BALKAN MCO 2011 - E. Vrdoljak - Combined chemoradiotherapy
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BALKAN MCO 2011 - E. Vrdoljak - Combined chemoradiotherapy
- 1. Professor Eduard Vrdoljak, MD PhD Center of Oncology, Clinical Hospital Center Split, Split, Croatia COMBINED CHEMORADIOTHERAPY
- 2. Started with W. Roentgen, machines from 1933 and 1937
- 3. From older radiotherapy (RT) techniques to conformal 3D treatment
- 4. Further technological improvements – way to better results
- 9. Benefits of IGRT: 1. Ensure proper daily alignment of patient - Verify proper targeting of tumors 2. Assess response of tumors during RT course - Adapt treatment to the changing tumor during course of RT IGRT
- 10. 4DCT based respiration-gated RT Radiation beam ‘on’ Treatment beam fixed in space and gated to turn on only when the target (or surrogate signal) comes into the pre-planned area
- 16. RT vs . i nduction c hemotherapy/RT in u nresectable s tage III NSCLC – t he “Dillman” t rial RANDOMI ZED 2 cycles of cisplatin based chemotherapy ( vinblastine 5 mg/m 2 /weekly x5 cisplatin 100 mg/m 2 , days 1, 29 ) followed by RT 60 Gy, starting on day 1 (N=78) RT, TD:60 Gy, (N=77) Total: 155 patients Dillman RO et al. N Engl J Med. 1990;323:940-945.
- 17. RT vs . i nduction c hemotherapy/RT in u nresectable s tage III NSCLC – t he “Dillman” t rial Dillman RO et al. N Engl J Med. 1990;323:940-945. 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0 - Proportion Months 0 10 20 30 40 50 60 70 80 90 155 Total P =.0106 13.74 78 CT/RT 9.56 77 RT only Chi 2 6.5371 Median Survival N Stratum
- 18. RANDOMI ZED CT+RT (n=191 ) cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1-5, d29-33 (PE) and RT to 45 Gy starting day 1 . Than completed RT to 61 Gy with PE X2 CT+RT+Surgery (n=201 ) cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1-5, d29-33 (PE) and RT to 45 Gy starting day 1. than resection if no progression, then PE X2 Total: 392 patients Stage IIIA Concomitant CRT +/- surgery INT 0139/RTOG 9309 Albain KS et al. Lancet 2009;374:379-86 .
- 19. OS 23.6 vs. 22.2 p=0.34 PFS 12.8 vs. 10.5 p=0.0 2 Concomitant CRT +/- surgery INT 0139/RTOG 9309 Albain KS et al. Lancet 2009;374:379-86. Percent Alive Months 0 20 40 60 80 100 0 6 12 18 24 30 36 42 48 CT+RT+Surgery (n=201) CT+RT (n=191 )
- 20. RTOG 94-10 Treatment Schema Curran W et al 2003. Abstract 2499. Am Soc Clin Oncol. Stratify by stage and K P S RANDOMI Z E N = 610 Sequential arm: vinblastine 5 mg/m 2 /weekly x5 cisplatin 100 mg/m 2 , days 1, 29 RT 60 Gy, starting on day 50 Concurrent arm: vinblastine 5 mg/m 2 /weekly x5 cisplatin 100 mg/m 2 , days 1, 29 RT 60 Gy, starting on day 1 Concurrent hyperfractionated arm: oral etoposide 50 mg bid x 10 days on weeks 1, 2, 5, and 6 Cisplatin 50 mg/m 2 , day 1, 8, 29, and 36 RT 69.6 Gy (1.2 Gy bid ) starting day 1
- 21. RTOG 94-10 Median Survival Time Sequential Concurrent Concurrent hyperfractionated 14.6 months 17.0 months 15.2 months Curran W et al. Am Soc Clin Oncol . 2003. Curran W et al 2003. Abstract 2499. Am Soc Clin Oncol. P=0.04
- 22. Co ncomitant or sequential ? Bayman et al. Clin Lung Cancer 2008 Bayman et al. Clin Lung Cancer 2008
- 23. Absolute benefit in OS with co mbined CT: At 2 years: At 3 years: At 5 years: 5.3% 5.7% 4.5% HR= 0.84 [0.74 - 0.95] , p=0.004 Meta - analysis of combined vs. sequential CRT - OS Auperin A et al, J Clin Oncol 2010;28:2181-90 RT + conc CT RT + seq CT Su rvival (%) 0 20 40 60 80 100 Time from randomisation (Years) 0 1 2 3 4 > 5 35.6 23.8 15.1 30.3 18.1 10.6
- 24. Absolute reduction in LRP with co mbined CT : At 1 year: At 2 years: At 3 years: - 4.5% - 5.6% - 6.0% HR=0.77 (95%CI: 0.62-0.95), p=0.01 C umulative i ncidence of l oco-regional p rogression (5 trials) Auperin A et al, J Clin Oncol 2010;28:2181-90 100 Risk of recurrence (%) 0 20 40 60 80 Time from randomisation (Years) 0 1 2 3 4 > 5 19.2 26.1 28.1 23.7 31.7 34.1 RT + conc CT RT + seq CT
- 31. Individualised approach to CT-RT Treatment paradigm applied at VUmc, Amsterdam
- 32. Dose-volume histograms Dose Organ volume Volume of both lungs minus PTV tumo r 66 Gy 20 Gy 0% 100% V 20 = 30% V 20 to predict risk of radiation pneumonitis
- 33. Impact of V 20 on toxicity & survival Gaspar L. 2006 SWOG 0023 analysis V 20 ≤ 35% V 20 >35% Radiation pneumonitis ≥ Grade 3 4 % 10 % Median survival 24 mo 12 mo
- 34. Is consolidation chemotherapy needed ? Concurrent CRT PE: Cisplatin 50 mg/m 2 IV d 1, 8, 29, 36 Etoposide 50 mg/m 2 IV d 1-5, 29-33 RT: 45 Gy (1.8 Gy/fraction) 16 Gy boost (2 Gy/fraction) Consolidation Docetaxel X 3 cycles Median survival 26 months 5-year survival 29% Overall survival Gandara et al JCO 2003;21:2004-10 SWOG S9504
- 36. Comparison of p atient and d isease c haracteristics Study Variable SWOG 9504 HOG 01-24 No. Pts 83 203 Median Age 60 63 Female Pts. 27% 34% PS 0/1 94% 100% Stage IIIB 100% 61% FEV-1 > 2 100% 47% Median survival 26 months 21.1 months
- 37. Induction CT CALGB 39801 Vokes et al. J Clin Oncol 2007 Vokes EE et al. J Clin Oncol 2007;25:1698-704 CTRT CT CTRT p N 161 170 Oesophagitis (grade 3-4) 32% 36% ns Pneumonitis (grade 3-4) 4% 10% ns Median survival 12 months 14 months 0.3 2 year survival 29% 31%
- 38. CALGB 39801: OS by risk factors Stinchcombe TE et al, J Thorac Oncol 2009;4:1117-25 Variable Hazard Ratio 95% CI P-value Weight loss (≥5% vs <5%) 1.92 1.33 to 2.76 <0.01 Hgb (<13 vs ≥ 13) 1.65 1.24 to 2.20 <0.01 Age (≥70 vs <70) 1.45 1.11 to 1.90 0.01 PS (1 vs 0) 1.35 1.06 to 1.71 0.01
- 44. Kelly et al. JCO 2008; 26: 2450-56 Gefitinib maintenance : Consolidation CT SWOG 0023 1% of patients died as a consequence of pneumonitis Kelly K, et al. J Clin Oncol 2008;26: 2450-6. R Docetaxel 75mg/m 2 / 3 w (3 cycles) Cisplatin 50mg/m 2 D1, 8, 29, 36 Etoposide 50 mg/m 2 D1-5, D29-33 RT 61 Gy Gefitinib 500 mg/d 250 mg/d Placebo Gefitinib n = 118 Placebo n = 125 Median survival 23 months 35 months 2 yr survival 46% 59% Deaths 71 54 Cancer deaths 61 (86%) 42 (78%) Toxic deaths after randomisation 2 (2%) 0
- 45. CALBG 30407 – Phase II trial R. Govindan et al JClin Oncol 2008:28 ( May 20 suppl;abstr 7518) Median OS Arm A: 21.2 mo Arm B: 22.4 mo 18 mo OS Arm A: 56% Arm B: 51% Median follow up: 23 mo
- 47. Locally Advanced NSCLC Improving Median OS (Months) Radiation therapy and planning and delivery suportive care 1980 1990 2000 2008 9 13 16 21 Chemotherapy sequential Chemotherapy combined with RT
- 49. Intergroup Study 0096 RANDOMI ZED TD 45 Gy daily fractionated RT 1.8 Gy/25F (with 4 cycles of etoposide and cisplatin) TD 45 Gy of accelerated hyperfractionated RT BID 1.5 Gy/30F (with 4 cycles of etoposide and cisplatin) Total: 407 patients Turrisi et al. NEJM 1999 .
- 50. Turrisi et al. NEJM 1999 .
- 53. The survival at 5 years as a function of the start of any treatment and the end of radiotherapy (SER) De Ruysscher, D. et al. J Clin Oncol 2006 ;24:1057-1063 .
Editor's Notes
- High energy photons (15MeV, 18MeV, etc) may be preferable when used to treat larger GTV’s (gross tumor volumes) surrounded by consolidated and/or atelectic lung tissue, bulky lymphadenopathy or large blood vessels, thus achieving a better dose distribution and also an improved therapeutic ratio.
- Conc>seq but not for all patients Short overall treatment time- reduces risk of repopulation and better for patient convenience
- def. 2 cycles of cisplatin-based CT preceding chest RT improved survival with median survival increased to 14 months and 5-year survival to 17%. Subsequent randomized trials and meta-analyses confirmed these results, and combined therapy is recommended in the ASCO guidelines.
- All received cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1-5, d29-33 (PE) and RT to 45 Gy starting day 1. Arm 1 had resection if no progression (PD), then PE X2; Arm 2 completed RT to 61 Gy with PE X2.
- Neoadjuvantna studija: bolesnici sa stadijem bolesti IIIA: signifikantno bolji PFS, ali ne i OS kada nakon ctrt ide operativni zahvat. Eksplorativne analize pokazuju TREND PREMA POBOLJŠANJU 5-GOD PREŽIVLJENJA.
- In their comparison of sequential versus concurrent chemoradiation, Curran and colleagues studied 595 evaluable patients, using Radiation Therapy Oncology Group (RTOG) protocol 94-10. Patients were randomized to 1 of 3 arms: Sequential—patients received vinblastine 5 mg/m 2 weekly x5; cisplatin 100 mg/m 2 on days 1 and 29; standard radiation therapy (RT) to 60 Gy, starting on day 50 Concurrent/qd—patients underwent chemotherapy as in the sequential arm; standard RT to 60 Gy, starting on day 1 Concurrent hyperfractionated—patients received oral etoposide 50 mg bid x 10 days on weeks 1, 2, 5 and 6; cisplatin 50 mg/m 2 on day 1, 8, 29, and 36; hyperfractionated RT to 69.6 Gy (1.2 Gy bid), starting on day 1 Curran W, Scott C, Langer C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with stage III NSCLC. A report of RTOG 94-10. Presented at: the 39th Annual Meeting of the American Society of Clinical Oncology; May 31-June 3, 2003; Chicago, Ill. Curran W, Scott C, Langer C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. In: Program and abstracts of the 39th Annual Meeting of the American Society of Clinical Oncology; May 31-June 3, 2003; Chicago, Ill. Abstract 2499.
- Curran and colleagues found that median survival was better in concurrent therapy (17.0 months) compared with sequential therapy (14.6 months), P = .046. Curran W, Scott C, Langer C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with stage III NSCLC. A report of RTOG 94-10. Presented at: the 39th Annual Meeting of the American Society of Clinical Oncology; May 31-June 3, 2003; Chicago, Ill.
- Toxicity Increased risk of grades 3 et 4 œsophagitis with conc CTRT HR = 4.9 (CI 95 %: 3.1-7.8 ; p < 0.0001) No increase in risk of acute pneumonitis HR = 0,69 (CI 95 % : 0.42-1.12; p = 0.13) Long term toxicity?
- IFI arm achieved better overall response rate (90% vs. 79%, P = 0.032) and better 5-years local control rate . The radiation pneumonitis rate in patients with IFI was lower than in patients with ENI (17% vs. 29%, P = 0.044), and similar trends appeared in the radiation esophagitis, myelosuppression, and radiation pericarditis between 2 study arms, although not significantly. The 1-, 2-, and 5-year survival rates were 60.4%, 25.6%, and 18.3% for the ENI arm and 69.9%, 39.4%, and 25.1% for the IFI arm, respectively. Only the 2-year survival rates were statistically significant (P = 0.048).
- Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC. Terminated early on the basis of futility after an interim analysis febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel ( v 8.1% in observation arm), and 5.5% died as a result of docetaxel.
- evaluated whether induction chemotherapy before CCRT would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy.
- The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group. PATIENTS AND METHODS: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb. RESULTS: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or <or=1 factor (n = 166). The hazard ratio (HR) for overall survival for the patients with >or=2 versus patients with <or=1 was 1.88 [95% confidence interval (CI), 1.49-2.37; p = <0.0001]; median survival times observed were 9 (95% CI, 8-11) and 18 (95% CI, 16-24) months, respectively. There was no significant difference in survival between treatment arms in patients with >or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or <or=1 factor (HR = 0.97, 95% CI, 0.70-1.35; p = 0.87). CONCLUSIONS: There is no evidence that induction chemotherapy is beneficial in either prognostic group.
- Show CT William Parkinson
- In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.
- Role of RT SCLC is modest because only one third of patients present with localized disease. Concomitant chemoradioterapy is standard of treatment for this group of pts. A meta-analysis of trials comparing chemotherapy alone to chemoradiotherapy reported a modest improvement in survival rates for patients treated with combined-modality therapy. OS after 3 years was 8.9% in the chemotherapy group compared with 14.3% in the combined-modality group. At 2 years, the local failure rate was 23% for irradiated patients and 48% for nonirradiated patients ( P = 0.0001).
- The survival at 5 years as a function of the start of any treatment and the end of radiotherapy (SER). The relative risk for the 5-year survival is significantly in favor of the study arms with the lowest SER ( P = .0003). (B) The survival at 5 years as a function of the timing of the chest radiotherapy. The RR for the 5-year survival is significantly in favor of the study arms with early radiotherapy ( P = .007).