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D. Ball
Moderator of
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OA08 - Targeted Therapies in Brain Metastases (ID 381)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:D. Ball, B. Perin
- Coordinates: 12/05/2016, 16:00 - 17:30, Schubert 1
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- Abstract
- Presentation
Background:
About 10% of non-small cell lung cancer (NSCLC) patients with EGFR mutations will develop leptomeningeal metastasis (LM) either at initial diagnosis or during treatment. LM is a devastating complication of NSCLC associated with poor prognosis. The median overall survival is 4.5-11 months, with ~60% death due to LM or LM together with systemic lesions. However, the underlying mechanisms of the metastasis process are still poorly understood.
Methods:
we performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM at initial diagnosis, and 8 patients developed LM during 1[st] generation EGFR-TKI treatment, while such clinical information was missing for 1 patient.
Results:
The status of EGFR active mutations was the same in the primary tumor and CSF of all the patients, except one whose EGFR mutation was undetectable in the primary site probably due to low sequence coverage. In total, there were 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dual mutation. One patient also had de novo EGFR T790M in the primary site. None of the CSF samples showed EGFR T790M mutation, suggesting that it was not the resistance mechanism for the 8 patients who developed LM during TKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified in primary site and/or CSF of 6 patients. Although with small sample size, this ratio is much higher than what was reported in general EGFR L858R or 19Del positive lung adenocarcinoma patient population (~2% from 4 datasets), implicating that alternations in PI3K pathway may associate with LM risk. Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samples overlapped with those in primary site, suggesting tumor heterogeneity, divergence and clonal evolution during LM development. Moreover, when we cataloged the recurrent CSF-unique somatic genomic alterations existing in >5 patients, we identified genes involved in DNA repair pathway, cell cycle regulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE, CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX).
Conclusion:
In summary, our study has shed light on the genomic variations of LM and paved the way for potential therapeutic approaches to this unmet medical need.
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OA08.02 - Phase II Study of Erlotinib in Advanced Non-Small Cell Lung Cancer Patients with Leptomeningeal Metastasis (LOGIK1101) (ID 5099)
16:10 - 16:20 | Author(s): K. Ota, Y. Shiraishi, T. Harada, D. Himeji, T. Kitazaki, N. Ebi, A. Hamada, T. Yamanaka, K. Nosaki, M. Takenoyama, K. Sugio
- Abstract
- Presentation
Background:
Leptomeningeal metastases (LM) occur in almost 5% of non-small cell lung cancer (NSCLC) patients (pts) and are associated with a poor prognosis. To date, no prospective study has identified active chemotherapy for NSCLC pts with LM. In retrospective studies, EGFR-TKI treatment is reported to be effective in the treatment of LM. We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of erlotinib in pts with LM.
Methods:
NSCLC pts with cytologically confirmed LM were eligible and received erlotinib 150mg daily. Overall cytological response rate (ORR; defined “number of pts who achieves complete remission in CSF / number of all pts”), time to LM progression (TTP), overall survival (OS) and pharmacokinetics were analyzed. Under the null hypothesis, the regimen would be rejected if confirmed ORR was 5% or less. This study was closed because of low accrual with only 21 of required 32 pts (66 %) accrued.
Results:
From Dec 2011 to May 2015, 21 pts (17 pts with EGFR mutation) were enrolled. CSFs available for EGFR mutation analysis (N=17) were all EGFR T790M negative. ORR was 30 % (95%CI 12 -54 %). Median TTP was 2.3 months. Median OS was 3.1 months. Significantly longer TTP and OS were observed in EGFR-mutant than in EGFR-wild type (P=0.0054 and P<0.0001, respectively). Seven pts survived longer than 6 months. CSF penetration rate (Mean + SD) was 3.3 + 0.8 %. There was no correlation between CSF concentration and clinical efficacy.
Conclusion:
Erlotinib treatment for LM is active, especially in EGFR-mutant. Our findings suggest that erlotinib could represent a treatment option for EGFR mutated pts. CSF penetration in LM patients is equivalent to those in previous reports. Table1. Summary of ORR, TPP and OSORR (%) mTTP (M) mOS (M) All (N=20) 30 2.3 3.1 EGFR mutant (N=17) 35 2.7 4.0 EGFR wild (N=3) 0 0.7 0.8 P value (mt vs. wt) - 0.0054 <0.0001
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OA08.03 - MET Copy Number Gain Associates with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR Mutant Lung Cancer (ID 4364)
16:20 - 16:30 | Author(s): S. Yano, S. Nanjo, S. Arai, S. Takeuchi, T. Yamada, Y. Okada, A. Hata, N. Katakami
- Abstract
- Presentation
Background:
Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs frequently in EGFR mutant lung cancer. EGFR-TKIs are generally effective to CNS metastasis in EGFR mutant lung cancer patients who are naïve to TKI treatment. Nevertheless, progression of CNS lesions are frequently observed during EGFR-TKI treatment. Brain metastases are manageable by concomitant use of EGFR-TKI and local intervention, including whole brain irradiation and stereotactic radiotherapy. There is, however, no established therapy for LMC, which is resistant to first and second generation EGFR-TKIs. Therefore, novel and effective therapies need to be developed for managing LMC in EGFR mutant lung cancer patients who become refractory to these EGFR-TKIs. The purpose of this study is to clarify the mechanism of EGFR-TKI resistance in LMC and establish novel therapeutic strategy.
Methods:
We examined EGFR mutations, including T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 LMC and 20 extracranial lesions (e.c., lung metastasis and malignant pleural effusions) of EGFR mutant lung cancer patients who became refractory to EGFR-TKI treatment. To clarify molecular mechanisms of acquired EGFR-TKI resistance in LMC, we utilized in vivo imaging model of LMC with EGFR mutant lung cancer cell line PC-9/ffluc and induced acquired resistance to gefitinib by continuous oral treatment.
Results:
We found that all 32 re-biopsy specimens had the same baseline EGFR mutations and that T790M was less frequent in LMC specimens than extracranial specimens (8% vs 55%). Compared with subcutaneous tumors, T790M was less frequent in LMC which acquired resistance to gefitnib. We further established PC-9/LMC-GR cells from the gefitinib-resistant LMC model and found that PC-9/LMC-GR cells were intermediately resistant to gefitinib and osimertinib (3[rd] generation EGFR-TKI). While EGFR-T790M was negative, MET copy number gain associated MET activation was involved in the gefitinib resistance in PC-9/LMC-GR cells. Moreover, combined use of EGFR-TKI and crizotinib, having inhibitory activity against MET, dramatically regressed LMC which already acquired resistance to gefitinib or osimertinib.
Conclusion:
These findings suggest that combined use of MET inhibitors may be promising for controlling LMC which acquires resistance to EGFR-TKIs including osimertinib.
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OA08.04 - Discussant for OA08.01, OA08.02, OA08.03 (ID 7004)
16:30 - 16:45 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Abstract not provided
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OA08.05 - Efficacy and Cerebrospinal Fluid Concentration of Afatinib in NSCLC Patients with EGFR Mutation Developing Leptomeningeal Carcinomatosis (ID 4210)
16:45 - 16:55 | Author(s): A. Tamiya, M. Tamiya, T. Nishihara, T. Shiroyama, K. Nakao, T. Tsuji, N. Takeuchi, S. Isa, N. Omachi, N. Okamoto, H. Suzuki, A. Iwazaki, K. Imai, T. Hirashima, S. Atagi
- Abstract
- Presentation
Background:
Afatinib (AFA) is an effective treatment in advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutation. However, there were few reports about the cerebrospinal fluid (CSF) penetration rate and the efficacy for central nervous system (CNS) metastasis. Therefore, we conducted the study to evaluate the CSF penetration rate and efficacy of AFA in NSCLC patients harboring EGFR mutation with leptomeningeal carcinomatosis (LC).
Methods:
Eligibility criteria included performance status (PS) 0-3, aged 20 years or older, pathologically proven NSCLC, harboring EGFR mutation, with LC, adequate organ function, and written informed consent. Patients received AFA (40mg/body every day). We analyzed the blood and CSF level of AFA before administrating AFA on the eighth day. The primary endpoint was the CSF penetration rate. Secondary endpoints included objective response rate (ORR), progression free survival (PFS), overall survival (OS), and safety profile.
Results:
A total of 11 patients were enrolled. And we could analyze the blood level in10 patients and the CSF level in 8 patients. Median patients-age was 66 years old. All patients were adenocarcinoma. In EGFR mutation status, 5 patients had exon 19 deletion, 3 had L858R and 3 had minor (exon18) mutation. The patients with PS 2 were 3 patients and PS 3 were 4 patients. Almost all patients received AFA after third-line or more line chemotherapy. The blood level was the Median 88.2 ng/ml (range: 30.4-373), the CSF level was Median 1.4 ng/ml (range: 0.39-2.85) and the CSF penetration rate was Median 1.65% (range: 0.1-9.25). The ORR is 27.3%, and two of three petients with exon 18 mutation showed the partial response. Median OS was 3.8 months (95%CI: 1.1-13.1) and median PFS was 2.0 months (95%CI: 0.6-5.8). Hematological toxicity was mild, however we have to take care of severe diarrhea and skin toxicities, especially in patients with poor PS.
Conclusion:
The median CSF penetration rate (1.65%) of AFA were higher than the penetration rate in previous case report. Although the efficacy for EGFR mutation positive patients with LC was moderate, the promising efficacy for the patient with LC harboring EGFR exon 18 mutation was demonstrated. And we have to take care of diarrhea and skin toxicities, especially in the patients with poor PS.
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OA08.06 - Brigatinib Activity in Patients with ALK+ NSCLC and Intracranial CNS Metastases in Two Clinical Trials (ID 4374)
16:55 - 17:05 | Author(s): S.N. Gettinger, D. Kim, M. Tiseo, C. Langer, M. Ahn, A. Shaw, R. Huber, M.J. Hochmair, S. Kim, L. Bazhenova, K.A. Gold, S. Ou, H. West, W. Reichmann, J. Haney, T. Clackson, F. Haluska, D. Kerstein, D..R. Camidge
- Abstract
- Presentation
Background:
Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).
Methods:
In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.
Results:
In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).
Conclusion:
Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.IRC-Assessed Confirmed Intracranial Response Rates for Patients With Measurable Brain Metastases at Baseline
Any No rad/active[a] Ph1/2[b] n=15 n=9 iORR 8(53) 6(67) iDCR 13(87) 8(89) ALTA[c] Arm A n=26 n=19 iORR 11(42) 8(42) iDCR 22(85) 16(84) Arm B n=18 n=15 iORR 12(67) 11(73) iDCR 15(83) 14(93) Data are n(%) iDCR=intracranial disease control rate iORR=intracranial objective response rate IRC=independent review committee [a]No prior brain radiotherapy (Ph1/2); active (untreated or treated and progressed) brain lesions (ALTA) [b]NCT01449461; last scan date: October 8, 2015 [c]NCT02094573; last scan date: April 14, 2016
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OA08.07 - BRAF-V600E Advanced Lung Adenocarcinoma with Leptomeningeal (LM) Disease Treated with Vemurafenib (ID 4800)
17:05 - 17:15 | Author(s): M.G.O. Fernandes, J.L. Costa, J. Reis, M.G. Jacob, C.S. Moura, J.C. Machado, V. Hespanhol
- Abstract
- Presentation
Background:
BRAF mutations occur in around 3% of non-small cell lung cancers (NSCLC) and V600E accounts for 50%. BRAF V600E is an attractive molecular target for cancer tyrosine kinase treatment, but ideal treatment is still not defined.
Methods:
A case of a patient with BRAF-mutated non–small cell lung cancer (NSCLC) detected by NGS Ion torrent technology who presented with LM disease and was treated with the selective BRAF inhibitor vemurafenib is described.
Results:
58 years old, female, non-smoker, who presented in the emergency department with pericardial effusion. Pericardial fluid cytology confirmed adenocarcinoma TTF1 positive. Multi-organ metastatic disease was diagnosed (bone, lung and thyroid) without EGFR mutation or ALK-EML4 translocation. Four cycles of chemotherapy with pemetrexed and carboplatin were done. She started with refractory headache and vomiting, brain CT and MRI showed no evidence of metastasis, a lumbar puncture confirmed malignant cells in the cerebrospinal fluid. A BRAF V600E was detected by NGS, Ion Torrence PGM technology in the initial tumour sample and in plasma circulating free DNA. An off-label treatment with vemurafenib 960 mg q12hr was offered to the patient, with clinical improvement and radiologic lung stability. At month 2 of treatment, the patient developed respiratory insufficiency with lung infiltrates and Influenza A virus was identified in a nasal swab. Vemurafenib was temporary suspended and re-introduced until 720 mg q12h and maintained until disease progression (large volume pleural effusion with positive cytology), at month 6 of vemurafenib tretament. Third line treatment is being planned.
Conclusion:
The authors highlight the importance of using a multiplex screening strategy to detect targetable mutations in advanced lung cancer patients. The application of next generation sequencing to the tumour and plasma cfDNA allowed the detection of a BRAF-V600E mutation. The improvement of neurologic symptoms and disease control achieved with vemurafenib supports vemurafenib´s efficacy. Care should be taken to the possibility of occurring lung toxicity.
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OA08.08 - Discussant for OA08.05, OA08.06, OA08.07 (ID 7079)
17:15 - 17:30 | Author(s): N. Reinmuth
- Abstract
- Presentation
Abstract not provided
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Author of
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.09 - Serial FDG and FLT PET/CT during Curative-Intent Chemo-Radiotherapy for NSCLC Impacts Patient Management and May Predict Clinical Outcomes (ID 4257)
16:54 - 17:00 | Author(s): D. Ball
- Abstract
- Presentation
Background:
FDG-PET/CT is the gold-standard for non-small cell lung cancer (NSCLC) diagnosis, staging and tumour delineation prior to chemo-radiation therapy (CRT). FDG-PET is superior to CT for subsequent response assessment. Sequential interim metabolic and proliferative tumour response assessment with FDG and 3'-Fluorothymidine (FLT) respectively, prior to and during CRT is novel and may predict outcome.
Methods:
Patients with FDG-PET-stage I-III NSCLC who were prescribed radical chemo-RT (60 Gy in 30 fractions @ 5/wk) were enrolled. FDG and FLT PET/CT scans were performed at baseline and at weeks 2 and 4 of CRT. Intra-treatment tumour response judged by reduction in FDG and FLT uptake was categorised as complete (CR)/partial response (PR), stable (SD) or progressive disease (PD) using EORTC criteria. Overall Survival (OS) and Progression Free Survival (PFS) were measured relative to intra-treatment scan dates and plotted using Kaplan-Meier curves. Univariate Cox regressions were used to calculate associations between 1. SUVmax of baseline FDG and FLT GTV and 2. intra-treatment FDG and FLT response with patient outcomes (OS and PFS).
Results:
Sixty patients were recruited between 2009-13; male 62%; median age 66 years, adenocarcinoma (42%). Two-year OS and PFS were 0.51 and 0.26 respectively. Of 332 PET/CT scans analysed, study scans provided additional information to FDG~BL~ in 21 (35%) patients. Distant metastasis was detected in 3 patients on FLT~BL~ and in 2 patients on FDG/FLT~wk2~ changed treatment intent to palliative. Loco-regional progression during RT was observed in 5 (8%) patients, prompting larger RT fields. FLT~wk2~ response (SD vs CR/PR vs PD) was associated with OS [HR (95%CI) 1 vs 2.02 (0.87, 4.65) vs 20.09 (4, 114), p=0.012] and PFS [1 vs 2.01 (0.92,4.37) vs 32.41 (3,348), p=0.024]. Associations between the baseline FDG and FLT SUV~max ~and patient outcomes were not significant, including OS where FDG SUVmax HR [95% CI] was 1.04 [0.98, 1.10], p=0.25 and FLT SUVmax HR [95% CI] was 1.07 [0.93, 1.22], p=0.33.
Conclusion:
Tumour response on FLT~wk2~ was associated with OS and PFS. The possible association between worse clinical outcomes and early suppression of FLT uptake during CRT may be a result of repair of tumour DNA damage. Baseline FLT, FLT~wk2~ and FDG~wk2~ detected rapid distant and loco-regional progression in 10 (17%) patients prompting changes in treatment intent and RT fields.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-001 - Psychological Intervention to Treat Distress and Suffering Experienced by People with Lung Cancer Nearing the End-Of-Life (ID 5973)
14:30 - 14:30 | Author(s): D. Ball
- Abstract
Background:
Despite advances in medical interventions, lung cancer continues to be associated with a poor prognosis with approximately 16% of people with lung cancer living five years post diagnosis. This poor prognosis can contribute to depression, anxiety, death anxiety and existential concerns and fears relating to meaning and purpose of life. There is a growing body of evidence indicating that behavioural and psycho-educational interventions are efficacious in treating depression and anxiety in lung cancer patients, however, little is known about how to psychologically treat suffering and distress nearer to the end-of-life.
Methods:
A comprehensive search using PsycINFO and Medline was undertaken to identify existential and meaning centered psychotherapies that were used towards the end-of-life with people with cancer. As the research in the area is in its infancy, all quantitative study designs and qualitative studies were included. Studies that focused on physical symptom management, dyads and bereavement interventions, measurement of psychological distress or existential concerns were excluded.
Results:
The search yielded a total of 62 articles, of which only 34 examined the use of psychotherapies towards the end-of-life care of people with cancer. The majority of these studies were focused on women with breast cancer, used different outcome measures and included very few, if any, participants with lung cancer. These studies identified and described at least 14 novel psychotherapeutic interventions that could be used towards the end-of-life. These interventions included: Legacy Activities, Life Review Therapy, Meaning-Centred Group Psychotherapy, Individual Meaning-Centred Psychotherapy, Dignity Therapy, Forgiveness Therapy, Meaning-Making Psychotherapy, Outlook Psychotherapy, Supportive Group Interventions, The Healing Journey Intervention, Cognitive Existential Interventions, Re-creating Your Life Therapy, Mindfulness Interventions and Managing Cancer and Living Meaningfully. These interventions varied in the number of sessions and the level of training required to administer the interventions. Some of these interventions were manualized and others were less structured in their approach. Some of these interventions show potential in alleviating distress and suffering, improving life satisfaction, self-esteem and mood.
Conclusion:
There are only a small number of studies that evaluate the efficacy of psychotherapeutic interventions to be used with people with advanced cancer towards the end-of-life. Although results are promising it is difficult to conclude that one intervention is better than another. Further research is required to trial and adapts these interventions for use with people with lung cancer towards the end-of-life.
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PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:P.A. Bunn, Jr., T. Mok
- Coordinates: 12/07/2016, 16:00 - 18:00, Hall C1
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PL05.03 - Radio-Oncology (ID 6916)
16:40 - 16:55 | Author(s): D. Ball
- Abstract
- Presentation
Abstract:
When I commenced training in radiation oncology in 1973, there were no CT scanners, calculations were done with slide rules, and chemotherapy, let alone combined modality therapy, had no established role in the treatment of non-small cell lung cancer. An influential trial published in the Lancet in 1971(1) had shown no difference in survival whether patients were randomized to radiotherapy, chemotherapy, a combination of the two or a policy of wait-and–see. Yet within 30 years, the standard of care for patients with inoperable lung cancer being treated for cure, both small cell and non-small cell, had, ironically, become, and remains, concomitant chemotherapy and radiotherapy. The outlook for patients generally regarded as incurable at the outset of my career is that up to one in three selected patients can now expect to live five years as a result of chemoradiation. Patients with stage I non-small cell lung cancer can have their cancer successfully ablated by non-invasive stereotactic radiotherapy in 90% of cases. The developments which led to these changes can be grouped according to three main themes: the impact of the computer revolution; a better understanding of the natural history and biology of the disease, and the introduction of mutimodality therapy. The computer revolution: imaging, treatment planning and delivery Better identification and delineation of the tumor are critical to the success of radiotherapy, in particular avoidance of the catastrophic “geographic miss”. Without computers, the CT and hybrid PET/CT scanners could not have been possible. These dramatically improved the accuracy of staging as well as providing 3D information on the relationship of the soft tissue target to the nearby dose-limiting organs at risk. As computing power increased it became possible to create 4D images of moving tumours, and to image the target with on-board CT scanners attached to the linac immediately before treatment, so making image guided stereotactic ablative radiotherapy possible. Powerful computerised treatment planning systems are now able to create complex dose distributions conforming to the irregularities of any target volume, and to provide dose-volume metrics predictive of risks of normal tissue damage. Improved understanding of the natural history and biology of the disease The recognition that the central nervous system is a sanctuary site which can harbour metastatic disease leading to treatment failure in spite of successful chemotherapeutic eradication of extracranial disease, particularly in small cell lung cancer, led to the introduction of prophylactic cranial irradiation. The British study of continuous hyperfractionated accelerated radiotherapy (CHART) which was given over 12 days to patients with inoperable non-small cell lung cancer resulted in better survival than treatment given over six weeks, even though the total dose was lower. This trial provided clinical support for the notion of treatment induced accelerated repopulation, and reinforced the principle that total treatment times should be kept short in both small cell and non-small cell lung cancer, both when radiotherapy is used alone, and when in combination with chemotherapy. Multimodality therapy The limitations of single modality therapy for a disease with a high propensity for developing genetically determined resistance have long been recognised, and have stimulated the development of strategies simultaneously employing non-cross resistant therapies to maximise tumor cell kill, in line with the principles espoused by Goldie and Coldman.(2) The use of concomitant platinum based chemotherapy with high dose radiotherapy is now well established by meta analysis as improving survival of both non-small cell and small cell lung cancers, but it is also more toxic. Amelioration of these toxicities represents a major challenge for the future. Future directions It is likely that the technical progress in radiation treatment planning and delivery is close to a plateau, and that future progress will depend more on understanding the biology of the disease and its response, and that of the normal tissues, to radiation damage. Biomarkers of response and toxicity, so spectacularly harnessed to advantage by our medical oncology colleagues, are desperately needed to tailor the radiotherapy prescription to the needs of each individual and their cancer. Finally, it is evident that in many jurisdictions, including industrialised wealthy nations, that many patients are either receiving substandard radiotherapy that might increase their chances of cure, or are not receiving treatment at all.(3) Unless these problems can be addressed, the benefits of the remarkable advances in technology and biology documented above will shamefully be restricted to only a fraction of those afflicted with locoregional disease. 1. Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971;1(7702):715-9. 2. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep. 1982;66(3):439-49. 3. Vinod SK. International patterns of radiotherapy practice for non-small cell lung cancer. Semin Radiat Oncol. 2015;25(2):143-50.
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