Radiation Oncology/NSCLC/Locally Advanced Unresectable

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Locally Advanced Unresectable NSCLC

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Treatment Overview[edit]

  • Patients were initially treated with radiation only, usually split course
  • Dose-escalation in RTOG 73-01 established 60 Gy in 2 Gy/fx as the standard regimen
  • Median survival was ~10 months, with 3-year survival <10%
  • Hyperfractionated RT alone did not show any beneft
  • Continuous Hyperfractionated Accelerated RadioTherapy (CHART) showed a significant improvement in OS. However, logistics of delivering RT TID x12 days straight, combined with OS improvement with chemotherapy have limited its adoption
  • CALGB, RTOG, and UK studies in mid-1990's established induction chemo + RT superior for median OS, although absolute benefit was not large (2-4 months). There was a significantly higher proportion of long term survivors. There was no impact on local progression, but distal failure was significantly less
  • Hyperfractionated RT after chemo induction did not show any benefit over standard RT
  • Induction chemo alone, without RT, was comparable in median OS, but inferior in long term survivors compared to induction chemo + RT. RT was considered a necessary component of treatment
  • At the same time, concurrent chemotherapy and RT were evaluated. The only survival benefit of concurrent chemo-RT over RT alone was in an EORTC trial, which used split-course RT with a 3 week rest. The other 3 trials with standard RT fractions were negative. The chemo used was a single agent.
  • Concurrent chemo (2 agents) with hyperfractionated RT resulted in OS benefit in 2 Yugoslavian trials
  • Small overall chemo benefit was demonstrated in a meta-analysis setting in 1995, and confirmed to be 4% absolute benefit at 2 years in a subsequent meta-analysis. Essentially any two agents are superior to any single agent; adding a third drug did not provide additional benefit
  • However, the timing of giving chemotherapy and RT was unclear. Both induction and concurrent chemo appear to provide survival benefit, induction chemo via improved distal control and concurrent chemo via improved local control.
  • Direct comparisons in several randomized trials established concurrent chemo-RT as the superior regimen, at the cost of increased in-field toxicity (especially esophagitis)
  • There is no benefit to induction chemotherapy, followed by concurrent chemo-RT (CALGB B39801, LAMP). The later RT starts, the worse the outcomes
  • The role of consolidative chemo after concurrent chemo-RT is under evaluation
  • The role of elective nodal irradiation is also evolving, with single institution series suggesting minimal benefit, and one randomized trial (China) finding that dose escalation to 68-74 Gy due to lower volume treated resulted in improved overall survival
  • The current standard of care can be considered concurrent chemo with 2 agents containing platinum, and thoracic RT to 60 Gy in QD fractions.

RT vs. Placebo[edit]

  • VA Lung Group (VALG) -- RT vs. placebo vs. chemotherapy
    • Randomized, 3 arms. 800 patients. Localized but inoperable (mostly due to bulky disease). KPS 80-100 33%, KPS 50-70 55%. Arm 1) RT vs. Arm 2) placebo (lactose) vs. Arm 3) chemo (not reported here). RT given: orthovolatage in 90% (200-260 kV), Cobalt-60 in 10%. Target dose 40-50 Gy, but 33% received <40 Gy (2/3 died, 1/3 medical complications)
    • 1968 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.)
      • Outcome: Median OS: RT 4.6 months vs. placebo 3.7 months (NS); 1-year survival: RT 18% vs. placebo 14% (p=0.05).
      • Long-term survivors (top 25%): RT 10 months vs. 7.6 months (SS). Better survival if longer symptomatic prior to diagnosis, suggesting slower rate of growth
      • Conclusion: RT does not impact median OS, but improves long-term survival

Radiation alone[edit]

  • Please see the RT Only section for detailed literature review
  • Survival: 7-10 months
  • RT dose:
    • Standard 2D: 60Gy in 2Gy/fx established in RTOG 73-01; but insufficient to control disease
    • RT alone (3D-CRT): 83.8 Gy tolerable, 90.3 Gy excess mortality (from RTOG 93-11)
    • RT with chemotherapy: maximum 70-74 Gy appears tolerable
  • Hyperfractionated RT alone did not show any beneft
  • Continuous hyperfractionated thereapy (CHART) showed a significant improvement in OS. However, logistics of delivering RT TID x12 days straight, combined with OS improvement with chemotherapy have limited its adoption
  • In mid-1990's induction chemotherapy followed by RT was shown to have modestly better OS over RT alone (see below), and efforts since have been targeted at optimizing CRT


Combined modality[edit]

RT alone vs. Chemo alone vs. Chemo-RT[edit]

  • Vanderbilt, 1990 - PMID 2161633 — "Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer." Johnson DH et al. Ann Intern Med. 1990 Jul 1;113(1):33-8.
    • 319 pts, locally advanced, unresectable. Randomized to 1) Vindesine weekly, 2) RT to 60 Gy (2 Gy/fx), or 3) Vindesine + RT. Vindesine was given weekly for 6 weeks then every other week. Cross over to the other arm was done for disease progression.
    • Minimum f/u 42 months. Response rate was 30% (RT alone), 34% (chemo + RT), 10% (chemo). No difference in survival. Median survival was 8.6 vs 9.4 vs 10.1 months; 5-yr OS 3% vs 3% vs 1%.
    • Conclusion: RT failed to improve survival.


RT alone vs. Induction Chemo-RT[edit]

  • CALGB 8433 published in 1990 (Dillman) PMID 2169587
    • Phase III trial of 155 patients with Stage III non-small cell lung cancer
    • RT only arm received 60 Gy in 2 Gy fractions; experimental arm received cisplatin 100 mg/m2 with vinblastine 5 mg/m2 for two cycles sequentially with same radiation starting day 50.
    • Median OS improved 13.8 vs 9.7 months (p<0.01) with chemoRT vs RT alone. 3-year OS improved 23% vs 11% as well.
  • Overall, there appeared to be a modest survival benefit with induction chemo followed by RT, in patients with good performance status and no weight loss.
  • There was a significantly higher proportion of long term survivors and improved distant failure-free survival, but essentially no impact on local recurrence
  • Later studies comparing induction chemo/RT versus concurrent chemo/RT demonstrated the superiority of concurrent chemo/RT


Please see the Induction Chemo RT section for literature review

Induction Chemo-RT vs. Induction Chemo Alone[edit]

  • Same median survival, but RT significantly improves long-term survival rate. Chemotherapy alone is not sufficient


  • Sakai (Japan) PMID 8040666 -- "Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer." (Kubota K, J Clin Oncol. 1994 Aug;12(8):1547-52.)
    • Randomized. 92 patients treated with chemotherapy (VP vs. MVP vs. EP/VM) x2 cycles, then randomized to RT or not. 50-60 Gy in 2 Gy/fx. 63 patients in second (RT) randomization
    • Median OS: comparable at 15 months. But 1-year, 2-year, 3-year OS: CT alone 66%, 9%, 3% vs. CT-RT 58%, 36%, 29%
    • Conclusion: No difference in median OS, but significantly better long-term survivors with CT-RT. Chest RT necessary.

RT Alone vs. Concurrent Chemo-RT[edit]

  • Only survival benefit of concurrent chemo-RT was in an EORTC trial, which used split-course RT with a 3 week rest. Three other trials with standard RT fractions were negative.
  • Two trials out of Yugoslavia, using hyperfractionated RT, were also positive
  • Meta-analysis of 9 trials showed a 4% absolute OS benefit with chemo-RT at 2 years, and established RT with chemotherapy as standard of care


Please see the Concurrent-Chemo RT section for literature review


Sequential vs. Concurrent Chemo and RT[edit]

Meta-analysis

  • NSCLC Collaborative Group; 2010 PMID 20351327 -- "Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non-Small-Cell Lung Cancer." (Auperin A, J Clin Oncol 2010 May 1;28(13):2181-2190.)
    • Meta-analysis. Individual patient data from 6 trials (CALGB 8831, WJLCG, RTOG 9410, GMMA Ankara, GLOT-GFPC NPC 95-01, EORTC 08972). 1205 patients. Median F/U 6 years
    • Outcome: Benefit of concomitant chemo-RT over sequential chemo->RT on OS (HR 0.84, SS), with absolute benefit at 3-years of 5.7% (18% to 24%), 5-years 4.5% (11% to 15%). No difference in PFS (HR 0.9, p=0.07). Decrease in locoregional progression (HR 0.777, SS), with absolute decrease of 6% at 5 years (35% to 29%). No difference on distant progression (HR 1.04, NS), with 5-year rate of ~40%
    • Toxicity: Acute Grade 3-4 esophageal toxicity worse (RR 4.9, SS), increase from 4% to 18%; no significant difference in acute pulmonary toxicity
    • Conclusion: Concomitant chemo-RT compared with sequential chemo-RT improved overall survival, primarily through better locoregional control, at cost of manageable increase in acute esophageal toxicity


Randomized evidence

  • CTRT99/97 Bronchial Carcinoma Therapy Group (Germany) (1997-2002) - Phase III
    • 303 pts. Stage IIIA-IIIB. Treated with induction chemo: carbo/taxol x 2 cycles. Then randomized to: 1) RT only 60 Gy, or 2) Chemo-RT with weekly taxol.
    • 2006 PMID 16983107 -- "Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group." (Huber RM, J Clin Oncol. 2006 Sep 20;24(27):4397-404.)
      • 214 pts randomized. Median f/u 13.6 mo. Induction therapy was well tolerated with mild toxicities. Median survival 14.1 mo (RT) vs 18.7 mo (Chemo-RT), NS. Median TTP 11.5 mo vs 14.7 mo (SS). No significant differences in toxicity between the two arms.
      • Conclusion: Induction chemo followed by chemo-RT is feasible. Response, time to progression, and survival favor chemo-RT vs RT.
  • GLOT-GFPC NPC 95-01 (French) (1996-2000) PMID 16087956 — "Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study." Fournel P et al. J Clin Oncol. 2005 Sep 1;23(25):5910-7.
    • Randomized 205 pts. Stage III. Treated A) Sequential: induction cisplatin/vinorelbine followed by RT 66 Gy vs. B) Concurrent/Consolidation: RT 66 Gy with cisplatin/etoposide, then cisplatin/vinorelbine
    • Median OS: sequential 14.5 months vs concurrent/consolidative 16.3 months (NS). 4-year OS: sequential 14% vs concurrent/consolidative 21% (NS)
    • Toxicity: Worse esophageal toxicity in concurrent arm (32% vs 3%)
    • Conclusion: no significant difference, but trend suggestive of potential benefit for concurrent therapy
  • Prague, 2004 (Czech) PMID 15364136 — "Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study." Zatloukal P et al. Lung Cancer. 2004 Oct;46(1):87-98.
    • Randomized. 102 patients (15 IIIA, 87 IIIB) treated with A) concurrent chemo-RT vs. B) sequential chemo-RT, with RT starting within 2 weeks. RT given as 60/30. Chemo given as cisplatin/vinorelbine
    • Median OS: concurrent 16.6 months vs. sequential 12.9 months (SS). Time-to-progression: 11.9 months vs. 8.5 months (SS)
    • Toxicity: Grade 3/4 more frequent in concurrent arm, leukopenia 53% vs. 19% (SS), nausea/vomiting 39% vs. 15% (SS)
    • Conclusion: concurrent significantly better survival, time to progression. Worse but acceptable toxicity
  • RTOG 94-10 (1994-98) PMID 21903745 — "Sequential vs Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410." Curran W et al. J Natl Cancer Inst. 2011 Sep 8. [Epub ahead of print]
    • Inoperable / unresectable Stage II-IIIB, ineligible for RTOG 93-03. Randomized. Elective nodal irradiation is required.
      • Arm 1: sequential chemo (vinblastine + cisplatin) followed by RT beginning on day 50. Vinblastine weekly x 5. Cisplatin 100 mg/m2 q3w x 2. RT 45 Gy + 2 Gy x 9 boost (63 Gy total).
      • Arm 2: concomitant chemo/RT (same chemo & RT as in Arm 1). (Based on RTOG 90-15 but with qd RT)
      • Arm 3: concomitant chemo (oral etoposide and cisplatin) and hyperfractionated RT. Oral etoposide 50 mg BID given on RT days only for weeks 1-4. Cisplatin 50 mg/m2 on days 1,8,29,36. RT dose 69.6 Gy at 1.2 Gy BID. (Based on RTOG 91-06)
    • Published at a median f/u of 11 yrs (prior ASTRO Abstract in 2003).
      • Median OS: SEQ 14.6 mo vs. CON-QD 17.0 mo (SS vs. SEQ) vs. CON-BID 15.6 mo
      • 5-year OS: SEQ 10% vs. CON-QD 16% (SS vs. SEQ) vs. CON-BID 13%
      • Conclusion: Concurrent chemo-RT with cisplatin confers a long-term survival benefit over sequential therapy.
    • RTOG 90-15 - PMID 7712445 - Phase I/II - BID RT with concurrent vinblastine + cisplatin. (Provided Arm 2 of RTOG 94-10)
    • RTOG 91-06 - PMID 8648357 - Phase II - BID RT with concurrent oral daily etoposide + IV cisplatin. (Provided Arm 3 of RTOG 94-10)
  • WJLCG; Japan (1992-94)
    • 1999 PMID 10561343 — "Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer." Furuse K et al. J Clin Oncol. 1999 Sep;17(9):2692-9.
    • 320 pts. Unresectable Stage III. Randomized Phase III.
      • Arm 1: Concurrent. Cisplatin (80 mg/m2, days 1 & 29) + vindesine (3 mg/m2, days 1, 8, 29, 36) + mitomycin C (8 mg/m2, days 1 & 29). RT began on day 2. 28 Gy, break of 10 days, then 28 Gy (total 56 Gy).
      • Arm 2: Induction. Same chemotherapy. RT began after chemotherapy, 56 Gy non-split course.
    • Median survival 16.5 months (concurrent) vs 13.3 months (sequential). Survival at 2, 3, 4, and 5 years in concurrent group (34.6%, 22.3%, 16.9%, and 15.8%) vs (27.4%, 14.7%, 10.1%, and 8.9%) in sequential group. Difference is S.S
    • Conclusion: Concurrent chemo/RT leads to better survial in selected pts than sequential chemo/RT.

Concurrent Chemo-RT +/- Induction Chemo[edit]

  • There appears to be no benefit to induction chemotherapy prior to concurrent chemo-RT in 2 randomized trials


  • CALGB B39801 (1998-2002) -- Induction carboplatin/paclitaxel -> RT vs chemo-RT
    • Randomized. 366 patients with unresectable Stage III NSCLC. Randomized to Arm 1) Concurrent carboplatin (AUC=2)/paclitaxel (50 mg/sq m) with RT 66 Gy. Arm 2) Induction with carboplatin(AUC=6)/paclitaxel (200 mg/sq m) x2 cycles, then concurrent chemo-RT as Arm 1
    • 2007 PMID 17404369 -- "Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B." (Vokes EE, J Clin Oncol. 2007 May 1;25(13):1698-704.)
      • Outcome: MS induction 12 months vs. no induction 14 months (NS); 2-year OS 29% vs. 31% (NS)
      • Toxicity: Induction chemo neutropenia (20% Grade 3-4), no difference between concurrent CRT arms
      • Conclusion: Addition of induction chemo added toxicity without survival benefit.
    • Comment: Low survival compared to other trials, possibly due to lower chemo dose due to using carboplatin and not cisplatin.
  • Locally Advanced Multimodality Protocol (LAMP), 2005 (1998-2001) - Randomized Phase II. Closed early due to nonaccrual. Opened before concurrent chemo-RT was established as standard, with Arm 1 sequential chemo-RT as control. Arm 2 was closed early at interim analysis. Eventually interest in Arm 1 slowed down, and trial was closed. Results compared to historical RTOG 88-08
    • 257 pts. Stage IIIA or IIIB (medically inoperable N2, T4, or T3). KPS >= 70%, wt loss <= 10%.
      • Arm 1: Sequential chemotherapy followed by RT. 2 cycles of paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 3 weeks. RT on day 42 (3 weeks after last chemotherapy cycle), 45 Gy + 18 Gy = 63 Gy, to postchemo volume.
      • Arm 2: Induction chemotherapy followed by concurrent chemo/RT. Two cycles of chemotherapy (as in Arm 1) followed by RT (as in Arm 1) given concurrently with weekly Taxol (45 mg/m2) + 2 cycles of carboplatin (AUC 2) q3weeks x 2 cycles
      • Arm 3: Concurrent chemo/RT followed by consolidative chemotherapy. Concurrent chemo/RT (as in Arm 2) followed by two cycles of chemotherapy (as in Arms 1&2) 3-4 weeks after completion of concurrent therapy.
    • PMID 16087941, 2005 — "Combined Chemoradiotherapy Regimens of Paclitaxel and Carboplatin for Locally Advanced Non-Small-Cell Lung Cancer: A Randomized Phase II Locally Advanced Multi-Modality Protocol." Belani CP et al. J Clin Oncol. 2005 Sep 1;23(25):5883-5891.
      • Median f/u 39.6 months. Median survivals 13 months vs 12.7 months vs 16.3 months. Overall survival at 1,2,and 3 years for Arm 1: 57%, 30%, 17; Arm 2: 53%, 25%, 15%; Arm 3: 63%, 31%, 17%. No S.S. difference for any of the arms compared to RTOG 88-08.
    • Conclusion: No statistically significant difference in survival for any of the arms (vs. RTOG 88-08). Suggestion of improved outcome for Concurrent chemo/RT -> consolidative chemo.


Induction chemo alternatives + chemo-RT[edit]

  • CALGB 30105 -- Induction/concurrent carbo/taxol vs. carbo/gemcitabine
    • 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.)
    • Randomized Phase II. Arm 2 closed prematurely due to toxicity. 69 patients, Stage IIIA-B. Arm 1) induction carboplatin AUC6 + paclitaxel 225 mg/m2 followed by concurrent carboplatin AUC2 + paclitaxel 45 mg/m2 + RT 74 Gy vs. Arm 2) induction carboplatin AUC5 + gemcitabine 35 mg/m2, followed by concurrent gemcitabine + RT 74 Gy. Primary endpoint OS at 1.5 years
      • Outcome: median OS carbo/taxol 2.0 years vs. carbo/gem 1.0 years
      • Toxicity: High Grade 4-5 rate in carbo/gem arm
      • Conclusion: Carbo/taxol arm better and will be compared with standard dose TRT

Chemo-RT +/- Chemotherapy Consolidation[edit]

  • Hoosier Oncology Group (Indiana) (2002-2006) -- Chemo-RT +/- docetaxel
    • Randomized. Stopped early due to interim analysis of futility. 147/203 patients with stage IIIA-B, FEV1 >=1 L, wt loss <5%. Concurrent RT 59.4 Gy with cisplatin/etoposide, then if no progression Arm 1) docetaxel 75 mg/m2 x3 cycles vs. Arm 2) observation
    • 2008 PMID 19001323 -- "Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology." (Hanna N, J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10.)
      • Outcome: Median OS docetaxel 1.8 years vs. observation 1.9 years (NS)
      • Toxicity: Grade 3+ febrile neutropenia 11%, pneumonitis 10%, hospitalization 29% vs. 8%, death 5%
      • Conclusion: Consolidation with docetaxel increased toxicity with no impact on survival
  • SWOG 0023 (2001-2005) -- Chemo-RT + adjuvant docetaxel +/- adjuvant gefitinib
    • Randomized. Closed early after worse survival with gefitinib. 243/672 patients, Stage III NSCLC. Concurrent cisplatin 50 mg/m2 + etoposide 50 mg/m2 + RT 61 Gy, then docetaxel 75 mg/m2 x3 cycles. If no progression, randomized Arm 1) gefitinib 250 mg/d vs. Arm 2) placebo until progression, toxicity or 5 years
    • 2008 PMID 18378568 -- "Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023." (Kelly K, J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31.) Median F/U 2.2 years
      • Outcome: median OS gefitinib 1.9 years vs. placebo 2.9 years (SS)
      • Toxicity: death rate gefitinib 2% vs. placebo 0%
      • Conclusion: Gefitinib didn't improve survival; decreased survival result of tumor progression and not gefitinib toxicity
  • SWOG S9504 PMID 12743155 -- "Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504." (Gandara DR, J Clin Oncol. 2003 May 15;21(10):2004-10.)
    • Phase II. Stage IIIB. Concurrent chemo (cisplatin/etoposide) and RT 61 Gy, followed by consolidation docetaxel 4-6 weeks later
    • Median OS: 26 months; 3-year OS 37%; brain mets most common site of failure

Chemotherapy combinations with RT[edit]

Ongoing studies:

  • RTOG 0617 (ongoing) - Phase III. Concurrent RT + Carbo/Taxol +/- Cetuximab


Completed studies:

  • RTOG 0324 -- Phase II. Concurrent RT + Cetuximab / Carbo / Taxol
    • 87 pts. Stage III unresectable. Received cetuximab weekly (17 weeks beginning 1 week prior to CRT), RT 63 Gy / 35 fx with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) for 6 weeks, followed by 2 doses of carbo (AUC 6) + paclitaxel (200 mg/m2) on weeks 12 - 17.
    • 2011 PMID 21555682 -- "Phase II Study of Cetuximab in Combination With Chemoradiation in Patients With Stage IIIA/B Non-Small-Cell Lung Cancer: RTOG 0324." (Blumenschein GR Jr, J Clin Oncol. 2011 Jun 10;29(17):2312-8.)
      • Median f/u 21.6 m. Response rate 62%, MS 22.7 m, 2-yr OS 49.3%.
      • Conclusion: combination of cetuximab and chemo/RT is feasible with promising activity. The median and OS were longer than any previous regimen in the RTOG.
  • CALGB 30407 -- Randomized Phase II. Carbo / Pemetrexid + RT +/- Cetuximab
    • 101 pts. Stage III. Arm A) Carboplatin (AUC 5) and Pemetrexid (500 mg/m2) q3w x 4 cycles concurrent with RT 70 Gy, Arm B) Same treatment plus Cetuximab concurrent with RT. Consolidation therapy with up to 4 cycles of Pemetrexid in both arms.
    • 2011 PMID 21747084 -- "Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407" (Govindan R, J Clin Oncol. Published online before print July 11, 2011.)
      • Adenoca in 44%, squamous in 35%. 18-mo OS 58% (Arm A) vs 54%. No significant difference in survival between pts with adenoca and squamous.
      • Conclusion: The regimen of carbo/pemetrexid/RT should be further studied.

Meta-analysis

  • Gustave-Roussy, 2004 PMID 15280345 -- "Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. (Delbaldo C, JAMA. 2004 Jul 28;292(4):470-84.)
    • 65 randomized trials performed 1980-2003 (13,601 patients)
    • Doublet vs. single-agent: better tumor response (OR 0.42), median OS (OR 0.3), 1-year OS (OR 0.80)
    • Triplet vs. doublet: better tumor response (OR 0.66), no impact on survival (OR 1.01, 1.00)
    • Conclusion: doublet better than single-agent; triplet no additional survival benefit

Radiation technique[edit]

RT Dose[edit]

With Concurrent Chemo:

  • RTOG 0617 (ongoing) - Phase III. 4 arm randomization. 60 Gy vs 74 Gy. Concurrent RT + Carbo/Taxol +/- Cetuximab.
    • Arms B and D (the two 74 Gy arms) were closed in 6/2011 after an interim analysis showed the high dose arms crossed a futility boundary. The trial will continue to accrue the 60 Gy arms A and C.
    • ASTRO 2011 Plenary


Without Concurrent Chemo:

  • Memorial Sloan Kettering
    • 2007 PMID 17762758 -- "High-dose radiotherapy for the treatment of inoperable non-small cell lung cancer." (Sura S, Cancer J. 2007 Jul-Aug;13(4):238-42.)
      • Retrospective. 82 patients, inoperable NSCLC Stage I-IIIB (I-II n=55; III n=27). Dose >= 80 Gy using 3D-CRT with sequential chemotherapy
      • 5-year Outcome: Stage I/II LC 67%, OS 36%, median OS 3.4 years; Stage III LC 39%, OS 31%, median OS 2.7 years
      • Conclusion: OS and LC comparable with other dose-escalation studies
    • 2005 (1991-2003) PMID 15830346 -- "Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma." (Rosenzweig KE, Cancer. 2005 May 15;103(10):2118-27.)
      • Phase I dose escalation. 104 patients, 28% Stage I-II, 33% IIIA, 32% IIIB, 6% recurrent. Pneumonitis NTCP had to be <25%. Dose 70.2 -> 75.6 -> 81.0 -> 84.0 -> 90 (1.8 Gy fx for 70.2-81; 2.0 Gy for 84-90). Protocol amended to omit elective nodal irradiation. Chemo: induction given in 16%; no concurrent chemo.
      • Outcome: Unacceptable toxicity at 90 Gy; 84.0 Gy considered MTD. 2-year LC 52%. OS improved significantly if dose >= 80.0 Gy
      • Toxicity: Crude late pulmonary toxicity 7%
      • Conclusion: MTD for NSCLC with NTCP constraint of 25% is 84.0 Gy
  • Michigan (1992-1999)
    • Phase I trial. 104 patients (Stage I 23%, Stage II 4%, Stage IIIA 41%, Stage IIIB 25%, Recurrent 7%). Patients stratified based on Veff into 5 groups, each group escalated independently. Starting doses were 63 Gy, 63 Gy, 65.1 Gy, 69.3 Gy, and 84 Gy. No ENI.
    • 2001 PMID 11134205 -- "Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial." (Hayman JA, J Clin Oncol. 2001 Jan 1;19(1):127-36.)
      • Outcome: MTD only established for largest Veff group at 65.1 Gy. Dose levels for other groups were 75.6 Gy, 84 Gy, 102.9 Gy, and 102.9 Gy
      • Conclusion: Dose escalation protocol reported
    • 2005 PMID 16168827 -- "High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study." (Kong FM, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):324-33.)
      • Median f/u 8.5 yrs. MS 19 mos. 5-yr OS 13%. On multivariate analysis, weight loss and RT dose were significant predictors for OS. 5-yr OS 4% (63-69 Gy), 22% (74-84 Gy), and 28% (92-103 Gy). 5-yr LRC 12%, 35%, and 49%.
      • Conclusion: higher radiation doses associated with improved outcome.

Accelerated RT[edit]

Concomitant boost

  • RTOG 84-07 (1984-89)
    • Phase I/II. 355 pts, ? stage. 45 Gy large fields (primary + regional nodes) + 18 Gy boost (primary and involved nodes only) = 63 Gy. Given as 45/1.8 Gy/5 weeks. Boost given as 10 fractions 2-3 times per week as 2nd fraction separated by 4-6 hrs. Dose escalated from 45+18=63 to 70.2 Gy/5.5 wks (50.4 + 19.8 Gy) to 70.2 Gy/5 wks (45 + 25.2 Gy).
    • PMID 7836079, 1993 — "A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07." Byhardt RW et al. Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):459-68.
      • Acute grade 3 toxicity in 7% vs 14% vs 17%. Grade 4 toxicity in 2-3% for all arms. Late toxicity in 5-9% grade 3 and 0-2% grade 4.
      • Survival not statistically different between arms. MS 9 months, 1-yr OS 39-44%, 2-yr OS 16-21%. For pts with Stage III/KPS > 70/no weight loss (i.e. eligible for CALGB 8433) 2-yr OS, 18-22%.


Hyperfractionated RT with chemotherapy[edit]

  • RTOG 92-04 (1992-94) - phase II randomized
    • 164 pts. Unresectable Stage IIIA-B. Randomized to 1) induction chemotherapy + concurrent chemo/RT (weekly vinblastine x 5, cisplatin days 1+29 followed by RT to 45+18=63 Gy beginning on day 50 with concurrent cisplatin q3week x 3) vs 2) concurrent chemotherapy + hyperfractionated RT (1.2 Gy BID to 50.4+19.2=69.6 Gy in 4 wks with oral etoposide on days 1-10 + cisplatin days 1+8)
    • First report, 1997 - PMID 9212017
    • PMID 12062596, 2002 — "Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04." Komaki R et al. Int J Radiat Oncol Biol Phys. 2002 Jul 1;53(3):548-57.
      • Lower in-field progression for Arm 2 than Arm 1 (26% vs 45% at 2 years; 30% vs 49% at 4 yrs; S.S.). Median, 2-yr OS, and 5-yr OS similar between arms. Higher rate of acute and chronic esophagitis in Arm 2 (37% vs 3.3% acute grade 3-4; 17% vs 4% late grade 3-4).
    • Conclusion: Hyperfractionation with chemo leads to improved local control at the expense of esophageal toxicity.
  • RTOG 94-10 - see above
  • Australia 1989-1995 PMID 10577698 -- "A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial." (Ball D, Radiother Oncol. 1999 Aug;52(2):129-36.)
    • Phase III. 204 with inoperable NSCLC randomized to 1) 60/30 in 6 weeks (R6), 2) 60/30 in 3 weeks (R3), 3) R6 + concurrent carboplatin, or 4) R3 + concurrent carboplatin
    • No difference in OS among groups.
    • Toxicity: hematologic greater with chemo, esophageal greater with ART (R3)
    • Critique PMID 11258343: underpowered for 2x2 design. ART hazard ratio 0.86 (0.56, 1.30), which is consistent with CHART trial results (0.78, SS). Recommend not sacrificing dose intensification at expense of concurrent chemotherapy


Elective nodal irradiation[edit]

  • International Atomic Energy Agency; 2008 PMID 18793953 -- "Report from the International Atomic Energy Agency (IAEA) consultants' meeting on elective nodal irradiation in lung cancer: non-small-Cell lung cancer (NSCLC)." (Belderbos JS, Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):335-42.)
    • Consultant meeting conference in 9/2006.
    • Conclusion: Routine omission may not be advisable in all patients, and may depend on stage, location, and other variables.
  • MSKCC (1991-2005)
    • 2007 PMID 17984185 -- "Involved-field radiation therapy for inoperable non small-cell lung cancer." (Rosenzweig KE, J Clin Oncol. 2007 Dec 10;25(35):5557-61.)
      • Retrospective. 524 patients, definitive IFRT. Only LN+ by biopsy or >=1.5 cm short axis by CT included in CTV. Elective nodal failure (ENF) defined as recurrence in initially LN- in absence of local failure. Median F/U 3.4 years
      • Outcome: ENF in 6%; 2-year elective nodal control 92%, local control 51%; median time to nodal failure 6 months
      • Nodal dose-response (from incidental nodal irradiation): 86% failures in regions receiving dose <45 Gy vs. 14% failures if receiving >45 Gy (SS). In nodal regions receiving <45 Gy, failure rate 1.4% vs. if >45 Gy failure rate 0.6% (SS)
      • Conclusion: IFRT didn't cause significant failure in LN regions not included in CTV
      • Editorial (PMID 17984182): Discrepancy between surgical data and RT data about LN failures. Discussion about incidental nodal irradiation and its dose-effect on nodal failure
    • 2001 PMID 11395236 -- "Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy." (Rosenzweig K, Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):681-5.)
      • 171 pts tx'd w/ 3D-CRT at MSKCC b/w 1991-98. Only +nodes by biopsy or >/= 1.5 cm in short axis on CT were included in CTV.
      • Tumor control at 2 yrs 38%, elective nodal control 91%.
      • Conclusion: Local control much more problematic than elective nodal control; omission of elective nodal irradiation did not significantly worsen nodal failures outside of CTV.
  • Shandong, 2006 (China) PMID 17551299 -- "A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer.." (Yuan S, American Journal of Clinical Oncology, 2007 30(3):239-44)
    • Randomized. 200 patients, inoperable Stage III NSCLC, treated with induction chemo x2 cycles followed by concurrent chemo-RT, followed by 2-3 cycles. RT randomized to elective nodal irradiation (ENI) vs. involved-field radiation (IFRT). Dose IFRT to 68-74 Gy and ENI to 60-64 Gy. IFRT defined as pre-CHT tumor volume and any mediastinal nodes bx+ or >1cm short-axis on CT. Chemo cisplatin-based doublet.
    • Toxicity: Pneumonitis ENI 29% vs. IFRT 17% (SS)
    • 2-year failure: local ENI 49%, IFRT 41%. Omission of ENI did not lead to isolated nodal failures
    • Survival: 2-years ENI 26% vs. IFRT 39% and 3-years 19% vs. 27% (SS)
    • Conclusion: No isolated nodal failures, local control still major issue, successful dose escalation to 68-74Gy and survival difference by omitting elective nodal irradiation
  • RTOG Analysis, 2003 PMID 12871784 -- "The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data." (Emami B, Lung Cancer. 2003 Aug;41(2):207-14.)
    • 1705 pts from 4 RTOG trials (7811, 7917, 8311, 8407) analyzed for in-field/out-of-field recurrence patterns.
    • Neither in-field progression or 2yr OS were affected by adequacy of nodal coverage in mediastinum, ipsi supraclav, contralat hilum.
  • Rotterdam, 2002 PMID 12419425 -- "Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy." (Senan S, Int J Radiat Oncol Biol Phys. 2002 Nov 15;54(4):999-1006.)
    • 50 pts w/ stage III NSCLC tx'd w/ sequential chemo + xrt to 70 Gy w/ omitted elective nodal irradiation.
    • 27% had in-field recurrences, 18% had distant mets alone, no elective nodal failures


Reviews

  • PMID 11040331, 2000 — "Point: the potential importance of elective nodal irradiation in the treatment of non-small cell lung cancer." Liengswangwong V et al. Semin Radiat Oncol. 2000 Oct;10(4):308-14.
  • PMID 11040332, 2000 — "Counterpoint: better radiation treatment of non-small cell lung cancer using new techniques without elective nodal irradiation." Williams TE et al. Semin Radiat Oncol. 2000 Oct;10(4):315-23.

Induction chemo followed by conventional RT vs. HART[edit]

  • No difference in survival or response rate


  • ECOG 2597, 2005 (1998-2001) - After induction chemotherapy, standard fractionation RT vs hyperfractionated accelerated radiation therapy (HART). No concurrent chemo. Closed early due to low accrual.
    • PMID 15837967 — "Phase III Study of the Eastern Cooperative Oncology Group (ECOG 2597): Induction Chemotherapy Followed by Either Standard Thoracic Radiotherapy or Hyperfractionated Accelerated Radiotherapy for Patients With Unresectable Stage IIIA and B Non-Small-Cell Lung Cancer." Belani CP et al. J Clin Oncol. 2005 Jun 1;23(16):3760-7.
    • 141 pts. Unresectable IIIA or IIIB. Induction chemo with carbo/taxol x 2 cycles q3weeks. Randomized to once-daily RT (QD) 64 Gy at 2 Gy/fx vs HART 57.6 Gy TID in 12 fx over 15 days. For HART, 1st and 3rd daily fractions were 1.5 Gy large field, 2nd fx was boost field 1.8 Gy; at least 4 hours between fractions.
    • No diffence in OS or response, but there was a trend for improved survival.
    • Weak study since no concurrent chemo/RT

RT Timing[edit]

  • Kragujevac (Yugoslavia) PMID 15577441 -- "Interfraction interval in patients with stage III non-small-cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy: final results in 536 patients." (Jeremic B, Am J Clin Oncol. 2004 Dec;27(6):616-25.)
    • Retrospective review of 3 Phase III and 1 Phase II. 536 patients treated with Hfx RT, 285 patients interfraction interval (IFI) 4.5-5.0 hrs, 251 patients IFI 5.5-6.0 hrs
    • Survival: short IFI significantly better OS, LRFS

IMRT[edit]

  • MD Anderson; 2007 (2002-2005) PMID 17321067 -- "Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy." (Yom SS, Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):94-102. Epub 2007 Feb 22.)
    • Retrospective. 68 patients, advanced NSCLC, treated with IMRT and concurrent chemotherapy. Compared with 222 similar patients treated with 3D-CRT. Median F/U 9 months
    • Dosimetry: Median dose IMRT 63 Gy vs. 3D-CRT 63 Gy. Median tumor volume 194 mL vs. 142 mL
    • Toxicity: 1-year Grade 3+ pneumonitis IMRT 8% vs. 3D-CRT 32% (SS)
    • Conclusion: In advanced NSCLC treated with concurrent chemo-RT, IMRT resulted in significantly lower level of Grade 3+ pneumonitis

Chemotherapy[edit]

  • Japan WJTOG 3405
    • Randomized. 172 chemo-naive patients, age <=75, Stage IIIB/IV NSCLC or postop recurrence, with EGRF mutation (exon 19 deletion or L858R point mutation). Arm 1) Gefitinib 250 mg QD vs Arm 2) cisplatin 80 mg/m2 and docetaxel 60 mg/m2 Q3W x 3-6 cycles. Primary endpoint PFS
    • 2009 PMID 20022809 -- "Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial." (Mitsudomi T, Lancet Oncol. 2009 Dec 18. [Epub ahead of print])
      • Outcome: Median PFG gefitinib 9 months vs. cisplatin/docetaxel 6 months (SS)
      • Toxicity: Myelosuppression, alopecia, and fatigue more frequent in cisplatin/docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea more frequent in the gefitinib group. Two patients (2%) developed interstitial lung disease
      • Conclusion: Patients with EGFR mutations have longer PFS on gefitinib than on cisplatin/docetaxel
  • ECOG 4599 PMID 17167137 -- "Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer." (Sandler A, N Engl J Med. 2006 Dec 14;355(24):2542-50.)
    • Randomized. 878 patients with IIIB (malignant pleural effusion) or IV NSCLC, no squamous cell tumors, no brain mets, no hemoptysis, no ECOG >1. Treated with 1) Paclitaxel/carboplatin vs. 2) paclitaxel/carboplatin + bevacizumab, until disease progression or toxicity
    • Median OS: carbo/taxol 10.3 months vs. carbo/taxol/bevacizumab 12.3 months (SS)
    • Treatment related deaths: 2 vs. 15 (5 pulmonary hemorrhage)
    • Conclusion: Bevacizumab improves survival, but significant risk of treatment-related death

Radioprotectors/Sensitizers[edit]

Amifostine[edit]

  • RTOG 9801 -- Induction -> concurrent chemo-AHFX RT +/- amifostine
    • Randomized. 243 patients with unresectable NSCLC (II-IIIB). Induction paclitaxel 225 mg/m2 and carboplatin AUC6 x2 cycles, then concurrent chemo-RT. RT 69.6/58 @ 1.2 GY BID with concurrent paclitaxel 50 mg/m2 and carboplatin AUC2. During chemo-RT Arm 1) placebo vs. Arm 2) amifostine 500 mg IV (72% received it per protocol)
    • 2005 PMID 15800308 -- "Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01." (Movsas B, J Clin Oncol. 2005 Apr 1;23(10):2145-54.)
      • Outcome: Grade 3+ acute esophagitis AM 30% vs no AM 34% (NS); patient reported dysphagia significantly better with AM (p=0.02). But, AM higher acute nausea (SS), vomiting (SS), CV toxicity (SS), and infection/neutropenia (SS). No difference in QOL
      • Survival: AM 17.3 months vs. no AM 17.9 months (NS)
      • Conclusion: Amifostine did not significantly reduce grade 3+ esophagitis, though patient self-assessment suggested an advantage
    • 2009 PMID 19858383 -- "Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801." (Movsas B, J Clin Oncol. 2009 Oct 26. [Epub ahead of print])
      • 239 patients, 91% baseline QOL score. Multivariate analysis for OS: KPS, stage, sex, age, race, marital status, histology, location, Hgb, tobacco, amifostine, QoL scores (QLQ-C30, LC-13). Median F/U 5 years if alive, 17 months for all
      • Outcome: On multivariate analysis, only baseline global QoL score was prognostic for survival; no other variables were significant. Patients with QoL score <67 (median value) had 70% higher rate of death (SS); 10-point increase in QoL corresponded to 10% decrease in hazard of death. Both physical functioning (QLQ-30) and dyspnea (LC-13) were independently predictive for OS on univariate analysis
      • Conclusion: Quality of life score replaced all known prognostic factors as sole predictor for long-term survival

Metoclopramide[edit]

  • Institute for Cancer Research, Oslo (1995-1998) -- observation vs metoclopramide
    • 2010 PMID 20165821 -- "CT Density in Lung Cancer Patients After Radiotherapy Sensitized by Metoclopramide : A Subgroup Analysis of a Randomized Trial." (Dale E, Strahlenther Onkol. 2010 Feb 22. [Epub ahead of print])
    • Randomized. Trial stopped prematurely due to financial difficulties. 30 patients enrolled, 16 analyzable, NSCLC stage IIIA/IIIB. RT 60/33. Arm 1) observation vs Arm 2) concurrent metoclopramide 2mg/kg TIW. Analysis of CT density
      • Outcome: Lung density increased with dose (SS). Patients on metoclopramide less increase in tissue density (SS)
      • Conclusion: Metoclopramide and large radiation dose seemed to protect against fibrosis development

Reviews and Guidelines[edit]

  • ASCO 2003 - PMID 14691125 — "American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003." Pfister DG et al. J Clin Oncol. 2004 Jan 15;22(2):330-53.

External links[edit]