Emerging developments of chemoradiotherapy in stage iii nsclc

ABSTRACT Over the past decade, concomitant chemotherapy and radiotherapy has become the established treatment for patients with stage III non-small-cell lung cancer (NSCLC). Unfortunately,

many patients with NSCLC are too old or have multiple comorbidities to withstand such aggressive treatments. Attempts to improve outcomes have included studies of radiotherapy dose

escalation and new chemotherapy combinations, as well as adding biological agents and cancer vaccines to existing regimens. Technical radiotherapy modifications, including

intensity-modulated radiotherapy and particle beam therapy, have also been investigated. Given the number of potential advances to current models of treatment development, phase III trials

of any single new treatment can take years to complete, which is inadequate. To advance research within shorter timescales to improve patient outcomes, we need methods of improving clinical

trial accrual, which might require changes in models of research governance, cooperative group activity, trial design and patient consent. Access through your institution Buy or subscribe

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EVOLUTION OF SYSTEMIC THERAPY FOR STAGES I–III NON-METASTATIC NON-SMALL-CELL LUNG CANCER Article 28 April 2021 RATIONALE FOR CONCURRENT CHEMORADIOTHERAPY FOR PATIENTS WITH STAGE III

NON-SMALL-CELL LUNG CANCER Article Open access 08 December 2020 THE CURRENT TREATMENT LANDSCAPE IN THE UK FOR STAGE III NSCLC Article Open access 08 December 2020 REFERENCES * Liu, B. Q. _

et al_. Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths. _BMJ_ 317, 1411–1422 (1998). Article  CAS  PubMed  PubMed Central  Google

Scholar  * van Meerbeeck, J. P. & Surmont, V. F. Stage IIIA-N2 NSCLC: a review of its treatment approaches and future developments. _Lung Cancer_ 65, 257–267 (2009). Article  PubMed 

Google Scholar  * O'Rourke, N., Roquéi Figuls, M., Farré Bernadó, N. & Macbeth, F. Concurrent chemoradiotherapy in non-small cell lung cancer. _Cochrane Database of Systematic

Reviews_, Issue 16. Art. No.: CD002140. http://dx.doi/org/10.1002/14651858.CD002140.pub3 * Aupérin, A. _ et al_. Meta-analysis of concomitant versus sequential radiochemotherapy in locally

advanced non-small-cell lung cancer. _J. Clin. Oncol._ 28, 2181–2190 (2010). Article  PubMed  CAS  Google Scholar  * Mauguen, A. _ et al_. Hyperfractionated or accelerated radiotherapy in

lung cancer: an individual patient data meta-analysis. _J. Clin. Oncol._ 30, 2788–2797 (2012). Article  PubMed  PubMed Central  Google Scholar  * Robinson, L. A., Ruckdeschel, J. C., Wagner,

H. Jr & Stevens, C. W. American College of Chest Physicians. Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition). _Chest_

132 (Suppl. 3), 243S–265S (2007). Article  PubMed  Google Scholar  * Jett, J. R., Schild, S. E., Keith, R. L. & Kesler, K. A. American College of Chest Physicians. Treatment of non-small

cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (2nd edition). _Chest_ 132 (Suppl. 3), 266S–276S (2007). Article  PubMed  Google Scholar  * van Meerbeeck, J.

P. _ et al_. on behalf of the European Organisation for Research and Treatment of Cancer–Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction

chemotherapy in stage IIIA-N2 non-small-cell lung cancer. _JNCI J. Natl Cancer Inst._ 99, 442–450 (2007). Article  PubMed  Google Scholar  * Albain, K. S. _ et al_. Radiotherapy plus

chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. _Lancet_ 374, 379–386 (2009). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Subramanian, J. _ et al_. Distinctive characteristics of non-small cell lung cancer (NSCLC) in the young: a surveillance, epidemiology, and end results (SEER)

analysis. _J. Thorac. Oncol._ 5, 23–28 (2010). Article  PubMed  Google Scholar  * De Ruysscher, D. _ et al_. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung

cancer patients: a prospective, population-based study. _Ann. Oncol._ 20, 98–102 (2009). Article  CAS  PubMed  Google Scholar  * Hardy, D., Liu, C.-C., Cormier, J. N., Xia, R. & Du, X.

L. Cardiac toxicity in association with chemotherapy and radiation therapy in a large cohort of older patients with non-small-cell lung cancer. _Ann. Oncol._ 21, 1825–1833 (2010). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Davidoff, A. J., Gardner, J. F., Seal, B. & Edelman, M. J. Population-based estimates of survival benefit associated with combined modality

therapy in elderly patients with locally advanced non-small cell lung cancer. _J. Thorac. Oncol._ 6, 934–941 (2011). Article  PubMed  Google Scholar  * Coate, L. E. _ et al_. Treatment of

the elderly when cure is the goal: the influence of age on treatment selection and efficacy for stage III non-small cell lung cancer. _J. Thorac. Oncol._ 6, 537–544 (2011). Article  PubMed 

Google Scholar  * Phernambucq, E. C. J. _ et al_. Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity. _Ann. Oncol._

22, 132–138 (2011). Article  CAS  PubMed  Google Scholar  * Semrau, S., Klautke, G., Virchow, J. C., Kundt, G. & Fietkau, R. Impact of comorbidity and age on the outcome of patients with

inoperable NSCLC treated with concurrent chemoradiotherapy. _Respir. Med._ 102, 210–218 (2008). Article  CAS  PubMed  Google Scholar  * Schild, S. E. _ et al_. for the North Central Cancer

Treatment Group. The value of combined-modality therapy in elderly patients with stage III nonsmall cell lung cancer. _Cancer_ 110, 363–368 (2007). Article  PubMed  Google Scholar  *

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_ 311, 899–909 (1995). * Cox, J. D. Are the results of RTOG 0617 mysterious? _Int. J. Radiat. Oncol. Biol. Phys._ 82, 1042–1044 (2012). Article  PubMed  Google Scholar  * US National

Library of Medicine. _Clinicaltrials.gov_ [online], (2011). * Perez, C. A. _ 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_ 45, 2744–2753 (1980). Article  CAS  PubMed  Google Scholar  * Maguire,

J. _ et al_. SOCCAR: sequential or concurrent chemotherapy and hypofractionated accelerated radiotherapy in inoperable stage III NSCLC [abstract 7039]. _J. Clin. Oncol._ 29 (Suppl.) (2011).

* Saunders, M. _ et al_. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART

Steering Committee. _Lancet_ 350, 161–165 (1997). Article  CAS  PubMed  Google Scholar  * Kratz, J. R. _ et al_. A practical molecular assay to predict survival in resected non- squamous,

non-small-cell lung cancer: development and international validation studies. _Lancet_ 379, 823–832 (2012). Article  PubMed  PubMed Central  Google Scholar  * National Cancer Institute at

the National Institutes of Health. _Clinical Trials Search Results_ [online]. * Belani, C. P. _ et al_. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced

non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. _J. Clin. Oncol._ 23, 5883–5891 (2005). Article  CAS  PubMed  Google Scholar  * O'Rourke, N.

& Edwards, R. Lung cancer treatment waiting times and tumour growth. _Clin. Oncol. (R. Coll. Radiol.)_ 12, 141–144 (2000). Article  CAS  Google Scholar  * Masters, G. A. _ et al_. A

phase II trial of high dose carboplatin and paclitaxel with G-CSF and peripheral blood stem cell support followed by surgery and/or chest radiation in patients with stage III non-small cell

lung cancer: CALGB 9531. _Lung Cancer_ 74, 258–263 (2011). Article  PubMed  Google Scholar  * Vokes, E. E. _ et al_. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or

vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. _J. Clin. Oncol._ 20,

4191–4198 (2002). Article  CAS  PubMed  Google Scholar  * Socinski, M. A. _ et al_. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated

thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. _J. Clin. Oncol._ 26, 2457–2463 (2008). Article  CAS  PubMed  Google Scholar  * Yamamoto, N. _

et al_. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan

Thoracic Oncology Group WJTOG0105. _J. Clin. Oncol._ 28, 3739–3745 (2010). Article  PubMed  Google Scholar  * Takeda, K. _ et al_. A phase II study of cisplatin and irinotecan as induction

chemotherapy followed by concomitant thoracic radiotherapy with weekly low-dose irinotecan in unresectable, stage III, non-small cell lung cancer: JCOG 9706. _Jpn J. Clin. Oncol._ 41, 25–31

(2011). Article  PubMed  Google Scholar  * Oshita, F. _ et al_. Phase II study of nedaplatin and irinotecan with concurrent thoracic radiotherapy in patients with locally advanced

non-small-cell lung cancer. _Br. J. Cancer_ 103, 1325–1330 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jalal, S. I. _ et al_. Updated survival and outcomes for older

adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III

trial from the Hoosier Oncology Group (HOG) and US Oncology. _Ann. Oncol._ 23, 1730–1738 (2012). Article  CAS  PubMed  Google Scholar  * Kelly, K. _ et al_. Phase III trial of maintenance

gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. _J. Clin. Oncol._ 26, 2450–2456 (2008).

Article  CAS  PubMed  Google Scholar  * Segawa, Y. _ et al_. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination

chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. _J. Clin. Oncol._ 28, 3299–3306 (2010). Article  CAS  PubMed  Google Scholar  *

Takigawa, N. _ et al_. Benefits and adverse events among elderly patients receiving concurrent chemoradiotherapy for locally advanced non-small cell lung cancer: analysis of the Okayama

Lung Cancer Study Group trial 0007. _J. Thorac. Oncol._ 6, 1087–1091 (2011). Article  PubMed  Google Scholar  * Senan, S. _ et al_. A randomized phase II study comparing induction or

consolidation chemotherapy with cisplatin-docetaxel, plus radical concurrent chemoradiotherapy with cisplatin-docetaxel, in patients with unresectable locally advanced non-small-cell lung

cancer. _Ann. Oncol._ 22, 553–558 (2011). Article  CAS  PubMed  Google Scholar  * Govindan, R. _ et al_. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or

without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. _J. Clin. Oncol._ 29, 3120–3125 (2011). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Gadgeel, S. M. _ et al_. Phase II study of pemetrexed and cisplatin, with chest radiotherapy followed by docetaxel in patients with stage III

non-small cell lung cancer. _J. Thorac. Oncol._ 6, 927–933 (2011). Article  PubMed  Google Scholar  * US National Library of Medicine. _Clinicaltrials.gov_ [online], (2012). * Ichinose, Y. _

et al_. _S_-1 plus cisplatin with concurrent radiotherapy for locally advanced non-small cell lung cancer: a multi-institutional phase II trial (West Japan Thoracic Oncology Group 3706).

_J. Thorac. Oncol._ 6, 2069–2075 (2011). Article  PubMed  Google Scholar  * Vokes, E. E. _ et al_. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone

for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. _J. Clin. Oncol._ 25, 1698–1704 (2007). Article  CAS  PubMed  Google Scholar  *

Stinchcombe, T. E. _ et al_. Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy

compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer. _J. Thorac. Oncol._ 4, 1117–1125 (2009). Article  PubMed  PubMed Central  Google Scholar  *

Harada, H. _ et al_. Comparison of chemotherapy regimens for concurrent chemoradiotherapy in unresectable stage III non-small cell lung cancer. _Int. J. Clin. Oncol._ 14, 507–512 (2009).

Article  PubMed  Google Scholar  * Wang, L. _ et al_. Randomized phase II study of concurrent cisplatin/etoposide or paclitaxel/carboplatin and thoracic radiotherapy in patients with stage

III non-small cell lung cancer. _Lung Cancer_ 77, 89–96 (2012). Article  CAS  PubMed  Google Scholar  * Martel, M. K. _ et al_. Estimation of tumor control probability model parameters from

3D dose distributions of non-small cell lung cancer patients. _Lung Cancer_ 24, 31–37 (1999). Article  CAS  PubMed  Google Scholar  * Partridge, M., Ramos, M., Sardaro, A. & Brada, M.

Dose escalation for non-small cell lung cancer: analysis and modelling of published literature. _Radiother. Oncol._ 99, 6–11 (2011). Article  PubMed  Google Scholar  * Fenwick, J. D. _ et

al_. Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement. _Clin. Oncol. (R. Coll. Radiol.)_ 21, 343–360 (2009).

Article  CAS  Google Scholar  * van Baardwijk, A. _ et al_. Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III

non-small-cell lung cancer. _J. Clin. Oncol._ 28, 1380–1386 (2010). Article  PubMed  Google Scholar  * Lee, C. B. _ et al_. Late complications of high-dose (>/=66 Gy) thoracic

conformal radiation therapy in combined modality trials in unresectable stage III non-small cell lung cancer. _J. Thorac. Oncol._ 4, 74–79 (2009). Article  PubMed  Google Scholar  * Salama,

J. K. _ et al_. Pulmonary toxicity in stage III non-small cell lung cancer patients treated with high-dose (74 Gy) 3-dimensional conformal thoracic radiotherapy and concurrent chemotherapy

following induction chemotherapy: a secondary analysis of Cancer and Leukemia Group B (CALGB) trial 30105. _Int. J. Radiat. Oncol. Biol. Phys._ 81, e269–274 (2011). Article  PubMed  PubMed

Central  Google Scholar  * Cuzick, J. _ et al_. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. _Cancer Treat Rep._ 71, 15–29 (1987). CAS  PubMed 

Google Scholar  * Rutqvist, L. E., Lax, I., Fornander, T. & Johansson, H. Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary

breast cancer. _Int. J. Radiat. Oncol. Biol. Phys._ 22, 887–896 (1992). Article  CAS  PubMed  Google Scholar  * PORT Meta-analysis Trialists Group. Postoperative radiotherapy in

non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. _Lancet_ 352, 257–263 (1998). * Allen, A. M. _ et al_.

Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. _Int. J. Radiat. Oncol. Biol. Phys._ 65, 640–645 (2006). Article  PubMed  Google Scholar  *

Minami-Shimmyo, Y. _ et al_. Risk factors for treatment-related death associated with chemotherapy and thoracic radiotherapy for lung cancer. _J. Thorac. Oncol._ 7, 177–182 (2012). Article 

CAS  PubMed  Google Scholar  * Bradley, J. D., Wahab, S., Lockett, M. A., Perez, C. A. & Purdy, J. A. Elective nodal failures are uncommon in medically inoperable patients with stage I

non-small-cell lung carcinoma treated with limited radiotherapy fields. _Int. J. Radiat. Oncol. Biol. Phys._ 56, 342–347 (2003). Article  PubMed  Google Scholar  * Yuan, S. _ et al_. A

randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. _Am. J. Clin.

Oncol._ 30, 239–244 (2007). Article  CAS  PubMed  Google Scholar  * Hatton, M. _ et al_. Induction chemotherapy and continuous hyperfractionated accelerated radiotherapy (CHART) for

patients with locally advanced inoperable non-small-cell lung cancer: the MRC INCH randomized trial. _Int. J. Radiat. Oncol. Biol. Phys._ 81, 712–718 (2011). Article  PubMed  Google Scholar

  * Baumann, M. _ et al_. Final results of the randomized phase III CHARTWELL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in

non-small cell lung cancer (NSCLC). _Radiother. Oncol._ 100, 76–85 (2011). Article  CAS  PubMed  Google Scholar  * De Ruysscher, D. _ et al_. Individualised isotoxic accelerated radiotherapy

and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective population-based study. _Radiother. Oncol._ 102, 228–233 (2012). Article 

PubMed  Google Scholar  * Krause, M. _ et al_. Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225

during fractionated irradiation. _Radiother. Oncol._ 76, 162–167 (2005). Article  CAS  PubMed  Google Scholar  * Eriksen, J. G. _ et al_. Molecular profiles as predictive marker for the

effect of overall treatment time of radiotherapy in supraglottic larynx squamous cell carcinomas. _Radiother. Oncol._ 72, 275–282 (2004). Article  CAS  PubMed  Google Scholar  * Koukourakis,

M. I. _ et al_. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2α and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck

cancer patients recruited in the CHART randomized trial. _J. Clin. Oncol._ 24, 727–735 (2006). Article  CAS  PubMed  Google Scholar  * De Ruysscher, D., Nestle, U., Jeraj, R. &

Macmanus, M. PET scans in radiotherapy planning of lung cancer. _Lung Cancer_ 75, 141–145 (2012). Article  PubMed  Google Scholar  * US National Library of Medicine. _Clinicaltrials.gov_

[online], (2012). * Feng, M. _ et al_. Using fluorodeoxyglucose positron emission tomography to assess tumor volume during radiotherapy for non-small-cell lung cancer and its potential

impact on adaptive dose escalation and normal tissue sparing. _Int. J. Radiat. Oncol. Biol. Phys._ 73, 1228–1234 (2009). Article  PubMed  PubMed Central  Google Scholar  * Aerts, H. J. _ et

al_. Identification of residual metabolic-active areas within NSCLC tumours using a pre-radiotherapy FDG–PET–CT scan: a prospective validation. _Lung Cancer_ 75, 73–76 (2012). Article 

PubMed  Google Scholar  * Liao, Z. X. _ et al_. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant

chemoradiotherapy. _Int. J. Radiat. Oncol. Biol. Phys._ 76, 775–781 (2010). Article  PubMed  Google Scholar  * Shumway, D. _ et al_. Pathologic response rates following definitive dose

image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer. _Lung Cancer_ 74, 446–450 (2011). Article  CAS  PubMed  Google Scholar  * Korreman, S., Persson,

G., Nygaard, D., Brink, C. & Juhler-Nøttrup, T. Respiration-correlated image guidance is the most important radiotherapy motion management strategy for most lung cancer patients. _Int.

J. Radiat. Oncol. Biol. Phys._ 83, 1338–1343 (2012). Article  PubMed  Google Scholar  * Giraud, P. _ et al_. Respiratory gating techniques for optimization of lung cancer radiotherapy. _J.

Thorac. Oncol._ 6, 2058–2068 (2011). Article  PubMed  Google Scholar  * Grutters, J. P. _ et al_. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for

non-small cell lung cancer: a meta-analysis. _Radiother. Oncol._ 95, 32–40 (2010). Article  CAS  PubMed  Google Scholar  * Chang, J. Y. _ et al_. Phase 2 study of high-dose proton therapy

with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. _Cancer_ 117, 4707–4713 (2011). Article  CAS  PubMed  Google Scholar  * Ready, N. _ et al_.

Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a

CALGB-stratified phase II trial. _J. Thorac. Oncol._ 5, 1382–1390 (2010). Article  PubMed  Google Scholar  * Nieder, C., Pawinski, A., Dalhaug, A. & Andratschke, N. A review of clinical

trials of cetuximab combined with radiotherapy for non-small cell lung cancer. _Radiat. Oncol._ 7, 3 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hallqvist, A. _ et al_.

Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite—a phase II study from the Swedish Lung Cancer Study Group. _Lung Cancer_

71, 166–172 (2011). Article  CAS  PubMed  Google Scholar  * Mutter, R. _ et al_. A phase II study of celecoxib in combination with paclitaxel, carboplatin, and radiotherapy for patients with

inoperable stage IIIA/B non-small cell lung cancer. _Clin. Cancer Res._ 15, 2158–2165 (2009). Article  CAS  PubMed  Google Scholar  * Lind, J. S., Senan, S. & Smit, E. F. Pulmonary

toxicity after bevacizumab and concurrent thoracic radiotherapy observed in a phase I study for inoperable stage III non-small-cell lung cancer. _J. Clin. Oncol._ 30, e104–108 (2012).

Article  CAS  PubMed  Google Scholar  * Spigel, D. R. _ et al_. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. _J. Clin.

Oncol._ 28, 43–48 (2010). Article  CAS  PubMed  Google Scholar  * Butts, C. _ et al_. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.

_J. Clin. Oncol._ 23, 6674–6681 (2005). Article  CAS  PubMed  Google Scholar  * Butts, C. _ et al_. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer

receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. _J. Cancer Res. Clin. Oncol._ 137, 1337–1342 (2011). Article  CAS  PubMed  Google Scholar  *

US National Library of Medicine. _Clinicaltrials.gov_ [online], (2012). * Curran, W. J. Jr, Schiller, J. H., Wolkin, A. C. & Comis, R. L. Scientific Leadership Council in Lung Cancer of

the Coalition of Cancer Cooperative Groups. Addressing the current challenges of non-small-cell lung cancer clinical trial accrual. _Clin. Lung Cancer_ 9, 222–226 (2008). Article  PubMed 

Google Scholar  * Price, A., Dixon, B., Erridge, S. C., Mohammed, N. GRiN: a trial and tribulation in respiratory radiotherapy research. _Clin. Oncol. (R. Coll. Radiol.)_ 17, 328–331 (2005).

Article  CAS  Google Scholar  * Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the community code relating to medicinal

products for human use. _Off. J. Eur. Union_ 47 (L136), 34–57. * Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. _Science_ 331, 1553–1558 (2011). Article  CAS 

PubMed  Google Scholar  * Berry, D. A. Adaptive clinical trials in oncology. _Nat. Rev. Clin. Oncol._ 9, 199–207 (2012). Article  CAS  Google Scholar  * Strebhardt, K. & Ullrich, A. Paul

Ehrlich's magic bullet concept: 100 years of progress. _Nat. Rev. Cancer_ 8, 473–480 (2008). Article  CAS  PubMed  Google Scholar  * Overgaard, J. Clinical evaluation of

nitroimidazoles as modifiers of hypoxia in solid tumors. _Oncol. Res._ 6, 509–518 (1994). CAS  PubMed  Google Scholar  * Radiotherapy and hyperbaric oxygen. Report of a Medical Research

Council Working Party. _Lancet_ 2, 881–884 (1978). * Medicines and Healthcare products Regulatory Agency. _Clinical trials for medicines: Safety reporting—SUSARs_ [online] (2012). Download

references ACKNOWLEDGEMENTS My thanks to the organizers of the European Cancer Conference in Stockholm, Sweden for inviting me to give the lecture from which this Review arose. I also thank

anonymous peer reviewers for their helpful and stimulating comments, and to the editors at _Nature Review Clinical Oncology_ for their invitation, support, advice and editing skills. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Edinburgh Cancer Centre, NHS Lothian and University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK Allan Price Authors *

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