Lung Service, Peter MacCallum Cancer Centre, East Melbourne, Victoria. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria
Almost untreatable in 1973, except by surgery, lung cancer is now susceptible to radiotherapy and chemotherapy as well and is often treated by all three modalities in combination. Although tobacco is the major cause of lung cancer, specific subtypes of the disease due to mutations unrelated to smoking have been recently identified, and have opened up opportunities for ‘personalised’ therapy. While these developments in treatment have led to a reduction in lung cancer mortality, by far the biggest factor contributing to the declining death rate has been the success of public health campaigns directed at reducing tobacco consumption.
In 1973, the Australian lung cancer epidemic was at its peak, yet the only treatments available were surgery for the small proportion of patients with operable early stage cancers, and palliative radiotherapy for more advanced cases. An influential but nihilistic British trial had shown that active treatment was no better than best supportive care.1 The message was clear: only prevention through reduced tobacco consumption could reduce the number of deaths. As a result of this trial, progress in the treatment of non-small cell lung cancer (NSCLC), in particular, stalled and it would be another two decades before evidence became available that treatment could alter the natural history of inoperable NSCLC. Since 1973, the character of the disease has changed. Squamous cell cancer was replaced by adenocarcinoma as the most common form of NSCLC, and the proportion of small cell lung cancer (SCLC) fell to 15% of all lung cancers. Lung cancer mortality has fallen, partly a result of more effective treatment, but mostly the consequence of successful public health policy in which Australian campaigners have a proud and internationally acclaimed record. Strategies championed by the health lobby which have resulted in reduced tobacco consumption have included media advertising, using confronting images, and punitive taxation.2
This review will however now focus on practice changing treatment developments decade by decade; citations which were either Australian or had a significant Australian contribution are underlined.
1970s: understanding and mapping the disease
The importance of stage (disease extent) and performance status as critical prognostic factors came to be recognised in studies by the Veterans Administration Lung Cancer Group in the US.3 One of the most important developments in this decade was the introduction of computed tomography of the chest for disease staging and radiotherapy planning.4 The distinct nature of small cell lung cancer, with its more aggressive natural history and propensity for early distant metastasis, came to be appreciated, with a resulting shift away from surgical resection to systemic therapy. Initially, this consisted of single agent alkylating agents,5 and then combination chemotherapy.6 It was also at this time that a possible role for prophylactic cranial irradiation was suggested by Hansen, although it would be 15 years before an impact on survival could be demonstrated.7,8
1980s: the small cell cancer decade
In the landmark RTOG 7301 trial, 60 Gy was established as the most effective radiotherapy dose for locally advanced NSCLC and it has remained the standard of care to now.9 But the 1980s really belonged to SCLC. Non-platinum containing regimens gave way to combinations containing cisplatin, and then carboplatin.10,11 It was also in this decade that the addition of thoracic radiotherapy to chemotherapy in patients with limited disease was shown to improve survival,12,13 later confirmed by meta-analysis.14
1990s: treatment for NSCLC works as well
Although the activity of platinum based agents had been demonstrated in NSCLC during the 1980s,15 the effect on survival and quality of life remained contentious.16 Then, after two decades of negligible progress, the combination of cisplatin and radiotherapy administered either sequentially17 or concomitantly,18 was shown to improve survival compared with radiotherapy alone in patients with inoperable NSCLC. For the most common scenario – metastatic disease – the landscape changed in 1995 when a practice-changing meta-analysis confirmed that cisplatin chemotherapy did indeed increase survival compared with best supportive care in advanced NSCLC,19 and so the modern era of NSCLC treatment began.
In surgery, lobectomy was shown to be superior to limited resection for stage I NSCLC,20 and the first references to the use of video-assisted thoracic surgery began to appear.21 In radiotherapy, shortening the overall treatment time with multiple treatments per day produced a survival benefit in both NSCLC,22 and SCLC,23 subsequently confirmed in meta analysis.24
In imaging, the first reports of the impact of fluorodeoxyglucose (FDG) PET scanning – which would revolutionise the staging and management of NSCLC in the next decade – were published.25–26
2000 onwards: the desert blooms.
Chemotherapy was by now an established standard of care for good performance status patients with metastatic NSCLC, and various platinum-based regimens containing two drugs seemed to be similarly effective.27 If chemotherapy prolonged survival in patients with advanced disease, might it not be even more effective in patients with subclinical metastatic disease, as was the case in patients with breast cancer? The IALT study of adjuvant platinum based chemotherapy in patients with completely resected early stage NSCLC was the first to confirm that adjuvant chemotherapy did improve survival.28 This was confirmed by a subsequent meta analysis.29 In patients with unresectable locally advanced NSCLC, concomitant chemotherapy and radiotherapy were shown to be superior to sequential treatment.30
Recognition that there are lung cancers arising in non-smokers which are associated with specific mutations – some of which occur with greater frequency in particular ethnic populations – dramatically changed the perception that lung cancer was only a disease of smokers. The demonstration that tyrosine kinase inhibitors could prolong progression free survival in patients with EGFR mutations,31 and that crizotinib was active against tumours with ALK gene rearrangements,32 opened up a new range of treatment options, and the era of personalised targeted therapies was born, with treatment based on molecular profiling rather than light microscopy.
In other developments, a new non-surgical treatment option for patients with stage I NSCLC appeared in the form of hypofractionated stereotactic radiotherapy,33 and its role is undergoing refinement. The TNM staging system was revised in 2009, based on over 100,000 cases, the result of a huge international collaboration.34 Finally, the ability to detect early stage lung cancer by CT screening and so reduce mortality was confirmed by a large randomised trial.35
In 2013, survival for lung cancer remains among the worst for any cancer, but as the last four decades have demonstrated, the research effort has accelerated with demonstrable improvements in outcomes. While progress in SCLC treatment has slowed, there is no sign of that in NSCLC, and the challenge now is to identify the most promising of the many strategies available for further research.
- Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. The Lancet. 1971 Apr 10;1(7702):715-9.
- Wakefield MA, Durkin S, Spittal MJ, Siahpush M, Scollo M, Simpson JA, et al. Impact of Tobacco Control Policies and Mass Media Campaigns on Monthly Adult Smoking Prevalence. Am J Public Health. [doi: 10.2105/AJPH.2007.128991]. 2008 2008/08/01;98(8):1443-50.
- Hyde L, Wolf J, McCracken S, Yesner R. Natural course of inoperable lung cancer. Chest. 1973 Sep;64(3):309-12.
- Emami B, Melo A, Carter B, Munzenrider J, Piro A. Value of computed tomography in radiotherapy of lung cancer. Am J Roentgenol. 1978 July 1, 1978;131(1):63-7.
- Hansen HH. Management of lung cancer. Med Clin North Am. 1977 Sep;61(5):979-89.
- Hansen HH, Selawry OS, Simon R, Carr DT, van Wyk CE, Tucker RD, et al. Combination chemotherapy of advanced lung cancer: a randomized trial. Cancer. 1976 Dec;38(6):2201-7.
- Hansen HH. Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chemother Rep 3. 1973 Mar;4(2):239-41.
- Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84.
- Perez CA, Stanley K, Rubin P, Kramer S, Brady L, Perez-Tamayo R, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer. 1980 Jun 1;45(11):2744-53.
- Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst. 1991 Jun 19;83(12):855-61.
- Bishop JF, Raghavan D, Stuart-Harris R, Morstyn G, Aroney R, Kefford R, et al. Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer. J Clin Oncol. 1987 Oct;5(10):1574-8.
- Bunn PA, Jr., Lichter AS, Makuch RW, Cohen MH, Veach SR, Matthews MJ, et al. Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. A prospective, randomized trial. Ann Intern Med. 1987 May;106(5):655-62.
- Rosenthal MA, Tattersall MHN, Fox RM, Woods RL, Brodie GN. Adjuvant thoracic radiotherapy in small cell lung cancer: ten-year follow-up of a randomized study. Lung Cancer. 1991;7:235-41.
- Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992 Dec 3;327(23):1618-24.
- Bunn PA, Jr. The expanding role of cisplatin in the treatment of non-small-cell lung cancer. Semin Oncol. 1989 Aug;16(4 Suppl 6):10-21.
- Woods RL, Williams CJ, Levi J, Page J, Bell D, Byrne M, et al. A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer. 1990 Apr;61(4):608-11.
- Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5.
- Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30.
- Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995 October 7, 1995;311(7010):899-909.
- Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995 Sep;60(3):615-22; discussion 22-3.
- Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg. 1999 Jun;117(6):1102-11.
- Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. The Lancet. 1997 Jul 19;350(9072):161-5.
- Turrisi AT, 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71.
- Mauguen A, Le Péchoux C, Saunders MI, Schild SE, Turrisi AT, Baumann M, et al. Hyperfractionated or Accelerated Radiotherapy in Lung Cancer: An Individual Patient Data Meta-Analysis. J Clin Oncol. 2012 August 1, 2012;30(22):2788-97.
- Kiffer JD, Berlangieri SU, Scott AM, Quong G, Feigen M, Schumer W, et al. The contribution of 18F-fluoro-2-deoxy-glucose positron emission tomographic imaging to radiotherapy planning in lung cancer. Lung Cancer. 1998 Mar;19(3):167-77.
- Hicks RJ, MacManus M, Kalff V, Binns DS, Ware R, Hogg A, et al. Clinical Impact of PET Scanning in Patients Being Staged with Non-Small-Cell Lung Cancer (NSCLC) in a Radiation Oncology Facility. Clin Positron Imaging. 1999 Nov;2(6):329.
- Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8.
- IALT. Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non–Small-Cell Lung Cancer. N Engl J Med. 2004;350(4):351-60.
- Pignon J-P, Tribodet H, Scagliotti GV, Douillard J-Y, Shepherd FA, Stephens RJ, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008 July 20, 2008;26(21):3552-9.
- Auperin A, Le Pechoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non-Small-Cell Lung Cancer. 10.1200/JCO. 2009.26.2543. J Clin Oncol. 2010 May 1, 2010;28(13):2181-90.
- Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. 10.1056/NEJMoa0810699. N Engl J Med. 2009 September 3, 2009;361(10):947-57.
- Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer. N Engl J Med. 2010;363(18):1693-703.
- Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer
10.1001/jama.2010.261. JAMA. 2010 March 17, 2010;303(11):1070-6.
- Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007 Aug;2(8):706-14.
- Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409.