# Radiation Oncology/NSCLC/Locally Advanced Unresectable/RT Only

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    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 treatment 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
** Survival: 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.
* Kraków (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, 1 cm 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, 1 cm 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