Radiation Oncology/NSCLC/Locally Advanced Unresectable/RT Only

See also: Early Stage RT alone (many of these trials included advanced stage patients also)

See also: Palliation section

RT vs. Placebo

• VA Lung Group (VALG) PMID 4170866 -- "The survival of patients with inoperable lung cancer: a large-scale randomized study of radiation therapy versus placebo." (Roswit B, Radiology. 1968 Apr;90(4):688-97.)
  • Randomized. 800 patients. Localized but inoperable KPS 80-100 33%, KPS 50-70 55%, Treated with: 1) RT, 2) placebo, 3) chemo
  • RT: 90% treated with orthovolatage (200-260 kV), 10% with Cobalt-60. Target dose 40-50 Gy, but 33% received <40 Gy
  • Median OS: RT 4.6 months vs. 3.7 months; 1-year survival: RT 18% vs. placebo 14% (p=0.05).
  • Long-term survivors (top 25%): RT 10 monts vs. 7.6 months (SS)
  • Conclusion: RT does not impact median OS, but improves long-term survival

Dose and Fields

• RTOG Review PMID 16015546 -- "A review of radiation dose escalation trials for non-small cell lung cancer within the Radiation Therapy Oncology Group." (Bradley J, Semin Oncol. 2005 Apr;32(2 Suppl 3):S111-3.)
  • Dose 60 Gy "standard" for the past 30 years; insufficient to control local disease
  • RT alone: 83.8 Gy using 3D-CRT tolerable, 90.3 Gy excess mortality (from RTOG 93-11)
  • RT with chemotherapy: maximum 70-74 Gy

• RTOG 93-11 (1995-2001) -- dose escalation
  • Phase I/II dose escalation. 176 patients. Stage I-III NSCLC, SCV LN+ excluded ( Prior chemotherapy allowed, concurrent chemotherapy not allowed. 3D treatement planning . GTV = primary tumor and enlarged LN. No elective nodal irradiation. PTV = GTV + 1 cm minimum; verified on fluoroscopy because of breathing motion. Dose prescribed to ICRU reference point within GTV, 93% isodose line to cover PTV, maximum PTV dose <=107%, no heterogeneity correction. Patients grouped based on V20 value using 2.15 Gy/fx:
    • Group 1 (V20 <25%): 70.9/33 -> 77.4/36 -> 83.8/39 -> 90.3/42 (Stage I 53%, Stage III 38%)
    • Group 2 (V20 25-36%): 70.9/33 -> 77.4/36 -> 83.8/39 (Stage I 21%, Stage III 75%) (accrual stopped after 77.4 Gy due to opening of RTOG 0117)
    • Group 3 (V20 >36%): 64.5/30 -> 70.9/33 -> 77.4/36 (accrual stopped after 2 patients)
  • 2005 PMID 15667949 — "Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma." (Bradley J, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):318-28.) Minimum median F/U 13.4 months
    • Acute toxicity: minimal. Group 1 had 9% Grade 3 pneumonitis at 90.3 Gy; Group 2 had 8% Grade 3 pneumonitis at 77.4 Gy. Acute dose-limiting toxicity not reached
    • Late toxicity. Predictors for pulmonary toxicity: mean lung dose, V20
      • Group 1 had 13% Grade 3-5 lung and 6% Grade 3-5 esophageal toxicity (1 death of hemoptysis, 1 death of tracheoesophageal fistula) at 90.3 Gy; tolerable otherwise. Late dose-limiting toxicity at 90.3 Gy level.
      • Group 2 had 16% Grade 3-4 lung toxicity, and 4% esophagus toxicity. Late dose-limiting toxicity not reached.
    • Outcome: 2-year LR 50-78% (but small individual group sizes); LR sole site 18%, component 38%. Elective nodal failure <10%
    • Conclusion: For Group 1 (V20 <25%), 83.8 Gy safe; for Group 2 (V20 25-36%), 77.4 Gy safe using 2.15 Gy/fx

• RTOG 73-01 (1973-78)
  • 447 pts. Unresectable Stage III (included T3N0). Randomized to 40 Gy split course (20 Gy in one week, 2 weeks rest, then 20 Gy in one week -- total 4 weeks), 40 Gy continuous (over 4 weeks), 50 Gy, or 60 Gy. Included tumor + mediastinal + hilar LN. Used spinal cord block to limit dose to cord.
  • PMID 6991092, 1980 (No abstract) — "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." Perez CA et al. Cancer. 1980 Jun 1;45(11):2744-53.
  • PMID 6998937, 1980 (No abstract) — "Patterns of tumor recurrence after definitive irradiation for inoperable non-oat cell carcinoma of the lung." Perez CA et al. Int J Radiat Oncol Biol Phys. 1980 Aug;6(8):987-94.
  • Update (1982): PMID 6286087 (no abstract) — "Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: report by the Radiation Therapy Oncology Group." Perez CA et al. Cancer. 1982 Sep 15;50(6):1091-9.
  • Update (1987): PMID 3032394 — "Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group." Perez CA et al. Cancer. 1987 Jun 1;59(11):1874-81.
    • Analysis of RTOG 73-01 and 73-02
  • Conclusion: Determined 60 Gy in 2 Gy/fx to be optimal dose.

• MGH PMID 6263449 1972-1977 -- "Improved survival of patients with unresectable non-small-cell bronchogenic carcinoma by an innovated high-dose en-bloc radiotherapeutic approach." (Choi NC, Cancer. 1981 Jul 1;48(1):101-9.)
  • Retrospective. 162 patients treated with RT. Initially 40-45 Gy small volume (AP/PA POP), evolved into 60-64 Gy large volume (Ap/PA POP plus AP-RPO-LPO) including regional lymphatics
  • Surival: Median survival independent of dose and volume, long-term (2-year) survival dose and volume dependent (36% vs. 10%). Local control also dose dependent
  • Failure: Squamous cell in primary/regional lymphatics, adeno in brain/bone

Concomitant boost:

• RTOG 83-12
  • Phase I/II, T3-T4 NSCLC. Concomitant boost at 1.8 Gy/fx to 50.4 Gy (elective nodal). Primary tumor to 2.68 Gy/day to total of 75 Gy in 28 fx.
  • PMID 7860394 (1995)

Hypofractionated

• QW vs. QD
  • 150 patients (120 evaluable). Locally advanced. Randomized to 1) 60 Gy at 5 Gy x 12 once a week, or 2) 60 Gy at 2 Gy std fractions. Average f/u 3 years
  • Final; 1988 PMID 2839442 -- "Once-a-week vs conventional daily radiation treatment for lung cancer: final report." (Slawson RG, 1: Int J Radiat Oncol Biol Phys. 1988 Jul;15(1):61-8.)
    • Comparable OS: 59% QW vs 49% QD at 1 year, 29% QW vs 23% QD at 2 years. No difference in late toxicity
  • Prelim; 1986 PMID 3519551 (1982-84) — "A prospective randomized trial comparing once-a-week vs daily radiation therapy for locally-advanced, non-metastatic, lung cancer: a preliminary report." Salazar OM et al. Int J Radiat Oncol Biol Phys. 1986 May;12(5):779-87.
    • No difference in outcome.

Hyperfractionation

• RTOG 81-08 - feasibility study
  • 120 pts. 1.2 Gy BID to 50.4 Gy - 74.4 Gy.
  • Update: PMID 1650526, 1991

• RTOG 83-11 (1983-87)
  • 848 pts. Unresectable Stage II-IV (without distant mets). 1.2 Gy BID to 60.0, 64.8, 69.6 Gy, 74.4 Gy or 79.2 Gy.
  • PMID 2167952, 1990 — "A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11." Cox JD et al. J Clin Oncol. 1990 Sep;8(9):1543-55.
    • Among 350 pts with good performance status, there was a dose response above 69.6 Gy (median 13.0 months; 2 yr OS 29%) significantly better than lower doses. No dose response above 69.6 Gy.

• Krakow (Poland) 1992-1996 PMID 10630160 -- "[Radiotherapy for stage III, inoperable, asymptomatic small cell lung cancer. Final results of a prospective randomized study (240 patients)]" - [Article in French]. (Reinfuss M, Cancer Radiother. 1999 Nov-Dec;3(6):475-9.)
  • Randomized. 240 Stage III asymptomatic patients. RT 50/25 vs. split course 20/5 + 20/5 after 4 weeks vs. delayed RT 20/5. No chemo.
  • Median survival: 12 months vs. 9 months vs. 6 months (SS)
  • Conclusion: conventional schedule best

CHART

• MRC CHART Trial (UK) 1990-1995
  • Stage IA-IIIB (60% Stage III)
  • Randomized 2:1. 563 patients to 1) 54 Gy in 1.5 Gy/fx TID continuously over 12 days vs 2) conventional 60 Gy in 2 Gy/fx over 30 days. No chemo. All non-operable, Stage III 61%, Stage I 30%. 81% Squamous cell.
  • RT: Large volume (tumor, mediastinum, 1cm margin, ipsilateral hilar LN, paratracheal LN, but not contralateral LN, max AP field 240 cm2) to either 37.5 Gy or 44 Gy, followed by boost (tumor, known LN, 1cm margin) to 54 Gy or 60 Gy total
  • Mature Update 1999 PMID 10577699 -- "Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee." (Saunders M, Radiother Oncol. 1999 Aug;52(2):137-48.)
    • 2-year OS: 30% (CHART) vs. 21% (22% reduction in RR, SS), 3-yr OS 20% vs 13%; Local control 2-yr: 23% vs. 16% (21% reduction in RR, SS), 3-yr: 17% vs 12%. 61% of deaths due to primary tumor, 21% of deaths due to mets.
    • For squamous cell: 2-year OS: 33% vs. 20% (30% reduction in RR, SS), LC 27% reduction in RR
    • No difference in late toxicity
  • 1997: PMID 9250182 — "Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial." Saunders M et al. Lancet. 1997 Jul 19;350(9072):161-5.
    • Dysphagia occurred earlier in CHART, was more severe, but resolved. Severe dysphagia: 19% (CHART) vs 3%.
  • 1996: PMID 8664112 — "Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee." Saunders MI et al. Br J Cancer. 1996 Jun;73(12):1455-62.
  • Conclusion: CHART superior to conventional RT in both 2-year OS and local control