Locally Advanced NonSmall Cell Lung Cancer
Grand Rounds 5 May 2006
Staging “reminder” -Definition of LANSCLC
Mountain CF. The international system for staging lung cancer. Semin Surg Oncol. 2000 Mar;18(2):106-15.
Mountain CF. The international system for staging lung cancer. Semin Surg Oncol. 2000 Mar;18(2):106-15.
Keys to Management of LA- NSCLC
Three basic compartments:
Local Disease
Primary lung lesion Local Nodes Mediastinal Nodes Chest Wall
Distant Systemic Metastases ? Sanctuary Site- Brain
General Direction of Data
Flavors of LA- NSCLC
“Occult” LANSCLC “Resectable” LANSCLC “Unresectable” LANSCLC
Difficulties in Reviewing the Trials
Staging system has changed
1997 Revison of TNM system moved T3N0 tumors from stage III to stage IIB PET scanning has become much more common staging modality- discovery of clinically silent metastases Greater use of directed mediastinal evaluation
Staging methods have changed
Inhomogeneous populations in trials
Inadequately powered trials Outdated chemo regimens
Even More Issues
Trials include data tainted by enrollment bias-
patients need good enough PS to go on trial and tolerate therapy. Treatment can be split into operable Stage III and inoperable stage III Also tend to exclude “wet” IIIB (malignant effusion). They behave and are treated like metastatic disease
Significance of degree of N2 diseaseFrench series
686 patients with documented N2 disease
treated by resection from 1989-1996
CT staged patients Mediastinoscopy for nodes > 1 cm (70% of time)
Minimal N2 disease at one level (mN2L1) Minimal N2 disease at many levels (mN2L2+) Clinical N2 (>1 cm, med [+] or med not done and [+] confirmed at thoracotomy)at one level (cN2L1) Clinical N2 at multiple levels (cN2L2+)
Defined postoperatively as
Fabrice Andre, et al. Survival of Patients With Resected N2 Non–Small-Cell Lung Cancer: Evidence for a Subclassification and Implications. JCO Aug 16 2000: 2981–2989.
Significance of degree of N2 disease
Fabrice Andre, et al. Survival of Patients With Resected N2 Non–Small-Cell Lung Cancer: Evidence for a Subclassification and Implications. JCO Aug 16 2000: 2981–2989.
Influence of Number and Location of N2 Disease on Survival
Watanabe: Chest 100; 1991
General Direction of Data
Flavors of LA- NSCLC
“Occult” LANSCLC “Resectable” LANSCLC “Unresectable” LANSCLC
Truly Minimal N2 involvement: Stage IIIA disease “in Retrospect”
Some patients have Stage I or II disease on
initial evaluation, and are upstaged only after pathologic evaluation Best data for treatment is from the recent adjuvant trials
Stage III patients in Adjuvant Trials
Stage
IA=12% IB=32% II=26% IIIA=18%
ANITA
IALT
NCI-C
CALGB
Not Tested
Positive
Negative*
*Failed to retain significant differences on subset analysis
Positive Adjuvant Trials
Stages Included
IALT N=1867 Anybody and everybody
10% IA 25% IB, 25% II, 40% III
Regimen
“You name it” CIS + Navelbine or Etoposide
OS advantage
44.5% vs. 40.4% at 5 years
ANITA N= 840
CALGB N= 344
IB 35% II 30% IIIA 35%
IB only
Cisplatin + Navelbine
51%vs 43% at 5 years
71% vs 59% at 4 years
Carboplatin + Taxol
NCIC (JBR.10) N= 482
IB II
45% 55%
Cisplatin + Navelbine
69% vs 54% at 5 years
Adjuvant XRT
Randomized trial- LCSG
230 pts with resected squamous cell NSCLC 1/3 stage III 2/3 stage II Randomized to postoperative RT (50 Gy) or no further therapy No OS difference Locoregional recurrences 41% vs 3% PORT metanalysis 2128 patients in nine randomized trials 1966- 1994 7 percent absolute reduction in 2-yr survival overall No survival difference in stage III patients
(1) Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 1986 Nov 27;315(22):1377-81. (2) Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998 Jul 25;352(9124):257-63.
Adjuvant Chemoradiation
No randomized comparisons to no adjuvant
therapy, to adjuvant chemotherapy, or to sequential therapy Single negative ECOG study comparing to XRT alone, but mixed stage II and stage III population, with poor treatment compliance
“Incidental” Stage III: My Conclusions
Those with incidentally discovered N2
disease may have better outcomes Adjuvant chemotherapy appears to be a reasonable strategy to improve outcomes The role of additional radiation is unclear at this time
“Unresectable” Stage III
Heterogeneous population
N3 patients Bulky N2 Not fit for surgery
Some solid phase III data, some
extrapolations based on phase II
Sequential Chemo XRT better than XRT alone
2 year OS CALGB 8433 (1,2)*
Intergroup (3)
Cis100/ VBL5
5- year OS 17% vs 6%
26%vs 13%
32% vs 19% 8% vs 5%
1. 2.
3.
Dillman R, Seagren S, Propert K, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940-945, 1990 Dillman RO, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-5, 1996 Sause W, Kolesar P, Taylor SI, et al: 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. Chest 117:358-64, 2000
Full- dose concurrent Trials
Trial Chemo
Cis 100mg/m2 q4 VBL 5mg/m2/wk Cis 80mg/m2 q4 wk Mito 8mg/m2 q4 wk Vindesine 3mg/m2 d1,8 q 4 wk
XRT
OS
Notes
RTOG 9410 (1) WJLCG (2)
60Gy Split course XRT
21%vs 12% (4yr)
(p=0.046).
16.9% vs 10.1% (4yr)
(p=0.03998).
17% Brain as 1st relapse
(1)Curran WJ, Scott CB, Langer CJ, et al: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 22:621 (abstr 2499), 2003 (2)Furuse K, Fukuoka M, Kawahara M, et al: 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. J Clin Oncol 17:2692-, 1999
RTOG 9410
Toxicity Data
SWOG Stage IIIB phase II data
G4N G3/4 MST 5 yr Esop OS 32% 12/8% 15mos 15%
9019
N=83
cisplatin plus etoposide (PE) with qd RT (45 Gy). If no progression, RT to 61 Gy Followed by 2 X cisplatin plus etoposide consolidation
9504
N=50
PE+ 61 Gy RT followed by consolidation docetaxel 75-100 mg/m2 every 21 days for 3 cycles
54% 12/5% 26mos 29%
P: 50 mg/m2 days 1, 8, 29 and 36, E: 50 mg/m2 days 1-5 and 29-33
“Confirmatory” Trials
HOG LUN 01-24
Randomize to PE + XRT as in SWOG trials +/consolidation docetaxel Randomized to PE + XRT + con docetaxel +/maintenance gefitinib
Int S0023
ASCO 2005, Kelly et al. Low incidence of pneumonitis on SWOG 0023: A preliminary analysis of an ongoing phase III trial of concurrent chemoradiotherapy followed by consolidation docetaxel and gefitinib/placebo maintenance in patients with inoperabl e stage III non-small cell lung cancer
Toxicity Data
Other Clinical Trial Directions
Chemo XRT + Avastin feasibility trials Phase III Carbo/ Taxol XRT +/- Thalidomide
Anti- EGFR antibodies +/- CXRT Altered fractionation schemes
Unresectable: My Conclusions
Combined chemoradiation may provide long- term
disease free survival in selected fit patients
Appears superior to radiation alone Appears superior to sequential chemoradiation Appears to be a valid strategy for all stage III and unresctable patients Comes with the cost of increased toxicity
The “favored” regimen is unclear at this time Unknown if “consolidation” is useful (HOG will
hopefully answer)
Operable Stage III
What is useful?
Radiation alone? (No) Surgery Alone? (No) Surgery chemo (yes) Chemoradiation alone? (yes) Chemo Surgery? CXRT Surgery?
INT 0139 Design: Is surgery necessary?
PS 0-1 and T1-3, pN2, M0 NSCLC were randomized if resection was technically feasible. cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1-5, d29-33 (PE) and RT to 45 Gy starting day 1 +/- surgical resection (if nonprogressed) vs to 61Gy Consolidation with 2 X EP
K. S. Albain, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005 Abstract No: 7014
K. S. Albain, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005 Abstract No: 7014
Early mortality rates
Treatment-related deaths
Arm 1, 16 (7.9%), of which 10 (5.0%) were within 30 days postop Arm 2, 4 (2.1%).
Deaths by type of surgery
5/23 (22%) simple pneumonectomies 9/31 (29%) complex pneumonectomies 1/98 (1%) lobectomies.
K. S. Albain, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005 Abstract No: 7014
Adjusted for pneumonectomy
K. S. Albain, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005 Abstract No: 7014
K. S. Albain, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005 Abstract No: 7014
Conclusions from 0139
No benefit to adding surgery to CXRT in the
entire population Unplanned subset analysis suggests that there may be a benefit if you don’t need a pneumonectomy
Operable Stage III
What is useful?
Radiation alone? (No) Surgery Alone? (No) Surgery chemo (yes) Chemoradiation alone? (yes) Chemo Surgery? CXRT Surgery? (don’t know)
RTOG 0412
Opposing question: Is radiation an essential component of therapy in operable N2 disease?
From: ASCO 2006 Educational Book. Albain, wt al.
Overall Conclusions
Incidentally discovered N2 disease may be
treated with adjuvant chemotherapy All other LA- NSCLC may be reasonably treated with CXRT “Resectable” N2 disease continues to not have a clear treatment strategy, although surgery may play a role
This year’s trophy
Brain Metastases
In modern series, chemoradiotherapy approaches
have allowed for enough prolongation of survival to demonstrate significant brain metastasis rate.
Choi Stuschke SWOG 8805 Andre Law
Brain Metastasis rate Overall As 1st site N/A 30% 54% 30% 21% 15% 22% 15% 26%
Surgical Series
•Retrospective review of 177 patients who underwent multimodality therapy at B&W
•34% 3- year OS •34% developed brain mets as 1st site of recurrence, 40% at any time.
Mamon HJ, et al. High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and Radiation . JCO Mar 1 2005: 1530–1537.
Clinical Trials utilizing PCI
Trial Brain Mets OS notes
RTOG (1) n=187 VA (2) n= 323 (3) n= 97
19% vs 9% (NS) 13% vs 6% (in NSCLC) 27% vs 4%
NS NS NS
XRT alone Mixed pop XRT alone CXRT
(1) Russell AH, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1991 Aug;21(3):637-43. (2) Cox JD, at al.Cranial irradiation in cancer of the lung of all cell types. JAMA. 1981 Feb 6;245(5):469-72. (3) Umsawasdi T, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol. 1984;2(3):253-9.
Brain Metastasis/ PCI Summary
Brain metastases appear to be an important
site of 1st relapse in LA-NSCLC treated with combined modality approaches It has been demonstrated that that PCI can decrease brain recurrence rate, but no evidence of affecting mortality in old trials This approach remains a research question
RTOG 0214 will randomize Stage IIIA/B patients post definitive therapy to 30Gy PCI
Conclusions
Incremental improvement in the outcomes of
LA- NSCLC has been demonstrated with combined modality approaches The “correct” strategy has not yet been worked out, but several options are available:
For incidentally discovered LA- NSCLC: adjuvant chemo alone For microscopic, “operable” N2 disease, For “inoperable” LA disease, primary chemoradiation is a standard of care