Radiation Oncology/NSCLC/Locally Advanced Unresectable/Induction-Chemo RT

• First benefit of chemotherapy in addition to RT was established by CALGB 8433 published in 1990 (Dillman)
• Overall, there appears to be a modest survival benefit with induction chemo followed by RT, in patients with good performance status and no weight loss.
• There is a significantly higher proportion of long term survivors and improved distal failure-free survival, but essentially no impact on local recurrence

• CALGB 30105 -- Induction and concurrent carboplatin/paclitaxel vs. carboplatin/gemcitabine, RT 74 Gy
  • Randomized Phase II. Closed prematurely after Arm 2 had high Grade 4-5 pulmonary toxicity. 69 patients. Stage IIIA-B NSCLC. Arm 1) Induction carboplatin AUC 6 + paclitaxel 225 mg/m2 followed by concurrent RT 74 Gy + carboplatin AUC 2 + paclitaxel 45 mg/m2 vs. Arm 2) carboplatin AUC 5 + gemcitabine 1000 mg/m2
  • 2008 PMID 18487565 -- "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." (Socinski MA, J Clin Oncol. 2008 May 20;26(15):2457-63.)
    • Outcome: median OS carbo/taxol 2.0 years vs. carbo/gem 1.0 year; 1-year OS 67% vs. 50%
    • Toxicity: grade 4-5 pulmonary toxicity 5% vs. 16% (8% death)
    • Conclusion: Carboplatin/paclitaxel arm will be compared with standard RT in Phase III trial

• Big Lung Trial, 2005 (UK) (1995-2001) PMID 16094738 — "A randomised comparison of radical radiotherapy with or without chemotherapy for patients with non-small cell lung cancer: Results from the Big Lung Trial." Fairlamb D et al. Radiother Oncol. 2005;75(2):134-40.
  • 288 pts. Randomized to radical RT alone or sequential chemotherapy + radical RT. No surgery. Enrolled any pt eligible to receive radical RT (not limited by stage, ~70% III/IV). 3 cycles of chemotherapy q3week. Did not control for details of treatment. Chemotherapy was cisplatin-based, one of 4 types chosen by doctor. Could be given neoadjuvantly or adjuvantly (chosen by doctor, 60% induction, 40% concurrent). RT dose was most commonly 50-55 Gy in 20 fx (2.5-2.75 Gy/fx).
  • Median OS: 13 vs. 13.2 months. OS 50% at 1 yr, 30% at 2 yr. No difference in OS or PFS between arms

• Seoul, 2002 (Korea) PMID 12040280 -- "A phase III randomized trial of combined chemoradiotherapy versus radiotherapy alone in locally advanced non-small-cell lung cancer." (Kim TY, Am J Clin Oncol. 2002 Jun;25(3):238-43.)
  • Randomized. 89/101 patients unresectable IIIA/IIIB NSCLC. RT 60-65 Gy in 1.8-2Gy/fx +/- induction chemo (PEV - cisplatin, etoposide, vinblastine)
  • Median OS: Combined 13.8 months vs. RT alone 8.5 months (NS); nonsquamous histology 14 vs. 3.6 months (SS); stage IIIB 11.1 months vs. 7.2 months (SS). "Low risk" (squamous, IIIA) long survival 18.3 vs. 20.8 months (NS)
  • Conclusion: should use prognostic factors (histology, stage) to decide who gets chemo

• MIC-1 (UK) (1988-96)
  • 446 patients. Inoperable NSCLC (inoperable IIIA/non-bulky IIIB). Randomized to RT +/- MIC chemotherapy (mitomycin, ifosfamide, cisplatin).
  • 2001 PMID 11843243 — "The benefits of chemotherapy in patient subgroups with unresectable non-small-cell lung cancer." Billingham LJ et al. Ann Oncol. 2001 Dec;12(12):1671-5.
    • Subgroup analysis: OS benefit in patients with better performance status; palliation better but no OS benefit with poor performance status
  • 1999 PMID 10506617 — "Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life." Cullen MH et al. J Clin Oncol. 1999 Oct;17(10):3188-94.
    • Median OS: 11.7 vs 9.7 months (NS).
    • Note: OS benefit in MIC-2, which looked at palliative care +/- MIC in advanced patients

• RTOG 88-08/Intergroup (1989-92)
  • 458 pts. Stage II medically inoperable (6%) or unresectable IIIA and IIIB (94%). Randomized to 1) Standard RT (60 Gy), 2) induction cisplatin/vinblastine x2 months followed by standard RT (as in CALGB), or 3) hyperfractionated RT 69.6 Gy in 1.2 Gy BID. KPS >=70, weight loss <5%
  • 1995 PMID 7707407 — "Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer." Sause WT et al. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205.
    • Conclusion: chemo/RT arm superior to other 2 arms. Median survival 13.8 months, 60% 1-yr OS vs 11.4m/46% and 12.3m/51%. Confirmed findings from CALGB/Dillman.
  • 2002 Final results PMID 10669675 Full text — "Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group." Sause W et al. Chest. 2000 Feb;117(2):358-64.
    • Median survival and 5-year OS, Std RT (11.4 m / 5%), Chemo/RT (13.2 m / 8%), HF RT(12 m / 6%).
  • Failure patterns: PMID 9336129 (1997): less distant mets for chemo/RT
  • Trial conclusion: chemo/RT somewhat (SS) better OS; no difference between statndard and HF RT alone

• Le Chevalier (France) 1983-89
  • Randomized. 353 pts, squamous or large cell only (no adeno), medically inoperable Stage I/II (33 pts) or unresectable (320 pts). Arms:
    • RT alone (split course). RT dose 65 Gy (40+15+10 Gy; 2.5 Gy/fx)
    • Neoadjuvant chemotherapy + RT + adjuvant chemotherapy. 3 cycles of monthly VCPC chemotherapy (vindesine, lomustine, cisplatin, cyclophosphamide), followed by same dose of RT, then 3 additional cycles of VCPC.
  • PMID 1847977 Full text — "Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients." Le Chevalier T et al. J Natl Cancer Inst. 1991 Mar 20;83(6):417-23.
    • Survival 1-yr (41% RT vs 50% chemo/RT), 2-yr (14% vs 21%), 3-yr (5% vs 11%), trend p=0.08. Decreased risk of distant mets for chemotherapy arm (HR=2.0 for no chemo).
    • Distant mets: 67% vs. 45% (SS)
  • Update 1994: (Abstract) Lung Cancer, Volume 10 (Suppl 1), March 1994, S239-244.
    • 2-yr OS 14% vs 21% (S.S.). Decreased distant mets. 1-yr LC poor: 17% and 15%.
  • Trial conclusion: No difference in survival. Improved control of distant mets with chemotherapy. No difference in local control.

• NCCTG (1983-87) PMID 1656827 — "Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase III trial." Morton RF et al. Ann Intern Med. 1991 Nov 1;115(9):681-6.
  • Randomized. 121 pts. Unresectable Stage III. RT to 60 Gy. MACC is methotrexate, doxorubicin, cyclophosphamide, and oral lomustine(CCNU). Randomized:
    • 1) RT alone
    • 2) 2 cycles MACC -> RT -> 2 cycles MACC
  • No benefit

• CALGB 8433 (Dillman) (1984-87)
  • Randomized. 155 patients. T3 or N2 (Stage III, which is currently IIIA or IIIB). Induction chemo followed by RT vs RT alone. Chemotherapy: cisplatin (100 mg/m2) q28 days x 2, vinblastine weekly x 5. XRT began on day 50 to 60 Gy. KPS >=80, weight loss <5%
  • PMID 2169587, 1990 — "A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer." Dillman RO et al. N Engl J Med. 1990 Oct 4;323(14):940-5.
    • Median survival 13.8 months (chemo + RT) vs 9.7 months (SS). OS 1-year 55% vs 40%, 2-year 26% vs 13%, 3-yr 23% vs 11%
  • Update 1996: PMID 8780630 Full text — "Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial." Dillman RO et al. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5.
    • Median survival 13.7 vs 9.6 months (SS). OS 1-year 54% vs 40%, 2-year 26% vs 13%, 3-yr 24% vs 10%, 5-yr 17% vs 6%, 7-yr 13% vs 6%.
  • Trial conclusion: chemo induction + RT increases median survival by 50%, and 5-year survivors x3 compared to RT alone

• Finland PMID 2838288 — "Inoperable non-small cell lung cancer: radiation with or without chemotherapy." Mattson K et al. Eur J Cancer Clin Oncol. 1988 Mar;24(3):477-82.
  • 238 pts. Unresectable. RT was split course and consisted of 55 Gy (275 cGy x 20) over 7 weeks with a 3 week break. Chemotherapy was CAP (cyclophosphamide, adriamycin, cisplatin). Randomized:
    • 1) RT alone
    • 2) CAP x 2 cycles -> RT (with 1 cycle CAP given during split) -> CAP x 6 cycles
  • Conclusion: no significant survival advantage for chemo/RT