summary and recommendations

Of four major international guidelines, only one comments on the timing of PET/CT in the work up of lung cancer [4], observing that PET/CT is often best performed before biopsy. In patients potentially suitable for curative therapy, UK guidelines [1] recommend PET/CT as (i) the first test with low likelihood of mediastinal involvement and as (ii) an early test (along with EBUS TBNA) for patients with possible mediastinal involvement. In patients potentially suitable for curative therapy, the Chest guidelines[2] include PET/CT as an early test for patients without extra thoracic involvement on CT and acknowledge the multiple roles of PET/CT including guiding biopsy and staging. The Scottish national guidelines[3] recommend PET/CT for patients potentially suitable for curative therapy and discuss the utility of a negative PET/CT in the exclusion of adrenal metastases. The NCCN guidelines [4] give detailed recommendations for the use of PET/CT across all stages of NSCLC; these guidelines note that PET/CT may be best performed prior to biopsy. The recommendations are based on a range of studies (details in Table 2) evaluating the sensitivity and specificity of PET/CT compared with other imaging modalities and with tissue sampling.

Investigators have explored the use of PET/CT early in the diagnostic algorithm, performed directly after suspicious CXR without the use of interventing diagnostic CT and indicate the potential for greater efficiency without major increases in cost.[24]


Practice pointQuestion mark transparent.png

In the absence of evidence to guide optimal timing of PET/CT in the workup of known or suspected lung cancer (NSCLC) it is advisable to:


1. Offer PET/CT to all patients who are considered for curative therapy.
2. Consider the use of PET/CT prior to biopsy in order to guide biopsy as well as to stage disease.
3. Consider the use of PET/CT at any stage in order to evaluate the extent of metastatic disease.
4. Consider the use of "flat-top" table position for PET/CT as this is the radiotherapy planning position; this may avoid the need for a second scan to plan for radiotherapy.

Issues requiring more clinical research study

  1. Does the use of PET/CT prior to biopsy improve the efficiency and accuracy of diagnosis and staging?
  2. What factors weigh against the use of PET/CT in the workup of known or suspected NSCLC? 
  3. What are the potential benefits of early PET/CT, following CXR without intervening diagnostic CT? What is the cost-benefit analysis of this approach?

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References

  1. 1.0 1.1 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. NCCN 2011;Version 3 Abstract available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
  2. 2.0 2.1 2.2 2.3 2.4 Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5 Suppl):e211S-50S Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23649440.
  3. 3.0 3.1 Scottish Intercollegiate Guidelines Network (SIGN). Sign 137: Management of lung cancer. A national clinical guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2014 Available from: http://www.sign.ac.uk/guidelines/fulltext/137/index.html.
  4. 4.0 4.1 4.2 National Comprehensive Cancer Network (NCCN). Non small cell lung cancer. Version 4.2016. Fort Washington (PA): National Comprehensive Cancer Network; 2016 Available from: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
  5. 5.0 5.1 Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5 Suppl):e93S-120S Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23649456.
  6. 6.0 6.1 Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015 Aug;70 Suppl 2:ii1-ii54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26082159.
  7. Cronin P, Dwamena BA, Kelly AM, Carlos RC. Solitary pulmonary nodules: meta-analytic comparison of cross-sectional imaging modalities for diagnosis of malignancy. Radiology 2008 Mar;246(3):772-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18235105.
  8. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013 Sep 5;369(10):910-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24004118.
  9. Tammemägi MC, Church TR, Hocking WG, Silvestri GA, Kvale PA, Riley TL, et al. Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 2014 Dec;11(12):e1001764 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25460915.
  10. Al-Ameri A, Malhotra P, Thygesen H, Plant PK, Vaidyanathan S, Karthik S, et al. Risk of malignancy in pulmonary nodules: A validation study of four prediction models. Lung Cancer 2015 Jul;89(1):27-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25864782.
  11. Kozower BD, Meyers BF, Reed CE, Jones DR, Decker PA, Putnam JB Jr. Does positron emission tomography prevent nontherapeutic pulmonary resections for clinical stage IA lung cancer? Ann Thorac Surg 2008 Apr;85(4):1166-9; discussion 1169-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18355490.
  12. Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001 Feb 21;285(7):914-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11180735.
  13. Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007 Sep;132(3 Suppl):178S-201S Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17873168.
  14. 14.0 14.1 Pieterman RM, van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koëter GH, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000 Jul 27;343(4):254-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10911007.
  15. MacManus MP, Hicks RJ, Matthews JP, Hogg A, McKenzie AF, Wirth A, et al. High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy. Int J Radiat Oncol Biol Phys 2001 Jun 1;50(2):287-93 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11380213.
  16. 16.0 16.1 Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009 Jul 2;361(1):32-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19571281.
  17. Boland GW, Dwamena BA, Jagtiani Sangwaiya M, Goehler AG, Blake MA, Hahn PF, et al. Characterization of adrenal masses by using FDG PET: a systematic review and meta-analysis of diagnostic test performance. Radiology 2011 Apr;259(1):117-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21330566.
  18. R Chin Jr, R Ward , J W Keyes , R H Choplin , J C Reed , S Wallenhaupt , A S Hudspeth , and E F Haponik. Mediastinal staging of non-small-cell lung cancer with positron emission tomography. AJRCCM 1995 Dec 1;Volume 152; No.6 Abstract available at http://www.atsjournals.org/doi/abs/10.1164/ajrccm.152.6.8520780.
  19. Kernstine KH, Stanford W, Mullan BF, Rossi NP, Thompson BH, Bushnell DL, et al. PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg 1999 Sep;68(3):1022-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10510001.
  20. De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration. Eur Respir J 2009 Jan;33(1):201-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19118231.
  21. Kerr KM, Lamb D, Wathen CG, Walker WS, Douglas NJ. Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging. Thorax 1992 May;47(5):337-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1609375.
  22. Maziak DE, Darling GE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, et al. Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med 2009 Aug 18;151(4):221-8, W-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19581636.
  23. Darling GE, Maziak DE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, et al. Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial. J Thorac Oncol 2011 Aug;6(8):1367-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21587082.
  24. Macpherson R, Benamore R, Panakis N, Sayeed R, Breen D, Bradley K, et al. A proposed new imaging pathway for patients with suspected lung cancer. Clin Radiol 2012 Jun;67(6):564-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22300820.

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Appendices