Correspondence

Resolution of Non–Small-Cell Lung Cancer after Withdrawal of Anti-TNF Therapy

N Engl J Med 2008; 359:320-321July 17, 2008

Article

To the Editor:

We report the development of locally advanced non–small-cell lung cancer (tumor–node–metastasis [TNM] stage T4N2M0) in a 69-year-old woman with Crohn's colitis. Her condition had been diagnosed in 2000 and had required treatment with methotrexate (from 2003 to the present), together with anti–tumor necrosis factor (TNF) therapies — initially, episodic infliximab (from 2000 to 2004) and thereafter, maintenance adalimumab, until the tumor was diagnosed in June 2006. Remarkably, the tumor expressed TNF receptors and underwent regression and sustained remission on withdrawal of anti-TNF therapy, with no other therapeutic intervention.

In 1999, the patient, a former smoker (35 pack-years), was noted to have finger clubbing. A computed tomographic (CT) scan showed interstitial lung disease; she had normal pulmonary-function tests but remained under respiratory review. On repeat CT in June 2006, a pleural-based spiculated mass, 2.5 by 2.5 cm, was noted in the right lower lobe (Figure 1AFigure 1Representative CT Scans Obtained during and after the Withdrawal of Anti–Tumor Necrosis Factor (TNF) Therapy.) with two small satellite appendages. Mediastinal and hilar lymphadenopathy was present. CT-guided biopsy of the main lesion confirmed non–small-cell lung cancer, which was positive for TNF receptors type 1 and type 2 on immunostaining (data not shown). Adalimumab was withdrawn, but methotrexate was continued. The patient did not undergo surgery and did not receive radiotherapy, chemotherapy, or biologic therapy. In April 2007, on repeat CT scanning, there was virtually no evidence of primary lung tumor, nodules, or lymphadenopathy (Figure 1B). At the time of this report, she was in complete clinical and radiologic remission.

There is now real concern about the risk of lymphoma in patients exposed to anti-TNF therapies.1,2 In addition, there are reports of lung cancer, all in heavy smokers given infliximab. In the Mayo Clinic series of 500 patients with Crohn's disease, two lung cancers, deemed “possibly related” to infliximab, were reported in elderly smokers.3 In a 24-week trial involving patients with chronic obstructive pulmonary disease, a total of 12 cancers, including 6 lung cancers, were diagnosed in 157 patients treated with infliximab.4 In our unit, we have seen three lung cancers in patients treated with anti-TNF therapies, all of whom were smokers or former smokers over the age of 65 years.

The remarkable aspect of our case is the sustained remission on withdrawal of anti-TNF therapy. The overexpression of TNF receptors type 1 and type 2 implicates TNF blockade in carcinogenesis. This hypothesis is supported by data demonstrating a critical role of adaptive immunity in maintaining tumor dormancy after exposure to a carcinogen in cigarette smoke.5 We recommend special vigilance in the use of anti-TNF therapy in patients with a history of smoking or chronic lung disease, especially those over the age of 65 years.

Charles W. Lees, M.R.C.P.
Janet Ironside, F.R.C.P.
Western General Hospital, Edinburgh EH4 2XU, United Kingdom

William A.H. Wallace, F.R.C.P.Ed., F.R.C.Path.
Royal Infirmary of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Jack Satsangi, D.Phil.
Western General Hospital, Edinburgh EH4 2XU, United Kingdom
j.satsangi@ed.ac.uk

Dr. Lees reports receiving lecture fees from Schering-Plough and Abbott; and Dr. Satsangi, consulting and lecture fees from Abbott and UCB and consulting fees and grant support from Schering-Plough. No other potential conflict of interest relevant to this letter was reported.

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