Diagnosis and treatment of lung cancer: summary of updated NICE guidance

I note with interest the summary of NICE guidelines published by Baldwin and colleagues, which was revised in 2011. Focusing on the management of advanced non-small cell lung cancer (NSCLC), i.e. stage IIIb and beyond, the change in 2010 was the recommendation of gefitinib as a first-line treatment of advanced non-small cell lung cancer (NSCLC) based on the acceptance of clinical specialists’ advice that gefitinib’s efficacy depended on epidermal growth factor receptor tyrosine kinase (EGFR-TK) status, and that there was no reason to assume efficacy would differ according to histological subtype, gender, ethnicity and smoking status. [1] NICE also retained the combination of a third generation drug such as gemcitabine, vinorelbine, docetaxel or paclitaxel plus a platinum drug – carboplatin, cisplatin - which is the conventional treatment for advanced NSCLC. [1]

Gefitinib is a receptor tyrosine kinase (RTK) inhibitor that is targeted at patients with epidermal growth factor receptor (EGFR) mutations. The drug was evaluated in a phase III (IPASS) trial against the standard carboplatin-paclitaxel chemotherapeutic treatment, which featured in NICE’s recommendation for gefitinib as first-line treatment of advanced NSCLC, despite being evaluated in Asian patients (IPASS). [1] The gefitinib group had a significantly longer progression free survival (PFS) as compared with the standard chemotherapy group at 10.8 vs 5.4 months and significantly higher response rate at 73.7% vs 30.7%. On the basis of the significantly longer PFS result, the data and safety monitoring committee recommended termination of the study. However, longer PFS does not always translate into longer overall survival, and such was the case in this study. There was no significant difference in terms of median survival time and 2-year survival rates at 30.5 vs 23.6 months, and 61.4% vs 46.7% (P = 0.31). [2]

Thus, trial data has shown that there is no difference in median overall survival between conventional chemotherapy and the more recently recommended gefitinib therapy. Hence, the question is what other additional ways can be adopted in management of patients with advanced NSCLC, which demonstrate survival benefit as well as improved quality of life and mood?

A suggested approach in management of patients with advanced NSCLC would be early referral to palliative care whilst undergoing concurrent oncologic therapy which comprise of chemotherapy, radiotherapy or its combination. A seminal work by Temel and colleagues published in the New England Journal of Medicine was a randomised controlled trial, non-blinded that compared early palliative care plus standard oncologic treatment against standard oncologic treatment alone of advanced NSCLC patients. Oncologic treatment comprised platinum-based combination therapy, single agent, oral EGFR tyrosine kinase inhibitor (TKI), radiotherapy and chemoradiotherapy. For patient outcomes, health-related quality of life was evaluated using the Functional Assessment of Cancer Therapy – Lung (FACT-L), and mood was evaluated using the Hospital Anxiety and Depression Scale (HADS). 151 patients participated, and 107 completed the assessments. [3]

For the patients receiving early palliative care, median survival was significantly longer in the latter group at 11.6 vs 8.9 months (P = 0.02). FACT-L scores in the early palliative care group was also significantly higher at 98.0 vs 91.5 (P = 0.03), indicating significantly better quality of life. In addition, for HADS-D (Symptoms for depression), significantly fewer patients in the palliative group reported depressive symptoms as compared with the oncologic treatment group at 16% vs 38% (P = 0.01). [3] Finally, it was also interesting to note that Temel and colleagues published their study in 2010, before NICE issued the updated guidelines in April 2011.

One potential criticism of this article is the vast discrepancy in terms of overall survival results when comparing that of gefitinib versus standard chemotherapy against that of early palliative care integrated with oncologic care versus oncologic care alone – 30.5 vs 23.6 months for the former against 11.6 vs 8.9 months for the latter. This is attributed to the inclusion criteria of the IPASS trial, which includes non-smokers or light ex-smokers, defined as one who has ceased smoking at least 15 years before day 1 of study treatment and 10 pack-years or fewer. For the palliative care integrated with oncologic therapy trial, percentage of non-smokers or patients that smoked ≤ 10 packs/year who were randomised to the standard oncologic care group was 22% whilst for the standard oncologic care integrated with early palliative care group, the percentage was 24%, indicating that majority for both arms are smokers. Smoking is actually an important independent predictor of shortened lung cancer survival. [4]

Another important factor accounting for the discrepancy is the differences in populations in the two trials. The IPASS trial was conducted on Asian patients, whereas the palliative care integrated with oncologic therapy was done in Massachusetts General Hospital, US. Hence, we are looking at different populations – Asian vs western. It is known that Asian ethnicity is a favourable prognostic factor for survival in advanced stage NSCLC independent of smoking status. Furthermore, Asian patients have a longer survival and higher response rate in comparison with caucasians in the period prior to the use of EGFR TKIs as well as following the latter’s use. [5] As such, it is in my opinion that smoking status and ethnicity should merit a consideration as NICE evaluates guidelines for treatment of lung cancer.

Hence, while the updated NICE guidelines suggested chemotherapy modalities for management of advanced NSCLC [1], it is worth integrating such oncologic treatment approaches with palliative care early. At the end of the day, the outcome could turn out to be better - significantly longer median survival, better quality of life and lower incidence of depression symptoms. Which clinician would not want an approach that fulfils the latter three favourable outcomes?

However, there are challenges. We have to consider the possibility that the lay person may not be familiar with palliative care or have certain pre-conceived notions about the specialty which could be erroneous. Such can be overcome through patient education or public outreach programs.

1. NICE, . "Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer." . National Health Service, n.d. Web. 7 Oct 2013. .

2. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H,Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-2388. Information on clinical trial accessible at http://clinicaltrials.gov/ct2/show/NCT00322452

3. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-742. Information on clinical trial accessible at http://clinicaltrials.gov/show/NCT01038271

4. Tammemagi CM, Neslund-Dudas C, Simoff M, Kvale P. Smoking and lung cancer survival: the role of comorbidity and treatment. Chest. 2004 Jan;125(1):27-37.

5. Soo RA, Kawaguchi T, Loh M, Ou SH, Shieh MP, Cho BC, Mok TS, Soong R. Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol. 2012 Apr;8(4):451-462. Access to full journal available at Medscape: http://www.medscape.com/viewarticle/763160