# Radiation Oncology/NSCLC/Palliation

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NSCLC Palliation in Advanced Disease

## RT vs. Supportive Care

* 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.)
** Modest prolongation (few weeks) in OS

## RT

* Lot of randomized trials comparing various doses and fractionations
* RT dose does not appear to impact median survival, but higher dose results in higher 1-year OS
* Good ECOG status: longer schedules (30/10 up to 45/18) for better 1-year OS and longer palliation effects
* Poor ECOG status: shorter schedules (16/2, 20/5) reasonable
* Cochrane review: short schedules (1 or 2 fractions) should be used for most patients
* Australia 1984-1990 PMID 16432830 -- "Unexpected long-term survival after low-dose palliative radiotherapy for non-small cell lung cancer." (MacManus MP, Cancer. 2006 Mar 1;106(5):1110-6.)
** Retrospective. 2337 patients, palliative RT to <=36 Gy
** Median survival of cohort 4.6 months; 1.1% survived progression-free >5 years.
** RT dose not a factor. Caution to consider doses to critical structures, since some patients do survive long-term
* Holland 1999-2002 PMID 15860852 -- "Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer." (Kramer GW, J Clin Oncol. 2005 May 1;23(13):2962-70.)
** Multicenter randomized. 297 patients with IIIA/B, ECOG 3-4, substantial weight loss. RT 30/10 or 16/2. Outcome at 39 weeks
** Both arms equally effective over initial 39 weeks
** 30/10 schedule more prolonged palliation, with less worsening of symptoms
** 1-year OS: 30/10 20% vs. 16/2 11% (SS)
** Conclusion: 30/10 schedule preferred due to longer survival and longer duration of palliation
* Poland PMID 15770205 -- " prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC)" (Senkus-Konefka E, Br J Cancer. 2005 Mar 28;92(6):1038-45.)
** Randomized. 100 patients, median ECOG 2. RT 20/5 or 16/2 (day 1, 8)
** No difference in relief
** Median OS: 20/5 5.3 months vs. 16/2 8.0 months (SS)
** Conclusion: 16/2 useful, both improved survival and better convenience
* Edinburgh (UK) PMID 15714933 -- "Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules." (Erridge SC, Clin Oncol (R Coll Radiol). 2005 Feb;17(1):61-7.)
** Randomized. 149 patients. ECOG 0-3. RT 30/10 vs. 10/1
** No statistical difference in relief, but more patients with complete resolution and palliation with 30/10
** Median OS: 5.5 months vs. 7 months (NS)
* Norway PMID 14990635 -- "Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial." (Sundstrom S, J Clin Oncol. 2004 Mar 1;22(5):801-10.)
** Randomized. 421 patients with Stage III/IV, chest symptoms or tumor threatening airway. RT A) 17/2 vs. B) 42/15 vs. C) 50/25
** QOL and symptom relief comparable. Median OS: comparable
** Conclusion: Long course RT no improvement over short-term RT
* NCIC CTG SC.15 (Canada) PMID 12377323 -- "Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15)." (Bezjak A, Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):719-28.)
** Randomized. RT 10/1 vs. 20/5
** No difference in symptom control at 1 month; 20/5 better for overall symptoms, pain, normal activities, and QOL. Comparable toxicity
** Median survival: 2 months longer with 20/5 (SS)
** Conclusion: no difference in palliation, but better QOL and survival with 20/5
* Saarland (Germany) 1994-1998 PMID 10924977 -- "A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs. conventionally fractionated 60 GY: results of a randomized equivalence study." (Nestle U, Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):95-103.)
** Randomized. 152 patients with advanced Stage III or minimal Stage IV. Conventional RT 60/30 vs. accelerated RT 32/16 BID
** 1-year OS: 37%, no difference
** Palliation adequate and comparable. Side effects comparable
** Short-term course preferable to standard 60/30
* Bristol (UK) PMID 9135893 -- "Palliative radiotherapy for lung cancer: two versus five fractions." (Rees GJ, Clin Oncol (R Coll Radiol). 1997;9(2):90-5.)
** Randomized. 216 patients, RT 17/2 or 22.5/5
** No difference
* MRC (UK) 1989-1992 PMID 8814371 -- "Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party." (Macbeth FR, Clin Oncol (R Coll Radiol). 1996;8(3):167-75.)
** Randomized. 509 patients. Inoperable, no mets, good performance status. Palliative (17/2) vs. intensive RT (39/13)
** Median survival: 7 months vs. 9 months; 1-year OS 31% vs. 36%.
** Conclusion: 17/2 more rapid palliative effect, but 39/13 longer survival
* Groote Schuur (South Africa) 1990-1993 PMID 8581393 -- "Palliative radiation for stage 3 non-small cell lung cancer--a prospective study of two moderately high dose regimens." (Abratt RP, Lung Cancer. 1995 Oct;13(2):137-43.)
** Randomized. 84 patients with Stage III, WHO 0-2. RT 35/10 or 45/15
** Median OS: 8.5 months in both groups. No difference in response rate and esophagitis (23% vs. 41%, p=0.07)
* MRC (UK) PMID 1377484 -- "A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party." (No Authors, Br J Cancer. 1992 Jun;65(6):934-41.)
** Randomized. 235 patients. Main symptoms related to thoracic tumor, poor performance status. RT 17/2 or 10/1
** Palliation: comparable, ~50% cough, ~70% hemoptysis. Mean duration of palliation >50% of survival time. More dysphagia in 17/2
** Conclusion: 10/1 recommended for poor performance status
* MRC (UK) PMID 1705140 -- "Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Report to the Medical Research Council by its Lung Cancer Working Party. (No Authors, Br J Cancer. 1991 Feb;63(2):265-70.)
** Randomized. 369 patients. Symptoms related to thoracic tumor. RT 17/2 (1 week apart) or conventional (30/10 or 27/6)
** Palliation: comparable, ~60% cough, ~80% hemoptysis. Median duration of palliation >50% of survival time
** No difference in survival. Recommend 17/2 given 1 week apart.
* Hong Kong 1981-1984 PMID 2452146 -- "A randomized study on palliative radiation therapy for inoperable non small cell carcinoma of the lung." (Teo P, Int J Radiat Oncol Biol Phys. 1988 May;14(5):867-71.)
** Randomized. 291 patients to 45/18 vs 31.2/4 (once per week)
** Median OS: 5 months, no difference
** Palliation: 45/18 superior (71% vs. 54%, SS)
* RTOG 73-02 (1973–79) PMID 2579938, 1985 — "Palliative radiotherapy for inoperable carcinoma of the lung: final report of a RTOG multi-institutional trial." Simpson JR et al. Int J Radiat Oncol Biol Phys. 1985 Apr;11(4):751-8.
** 409 pts. T4 Any N, or Any N3 (now Stage IIIB). Palliative therapy. Randomized to 1) 30/10 fractions, 2) 40 Gy continuous course over 4 weeks, or 3) 40 Gy split course (as in 73-01).
** No difference in treatment arms. Palliation in 60%; 25% became symptom-free.
Review
* Cochrane, 2006 PMID 17054152 -- "Palliative radiotherapy regimens for non-small cell lung cancer." (Lester JF, Cochrane Database Syst Rev. 2006 Oct 18;(4):CD002143.)
** 14 randomized trials reviewed.
** Results: No strong evidence that any regimen gives greater palliation
** Modest survival benefit (5% at 1 year, 3% at 2 years) with higher dose in patients with better KPS
** Toxicity: Some regimens associated with radiation myelitis
** Conclusion: Majority of patients should be treated with short palliation (1 or 2 fractions)
* 2004 PMID 15552805 -- "Palliative percutaneous radiotherapy in non-small-cell lung cancer." (Budach W, Lung Cancer. 2004 Aug;45 Suppl 2:S239-45.)
** Review of 11 randomized trials (10 with survival data).
** Increase in total dose does not substantially prolong median survival, but results in significantly better 1-year survival
** ECOG >=3 do not benefit from higher doses, better ECOG patients do
** Poor ECOG or large distant tumor burden: 17/2 or 20/4 are appropriate
** Good performance status: total dose 30-45 Gy in 2.5-3.0 Gy/fx
* 2003 PMID 12714878 -- "Palliative thoracic radiotherapy for non-small-cell lung cancer: a systematic review." (Toy E, Am J Clin Oncol. 2003 Apr;26(2):112-20.)
** Review of 12 randomized trials. RT used with palliative intent in ~25% of patients
** RT effective in controlling symptoms
** No strong evidence about doses, but higher doses lead to greater toxicity. Modest survival benefit with higher doses with good performance
** Recommend short course (1-2 fxs) unless good performance

## Timing of RT

* For patients with minimal thoracic symptoms initially, can delay treatment until symptoms develop
* In one study, only 42% of delayed RT actually required RT prior to death
* Norway PMID 16094739 -- "Immediate or delayed radiotherapy in advanced non-small cell lung cancer (NSCLC)? Data from a prospective randomised study." (Sundstrom S, Radiother Oncol. 2005 May;75(2):141-8.)
** Data from randomised fractionation trial. 407 patients. Symptomatic (S) and non-symptomatic patients retrospectively compared
** Non-symptomatic: better baseline characteristics, better survival (11.8 months vs. 6 months)
** Timing: baseline NS better, up to week 14 NS developed symptoms while S had symptom relief, after week 14 no difference
** Conclusion: immediate RT in patients with no symptoms does not prevent development of symptoms. Wait-and-see policy acceptable
* MRC (UK) 1992-1999 PMID 12202326 -- "Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial." (Falk SJ, BMJ. 2002 Aug 31;325(7362):465.)
** Randomized, multicenter. 230 patient with untreated NSCLC, minimal thoracic symptoms.
** RT immediately vs. when symptomatic. 17/2 or 10/1. In delayed group, 42% received RT prior to death. Median time to start 15 days vs. 125 days
** Primary outcome (alive, without symptoms at 6 months after randomization): 28% vs. 26% (NS). No difference in survival, activity, anxiety, depression. Adverse events more common in immediate group
** Conclusion: If minimally symptomatic, can delay until symptoms require treatment

## RT Side Effects

* MRC Trials PMID 8814372 -- "Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party." (Macbeth FR, Clin Oncol (R Coll Radiol). 1996;8(3):176-81.)
** Review of 3 MRC trials. 5 patients out of 1048. 3/524 patients with 17/2, 2/153 with 39/13 (could be random)
** Cord doses: alpha/beta <3 Gy, possibly ~2 Gy. Recommend not exceeding 48 Gy to spine

## RT Technique

* Maastricht, 2006 (Holland) PMID 16730089 -- "Palliative chest irradiation in sitting position in patients with bulky advanced lung cancer." (Duisters C, Radiother Oncol. 2006 Jun;79(3):285-7. Epub 2006 May 26.)
** Some patients unable to lie down because of dyspnea. Sitting position technique developed.

## Chemo vs. "Supportive Care" (may include RT)

Meta-Analysis
* NSCLC Collaborative Group; 2008 PMID 18678835 -- "Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials." (NSCLC Meta-Analyses Collaborative Group, J Clin Oncol. 2008 Oct 1;26(28):4617-25. Epub 2008 Aug 4.)
** Data from 2714 patients from 16 RCTs.
** Outcome: 1-year OS chemotherapy 29% vs. supportive care 20% (HR 0.77, SS). No clear effect on drugs used, or whether single or combination. No clear difference in benefit across subgroups
** Conclusion: Chemotherapy improves OS in all patients with advanced NSCLC
Paclitaxel
* Multicenter UK PMID 10880550 -- "Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer." (Ranson M, J Natl Cancer Inst. 2000 Jul 5;92(13):1074-80.)
** Randomized. 157 with IIIB/IV with no prior chemo, ECOG 0-2. Paclitaxel IV q3w. Supportive care included RT (but not discussed)
** Median OS: paclitaxel 6.8 months vs. supportive care 4.8 months (SS); some aspects of QOL better
Cisplatin/etoposide
* Oslo (Norway) PMID 1849786 -- "Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer." (Kaasa S, Cancer. 1991 May 15;67(10):2443-7.)
** Randomized. 87 patients with inoperable extensive NSLCL. Cisplatin/etoposide vs. supportive care (including RT 42/15)
** OS: No difference at 10.5 months, but majority of patients crossed over on disease progression.
** Response rate: 21% vs. 42% (SS). Long-term survivors only if they received both
MIC (mitomycin, ifosfamide, cisplatin)
* MIC2 (1988–96) (Birmingham, UK)
** Randomized. 351 patients with IIIB/IV to palliative care vs. palliative care + MIC
** 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: 6.7 months CT + PC vs. 4. 8 months PC alone (SS)
*** Quality of Life: assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment.
** 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

## Anemia

* Canada (2001–2003)
** Randomized. Stopped early due to unplanned safety analysis. 70 patients assigned (out of 300 planned). NSCLC unsuitable for curative therapy, baseline Hgb <12.1 g/dL. Arm 1) placebo vs. Arm 2) Epo weekly to maintain Hgb 12-14 g/dL
** 2007 PMID 17312332 -- "Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia." (Wright JR, J Clin Oncol. 2007 Mar 20;25(9):1027-32. Epub 2007 Feb 20.)
*** Outcome: at analysis, median OS placebo 4.2 months vs. Epo 2 months (SS)
*** Conclusion: Decreased overall survival on unplanned safety analysis

## SBRT in Advanced Disease

* Multi-Institutional MD Anderson; 2019 PMID 31067138 -- "Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study." (Gomez DR, J Clin Oncol. 2019 Jun 20;37(18):1558-1565. doi: 10.1200/JCO.19.00201. Epub 2019 May 8.)
** Phase II randomized trial. Three institutions (MDACC, London Ontario, University of Colorado). 49 patients; trial stopped prematurely due to significant PFS benefit. Stage IV NSCLC, 3+ months of no progression on front-line systemic therapy. Arm 1) maintenance therapy/observation vs Arm 2) Local control with RT or surgery. Median F/U 3.2 years
** Outcome: Trial stopped early due to benefit. PFS observation/maintenance 4.4 months vs local control 14.2 months (SS). Over survival 17 months vs 41 months (SS). Survival after progression 9.4 months vs 38 months (SS).
** Conclusion: In these patients, local therapy prolonged PFS and OS
* Colorado; 2009 (2005–2008) PMID 19373699 -- "Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis." (Rusthoven KE, Acta Oncol. 2009;48(4):578-83.)
** Retrospective. 64 patients, measurable advanced stage NSCLC, first line systemic chemotherapy, 34 SBRT-eligible.
** Outcome: All patients progression local 64%, distant 9%, both 27%. SBRT-eligible 68%, 14%, 18%. Time to first progression if local 3.0 months vs if distant 5.7 months
** Conclusion: Predominant failure local. Increase in time-to-progression from SBRT could be 3 months

## Patient Preference

* National University Hospital, Singapore; 2008 PMID 19032397 -- "Patients' preference for radiotherapy fractionation schedule in the palliation of symptomatic unresectable lung cancer." (Tang JI, J Med Imaging Radiat Oncol. 2008 Oct;52(5):497-502.)
** Prospective. 92 patients. Choice of palliative treatment schedule 17/2 vs 39/13. Radiation oncologist made final decision
** Outcome: Short schedule chosen by 45% vs long schedule 55%. Longer schedule chosen for longer survival (90%) and better tumor control (12%). Shorter schedule chosen for shorter duration (80%), cost (61%), and better symptom control (20%). Change of schedule, 56% of short course and 4% of long course had their treatment altered by the radiation oncologist. Nevertheless, 100% patients satisfied with their involvement
** Conclusion: Both schedules useful, nearly half patients felt longer survival not as important as shorter duration and lower cost