- Email: [email protected]
157 Mortality rates after palliative radiotherapy for lung cancer from a single UK radiotherapy centre
Posters, 10th Annual British Thoracic Oncology Group Conference, 2012: Radiotherapy were cisplatin-vinorelbine (63%) and cisplatin-etoposide (26%). Eight (23%) routinely administer induction, 11 (31%) consolidation and five (14%) induction and consolidation chemotherapy. Nine (26%) centres indicated concerns in treating patients >75 years with cCTRT. Of those not offering cCTRT, common reasons were fear of toxicity (n = 6) and lack of evidence/preference of CHART (n = 4). Of all responding UKCC, nine (20%) have access to intensity-modulated radiotherapy. Concerning future clinical trials, 16 (36%) indicated interest in a phase III study of sequential versus cCTRT in the elderly, 23 (52%) a phase III study of 66 Gy/33# versus 55 Gy/20# in cCTRT and 17 (39%) a multi-arm phase II study of experimental regimen. Conclusions: A large proportion of UKCC now treat good PS, LANSCLC with cCTRT. However, there is substantial variability in treatment regimen and concerns remain regarding toxicity and efficacy; this is reflected by the considerable interest in further phase II/III trials. 155 Effect of radiation dose in consolidation radiotherapy for advanced/metastatic non small cell lung cancer H. Eldeeb *, C. Mak, P. Camilleri, A. Siddiqui. Northampton General Hospital, Northampton, UK Introduction: This is a retrospective study to assess the influence of consolidation radiotherapy dose following palliative chemotherapy in patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) who are not suitable for radical treatment. Method: This review included 41 patients treated at Northamptonshire Centre for Oncology during the period of January 2005 December 2010. Patients included in the review must have received at least more than one cycle of chemotherapy without evidence of progression. They were categorized to two groups. Group I (19) those who had adjuvant (early) radiotherapy 20 Gy/5 fractions. Group II (22) has no early radiotherapy. Results: Group I included 12 males and 7 females with an average age of 61. Group II included 10 males and 12 females with an average age of 60. Both groups had average PS 1. Stage: Group I included 4 stage IIIB and 15 stage IV. Group II included 3 stage IIIB and 19 stage IV. Histology: Group I included 4 SCC, 7 adenocarcinoma and 8 unspecified NSCLC. Group II included 11 SCC, 10 adenocarcinoma and 1 unspecified NSCLC. Chemotherapy: In Group I, 4 patients received second line. In Group II, 8 patients received second line and 1 patient received third line chemotherapy in both groups. Radiotherapy was given in a dose of 20 Gy over 5 fractions. Survival: The median overall survival for Group I was 318 days while it was 448 days in Group II. P value 0.69. Conclusions: Consolidation radiotherapy with 20 Gy/5 fractions does not seem to improve overall survival in contrast to our previous presented data where consolidation radiotherapy dose with 36 Gy/ 12 fractions has already shown a very good survival advantage in selected group of advanced/metastatic NSCLC. 156 The I-START trial: ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer J.F. Lester2 *, L. Nixon1 , P. Mayles3 , H. Mayles3 , Y. Tsang4 , A. Ionescu5 , N. Courtier1 , A. Nahum3 , J. Fenwick6 , C. Eswar3 , Z. Malik3 , N. Mohammed7 , G. Griffiths1 . 1 Cardiff University, Cardiff, UK, 2 Velindre Cancer Centre, Cardiff, UK, 3 Clatterbridge Centre for Oncology, Liverpool, UK, 4 Mount Vernon Hospital, Northwood, London, UK, 5 Royal Gwent Hospital, Newport, UK, 6 Oxford University, Oxford, UK, 7 Beatson West of Scotland Cancer Centre, Glasgow, UK Introduction: I-START is a phase I/II trial of isotoxic radiotherapy (20 daily fractions) in the treatment of patients with non-small cell lung cancer (NSCLC).
S51
Many patients are precluded from receiving concurrent chemoradiotherapy due to tumour and patient-related factors, but remain suitable for radical radiotherapy (RT). Evidence suggests that increasing the dose of RT may improve both local control of cancer and survival. The RT dose is limited by local normal structures, however the safe limit is not known for the oesophagus. The objectives of I-START are to establish the oesophageal RT dose limits and to investigate whether a novel “isotoxic” approach to individualised dose escalation is feasible and effective. Method: Patients with stage II to IIIb NSCLC suitable for radical RT are eligible. All participants will receive 20 fractions of RT over 4 weeks. Phase I will establish the maximum tolerated dose (MTD) of RT to the oesophagus in patients where the oesophagus lies within the Planning Treatment Volume (PTV). The Phase I will be stratified depending on the length of the oesophagus lying within the PTV (Group 1A, 6.5 cm; Group 1B, >6.5 cm). Cohorts of 6 or 12 patients will be allocated an increasing dose until MTD is reached. Progression to the next dose level depends on toxicity occurring up to 2 months after RT. Phase II will determine toxicity rate (grade 3 or 4) at 3 months. In patients where the oesophagus lies outside the PTV, the prescription dose for each patient will be individualised up to a 65 Gy maximum (in 20 fractions) in order to make the radiation pneumonitis risk the same for all patients. Results: I-START is open to recruitment in one centre and in set-up in a further 16 RT centres. Conclusions: If this novel method of increasing the RT dose for NSCLC patients is tolerable, safe and effective this may be compared against the best currently available standard treatment in a future larger randomised (Phase III) trial. I-START is funded by Cancer Research UK (C25518/A11535) and sponsored by Velindre NHS Trust. JL is supported by NISCHR AHSC. 157 Mortality rates after palliative radiotherapy for lung cancer from a single UK radiotherapy centre K. Gupta *, C. Faivre-Finn, P. Burt, J. Coote, A. Chittalia, M. Harris, H. Lander, L. Lee, L. Pemberton, H. Sheikh, P. Higham, N. Bayman. The Christie Hospital, Manchester, UK Introduction: Patients with metastatic lung cancer have a poor prognosis. Palliative radiotherapy is sometimes given for symptom control. Toxicity from palliative radiotherapy can in some cases continue for several weeks after treatment, and symptomatic benefit is often not noticed by patients until toxicity has resolved. To assess proportion of lung cancer patients living long enough to benefit from treatment, this study measures 14 and 30 day mortality after palliative radiotherapy. Method: Patient records and case notes were retrospectively reviewed and data recorded for all lung cancer patients receiving palliative radiotherapy in July-September 2010 at The Christie. Results: Of the 75 patients who received palliative radiotherapy for lung cancer, 62 had non-small cell (NSCLC) (74% stage IV), 4 had small-cell (SCLC) and 9 had no histological confirmation. Median age was 71 years (range 42 92 years). Most common sites for radiotherapy were lung (n = 43), bone (n = 14), brain (n = 5), and skin/soft tissue (n = 4). Median time to death (MTD) from start of radiotherapy was 73 days (2 413 days). 14 and 30 day mortality was 11% (n = 8) and 25% (n = 18) respectively. MTD from start of radiotherapy for WHO performance status (PS) 0 2 patients (n = 39) was 128 days and MTD for WHO PS 3 4 patients (n = 21) was 33 days. WHO PS was not recorded for 15 patients. Patients with 0 or 1 metastatic site had MTD of 88 days and patients with 2 metastatic sites had MTD of 41 days. MTD for patients receiving palliative thoracic radiotherapy was 44, 67 and 126 days for 1, 4 and 8 fraction regimens respectively.
S52
Posters, 10th Annual British Thoracic Oncology Group Conference, 2012: Radiotherapy
Conclusions: This study indicates that a significant proportion of lung cancer patients are likely to have died too soon after palliative radiotherapy to benefit from treatment. Future studies are required to determine predictive factors of benefit from palliative radiotherapy for lung cancer to help inform these complex treatment decisions. 158 Prophylactic cranial irradiation in lung cancer: a single institution experience J. Naidoo1 *, M. Kehoe1 , D. Hacking1 , W. Sasiadek1 , P. Calvert1 . 1 Waterford Regional Hospital, Waterford, Ireland, 2 UPMC, The Whitfield Clinic, Waterford, Ireland Introduction: Prophylactic cranial irradiation (PCI) is a treatment modality used to prevent the development of brain metastases in small cell lung carcinoma. Randomized phase III studies have demonstrated an overall survival benefit in limited and extensive stage disease. The aim of this study was to analyze the incidence of symptomatic brain metastases, overall survival and progression-free survival after PCI, in a single institution over a five year period. Method: We conducted a retrospective search of all patients who had received PCI between October 2006 and October 2011 at the Whitfield Clinic, the radiation oncology facility linked to our institution. Patient and disease-related characteristics, the subsequent development of brain metastases, progression-free survival, and overall survival data was collected. Results: 24 patients received PCI in a 5 year period in our institution. 58.3% of patients were male and 41.7% were female, with a mean age of 62.5 years (range 31 78) and a standard deviation of 9.96. All patients were smokers. 50% of patients had limited stage small cell lung cancer and 50% had extensive stage small cell lung cancer. No patients with extrapulmonary small cell carcinoma or non-small cell lung cancer received PCI. 8.2% of the patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage disease was 13 months (range 3 20) and 10 months (range 5 18) for extensive stage disease. Median OS was 15 months (range 4 29) for limited stage disease and 11 months (range 5 29) for extensive stage disease. Conclusions: PCI is a treatment modality used in limited and extensive stage small cell lung carcinoma. Our study demonstrated a reduced incidence of symptomatic brain metastases and an improvement in median PFS and median OS, in keeping with published phase III data. PCI in non-small cell lung cancer and extrapulmonary small cell carcinoma remains controversial. 159 Quality of life after treatment for brain metastases: An update on the QUARTZ trial one year on from an interim data release P. Mulvenna1 *, R. Barton2 , P. Wilson3 , C. Faivre-Finn4 , C. Pugh5 , M. Nankivell5 , R. Langley5 . 1 Northern Centre for Cancer Care, Newcastle, UK, 2 The Queen’s Centre for Oncology and Haematology, Castle Hill hospital, Hull, UK, 3 Bristol Haematology and Oncology Centre, Bristol, UK, 4 The Christie, Manchester, UK, 5 MRC Clinical Trials Unit, London, UK Introduction: The MRC QUARTZ trial assesses the value of whole brain radiotherapy (WBRT) for patients with inoperable brain metastases from non-small cell lung cancer. In this non-inferiority trial, all patients receive optimal supportive care (OSC) including treatment with steroids, and are randomised to receive WBRT or not. QUARTZ is a challenging trial to recruit patients to for many reasons, and in order to provide investigators with some randomised comparisons that may help with trial discussions; a release of interim data was undertaken in October 2010. Method: Results from the first 151 QUARTZ patients were first presented at a meeting of trial investigators, and were subsequently presented at several national conferences.
Results: The interim data provided no strong evidence that omitting WBRT was detrimental to patients. All baseline characteristics were well balanced and there were no clear differences in terms of side effects of steroid usage. The primary endpoint of quality adjusted life years was 31 days in the OSC+WBRT group, and 30 days in the OSC alone group. Overall survival was 49 days in the OSC+WBRT group, and 51 days in the OSC alone group (HR = 1.11, 95% CI (0.80, 1.53), p-value = 0.542). Following the interim data release, recruitment has slightly improved. In the first 9 months of 2011, 76 patients were entered, compared to 62 over the same period in 2010. Total trial recruitment has reached 305 patients of the required 534, and accrual will continue until the end of 2013. Conclusions: Releasing interim results seems to have had a positive effect on recruitment in this trial. They should re-assure clinicians and potential trial patients that omitting WBRT is not clearly detrimental. QUARTZ is a very important trial that still requires more patients to fully investigate how best to treat this poor prognosis group. 160 The impact of age and performance status on outcome of brain metastases in non-small cell lung cancer (NSCLC) E. Larbi1,3 *, G. Middleton1,2 , T. Partridge-James2 , S. Quirin3 , V. Hardacre3 , C. Broadbanks4 , L. Dennis4 , S. Russell1 , C. Davies1 , M. Illsley1 , V. Ezhil1,4 . 1 St Luke’s Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey, UK, 2 Frimley Park Hospital, Camberley, Surrey, UK, 3 East Surrey Hospital, Redhill, Surrey, UK, 4 St Peter’s Hospital, Chertsey, Surrey, UK Introduction: While surgery is recommended for solitary brain metastasis with controlled primary disease, the role of whole brain radiotherapy (WBRT) for multiple metastases is debatable. Interim analysis of data from the MRC QUARTZ clinical trial suggests similar outcomes for optimal supportive care (OSC) alone and WBRT. Objective: To evaluate the impact of age and performance status (PS) on outcome for NSCLC patients with brain metastases. Method: Prospective analysis of 34 patients from the SWSH cancer network with brain metastases between April and September 2010 was performed. Age, histology, previous treatment, PS, clinical symptoms, brain imaging, number of metastases, treatment, steroid requirement, and clinical response were recorded. Recursive partitioning analysis (RPA) was performed. All patients received steroids and OSC. Survival analysis was performed using Graph Pad Prism Software. Results: 73.5% had brain metastases at presentation. The mean age was 67.2 years and the commonest histology, adenocarcinoma (55.9%). A fifth (20.6%) had previously received radical treatment. Neurological deficits were present in 38.2%. PS was 0 1 in 47.1%. In 20.6%, brain metastases were solitary on magnetic resonance imaging (MRI). Management was neurosurgery and WBRT (S+WBRT) (20.6%), WBRT (58.8%), and OSC alone (20.6%). Of those who had WBRT, 88.9% received 20 Gray/5 fractions. Median survival (MS) for all patients was 3.8 months. With S+WBRT, WBRT, and OSC alone, MS was 11.4, 3.3, and 1.5 months respectively (p < 0.0001). In the WBRT group, MS by PS was 8.2 (PS0/1) and 2.3 months (PS2/3) (p = 0.608), and by age, 4.5 (<65 years) and 3.3 months (>65 years) (p = 0.2754). Conclusions: In this study, we demonstrate a strong trend of superior survival in patients of good PS receiving WBRT. PS may be a clinically useful predictive tool in selecting patients for WBRT over OSC alone as the optimal paradigm of care. Outcomes for patients receiving neurosurgery in this series were equivalent to those treated at stage IV without brain metastases.
S51
Many patients are precluded from receiving concurrent chemoradiotherapy due to tumour and patient-related factors, but remain suitable for radical radiotherapy (RT). Evidence suggests that increasing the dose of RT may improve both local control of cancer and survival. The RT dose is limited by local normal structures, however the safe limit is not known for the oesophagus. The objectives of I-START are to establish the oesophageal RT dose limits and to investigate whether a novel “isotoxic” approach to individualised dose escalation is feasible and effective. Method: Patients with stage II to IIIb NSCLC suitable for radical RT are eligible. All participants will receive 20 fractions of RT over 4 weeks. Phase I will establish the maximum tolerated dose (MTD) of RT to the oesophagus in patients where the oesophagus lies within the Planning Treatment Volume (PTV). The Phase I will be stratified depending on the length of the oesophagus lying within the PTV (Group 1A, 6.5 cm; Group 1B, >6.5 cm). Cohorts of 6 or 12 patients will be allocated an increasing dose until MTD is reached. Progression to the next dose level depends on toxicity occurring up to 2 months after RT. Phase II will determine toxicity rate (grade 3 or 4) at 3 months. In patients where the oesophagus lies outside the PTV, the prescription dose for each patient will be individualised up to a 65 Gy maximum (in 20 fractions) in order to make the radiation pneumonitis risk the same for all patients. Results: I-START is open to recruitment in one centre and in set-up in a further 16 RT centres. Conclusions: If this novel method of increasing the RT dose for NSCLC patients is tolerable, safe and effective this may be compared against the best currently available standard treatment in a future larger randomised (Phase III) trial. I-START is funded by Cancer Research UK (C25518/A11535) and sponsored by Velindre NHS Trust. JL is supported by NISCHR AHSC. 157 Mortality rates after palliative radiotherapy for lung cancer from a single UK radiotherapy centre K. Gupta *, C. Faivre-Finn, P. Burt, J. Coote, A. Chittalia, M. Harris, H. Lander, L. Lee, L. Pemberton, H. Sheikh, P. Higham, N. Bayman. The Christie Hospital, Manchester, UK Introduction: Patients with metastatic lung cancer have a poor prognosis. Palliative radiotherapy is sometimes given for symptom control. Toxicity from palliative radiotherapy can in some cases continue for several weeks after treatment, and symptomatic benefit is often not noticed by patients until toxicity has resolved. To assess proportion of lung cancer patients living long enough to benefit from treatment, this study measures 14 and 30 day mortality after palliative radiotherapy. Method: Patient records and case notes were retrospectively reviewed and data recorded for all lung cancer patients receiving palliative radiotherapy in July-September 2010 at The Christie. Results: Of the 75 patients who received palliative radiotherapy for lung cancer, 62 had non-small cell (NSCLC) (74% stage IV), 4 had small-cell (SCLC) and 9 had no histological confirmation. Median age was 71 years (range 42 92 years). Most common sites for radiotherapy were lung (n = 43), bone (n = 14), brain (n = 5), and skin/soft tissue (n = 4). Median time to death (MTD) from start of radiotherapy was 73 days (2 413 days). 14 and 30 day mortality was 11% (n = 8) and 25% (n = 18) respectively. MTD from start of radiotherapy for WHO performance status (PS) 0 2 patients (n = 39) was 128 days and MTD for WHO PS 3 4 patients (n = 21) was 33 days. WHO PS was not recorded for 15 patients. Patients with 0 or 1 metastatic site had MTD of 88 days and patients with 2 metastatic sites had MTD of 41 days. MTD for patients receiving palliative thoracic radiotherapy was 44, 67 and 126 days for 1, 4 and 8 fraction regimens respectively.
S52
Posters, 10th Annual British Thoracic Oncology Group Conference, 2012: Radiotherapy
Conclusions: This study indicates that a significant proportion of lung cancer patients are likely to have died too soon after palliative radiotherapy to benefit from treatment. Future studies are required to determine predictive factors of benefit from palliative radiotherapy for lung cancer to help inform these complex treatment decisions. 158 Prophylactic cranial irradiation in lung cancer: a single institution experience J. Naidoo1 *, M. Kehoe1 , D. Hacking1 , W. Sasiadek1 , P. Calvert1 . 1 Waterford Regional Hospital, Waterford, Ireland, 2 UPMC, The Whitfield Clinic, Waterford, Ireland Introduction: Prophylactic cranial irradiation (PCI) is a treatment modality used to prevent the development of brain metastases in small cell lung carcinoma. Randomized phase III studies have demonstrated an overall survival benefit in limited and extensive stage disease. The aim of this study was to analyze the incidence of symptomatic brain metastases, overall survival and progression-free survival after PCI, in a single institution over a five year period. Method: We conducted a retrospective search of all patients who had received PCI between October 2006 and October 2011 at the Whitfield Clinic, the radiation oncology facility linked to our institution. Patient and disease-related characteristics, the subsequent development of brain metastases, progression-free survival, and overall survival data was collected. Results: 24 patients received PCI in a 5 year period in our institution. 58.3% of patients were male and 41.7% were female, with a mean age of 62.5 years (range 31 78) and a standard deviation of 9.96. All patients were smokers. 50% of patients had limited stage small cell lung cancer and 50% had extensive stage small cell lung cancer. No patients with extrapulmonary small cell carcinoma or non-small cell lung cancer received PCI. 8.2% of the patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage disease was 13 months (range 3 20) and 10 months (range 5 18) for extensive stage disease. Median OS was 15 months (range 4 29) for limited stage disease and 11 months (range 5 29) for extensive stage disease. Conclusions: PCI is a treatment modality used in limited and extensive stage small cell lung carcinoma. Our study demonstrated a reduced incidence of symptomatic brain metastases and an improvement in median PFS and median OS, in keeping with published phase III data. PCI in non-small cell lung cancer and extrapulmonary small cell carcinoma remains controversial. 159 Quality of life after treatment for brain metastases: An update on the QUARTZ trial one year on from an interim data release P. Mulvenna1 *, R. Barton2 , P. Wilson3 , C. Faivre-Finn4 , C. Pugh5 , M. Nankivell5 , R. Langley5 . 1 Northern Centre for Cancer Care, Newcastle, UK, 2 The Queen’s Centre for Oncology and Haematology, Castle Hill hospital, Hull, UK, 3 Bristol Haematology and Oncology Centre, Bristol, UK, 4 The Christie, Manchester, UK, 5 MRC Clinical Trials Unit, London, UK Introduction: The MRC QUARTZ trial assesses the value of whole brain radiotherapy (WBRT) for patients with inoperable brain metastases from non-small cell lung cancer. In this non-inferiority trial, all patients receive optimal supportive care (OSC) including treatment with steroids, and are randomised to receive WBRT or not. QUARTZ is a challenging trial to recruit patients to for many reasons, and in order to provide investigators with some randomised comparisons that may help with trial discussions; a release of interim data was undertaken in October 2010. Method: Results from the first 151 QUARTZ patients were first presented at a meeting of trial investigators, and were subsequently presented at several national conferences.
Results: The interim data provided no strong evidence that omitting WBRT was detrimental to patients. All baseline characteristics were well balanced and there were no clear differences in terms of side effects of steroid usage. The primary endpoint of quality adjusted life years was 31 days in the OSC+WBRT group, and 30 days in the OSC alone group. Overall survival was 49 days in the OSC+WBRT group, and 51 days in the OSC alone group (HR = 1.11, 95% CI (0.80, 1.53), p-value = 0.542). Following the interim data release, recruitment has slightly improved. In the first 9 months of 2011, 76 patients were entered, compared to 62 over the same period in 2010. Total trial recruitment has reached 305 patients of the required 534, and accrual will continue until the end of 2013. Conclusions: Releasing interim results seems to have had a positive effect on recruitment in this trial. They should re-assure clinicians and potential trial patients that omitting WBRT is not clearly detrimental. QUARTZ is a very important trial that still requires more patients to fully investigate how best to treat this poor prognosis group. 160 The impact of age and performance status on outcome of brain metastases in non-small cell lung cancer (NSCLC) E. Larbi1,3 *, G. Middleton1,2 , T. Partridge-James2 , S. Quirin3 , V. Hardacre3 , C. Broadbanks4 , L. Dennis4 , S. Russell1 , C. Davies1 , M. Illsley1 , V. Ezhil1,4 . 1 St Luke’s Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey, UK, 2 Frimley Park Hospital, Camberley, Surrey, UK, 3 East Surrey Hospital, Redhill, Surrey, UK, 4 St Peter’s Hospital, Chertsey, Surrey, UK Introduction: While surgery is recommended for solitary brain metastasis with controlled primary disease, the role of whole brain radiotherapy (WBRT) for multiple metastases is debatable. Interim analysis of data from the MRC QUARTZ clinical trial suggests similar outcomes for optimal supportive care (OSC) alone and WBRT. Objective: To evaluate the impact of age and performance status (PS) on outcome for NSCLC patients with brain metastases. Method: Prospective analysis of 34 patients from the SWSH cancer network with brain metastases between April and September 2010 was performed. Age, histology, previous treatment, PS, clinical symptoms, brain imaging, number of metastases, treatment, steroid requirement, and clinical response were recorded. Recursive partitioning analysis (RPA) was performed. All patients received steroids and OSC. Survival analysis was performed using Graph Pad Prism Software. Results: 73.5% had brain metastases at presentation. The mean age was 67.2 years and the commonest histology, adenocarcinoma (55.9%). A fifth (20.6%) had previously received radical treatment. Neurological deficits were present in 38.2%. PS was 0 1 in 47.1%. In 20.6%, brain metastases were solitary on magnetic resonance imaging (MRI). Management was neurosurgery and WBRT (S+WBRT) (20.6%), WBRT (58.8%), and OSC alone (20.6%). Of those who had WBRT, 88.9% received 20 Gray/5 fractions. Median survival (MS) for all patients was 3.8 months. With S+WBRT, WBRT, and OSC alone, MS was 11.4, 3.3, and 1.5 months respectively (p < 0.0001). In the WBRT group, MS by PS was 8.2 (PS0/1) and 2.3 months (PS2/3) (p = 0.608), and by age, 4.5 (<65 years) and 3.3 months (>65 years) (p = 0.2754). Conclusions: In this study, we demonstrate a strong trend of superior survival in patients of good PS receiving WBRT. PS may be a clinically useful predictive tool in selecting patients for WBRT over OSC alone as the optimal paradigm of care. Outcomes for patients receiving neurosurgery in this series were equivalent to those treated at stage IV without brain metastases.