chemo rt in nsclc 2011- jk
TRANSCRIPT
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Combined Chemotherapy and Radiation in NSCLC.
Where do we put the chemo?
Jeremy Kilburn, MD
November 8, 2011
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Outline
• 1) CHEMO AND RADIATION vs Radiation Alone• 2) Sequential vs CONCURRENT CHEMO
• Auperin, JCO 2010 (NSCLC Col Grp Meta Analysis)• Curran, JNCI 2011 (RTOG 9410)
• 3) Concurrent chemoRT plus/minus INDUCTION• Belani, JCO 2005 (LAMP)• Vokes, JCO 2007 (CALGB 39801)
• 4) Elective nodal irradiation (B/C we are not covering enough in this lecture)
• Rosenzweig, JCO 2007• Yuan, AJCO 2007
• 5) Concurrent chemoRT plus/minus CONSOLIDATION• Gandara, JCO, 2003 (SWOG 9504)• Hoover, JCO, 2008 (HOG)
• Conclusions…
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Should radiation be delivered alone or with chemotherapy?
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Study-Phase III Chemotherapy Results
Le Chavalier et al. 1991 (French Group). JNCI. n=353
3 months of induction and adjuvant Vindesine, cyclophosphamide, Cisplatin, Lomustine.
MS 10 vs 12 mos. Improved DM rate.
Schaake-Konig et al. 1992. (EORTC) NEJM. n=331
Concurrent daily Cis 3 yr OS 2% vs 16%.
CALGB 8433. Dillman et al. 1996. JNCI. n=153
2 cycles of induction cisplatin/Vinblastine.
MS 9.6 vs 13.7 mos.
RTOG 8808. Sause et al. 2000. Chest. n=490
2 cycles of induction Cisplatin/Vinblastine
MS 11.4 vs 13.2 mos
Radiation Alone vs Chemo and Radiation
All studies confirmed benefit of combined treatment.MS 9-12 mos versus 12-14 mos.
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Should radiation be delivered before (sequential) or during (concurrent) radiation?
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• Randomized Trials directly comparing concomitant versus sequential chemotherapy.
• Primary Outcome-OS• Secondary Outcome-PFS, LRF, DF, Acute Toxicity.
• 6 Trials. 1205 pts w/ M FU 6 yrs.
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Overall Survival Favors Concurrent TherapyAbsolute survival benefit of 4.5% at 5 yrs. (15.1% vs 10.6%)
• Toxicity:• Acute Gr 3/4
Esophageal• 18% vs 4%
• Acute Gr 3/4 Pulmonary• No diff.
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Local Regional Control is improved. Absolute diff6% at 3 yrs. (35% vs 28.9%)
Distant Failure is not affected.40% at 3 yrs.
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Conclusions• Significant reduction in mortality with concomitant
therapy, 4.5% absolute benefit at 5 yrs. • “The survival improvement is likely to be due to a
decrease of locoregional failures as there was no difference between the two treatment options in distant failure rates.”
• Fit patients with minimal co-morbidities. • 50% of pts with WHO PS of 0.
• Elective nodal irradiation was systematic in these trials.
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RTOG 9410
• Combination chemo and radiation confers advantage over RT alone, but optimal delivery is unknown.
• 3 Arm Phase III Trial. n=610. Primary Endpoint-OS• CT Staging
• Stage II 2%• Stage IIIA 42%• Stage IIIB 55%• KPS 70-80. 23%• KPS 90-100. 77%
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Methods
• 45 Gy at 1.8 Gy/Fx to elective nodal regions.• 18 Gy at 2 Gy/Fx to known disease.
• Rx Compliance was excellent. ~85% in each arm.
ARM 1Sequential Cis/VinblastineConventional Daily Radiation
ARM 2Concurrent Cis/VinblastineConventional Daily Radiation
ARM 3Concurrent Cis/VinblastineHyperfractionated Radiation
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Results-M FU 11 yrs• Toxicity
• Acute: Higher with concurrent therapy.• Gr 3/4 Acute esophagitis. 4%, 22%, 45%. • 2% (n=14) Grade 5 fatality equal between arms.
• Mainly neutropenic sepsis. • Late: No difference.
• Gr 3/4 esophagitis. 1-4%. • 1% (n=8) Grade 5 fatality. Mainly pulmonary.
OS MS p=.046
5 yr OS
Arm 1 14.6 mos 10%
Arm 2 17.0 mos 16%
Arm 3 15.6 mos 13%
Patterns of Failure Analysis. No statistical Differences.
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Conclusions• 2 month increase in median survival or 5% increase
in 3 yr OS with concurrent chemotherapy and radiation vs sequential treatment.
• Acute esophagitis is worse but late toxicity does not differ.
• “This study does support the hypothesis that concurrent therapy should be the standard nonoperative regimen for eligible patients.”
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Previous trials treated elective nodes, but can this be safely omitted and thus spare toxicity?
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• MSKCC Retro Series. n=524. 1991-2005.• 3D-CRT plans. Treated only LN regions pathologically or
radiographically involved by tumor .• Began treating IFI in 1991 after dose escalation trials
proved too toxic with elective nodal coverage.
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Methods• 60% had PET staging.• LN considered involved
if..• Path proven• > 1.5 cm• PET avid
• 42% RT Alone• 41% Sequential Chemo• 15% Concurrent Chemo• Stage III Pts
• 72% sequential or concurrent
• 28% RT alone
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Results41 mos FU• 32 pts suffered
failures in ENI areas. (6.1%)
• 2 yr Control Rates• Primary 51%• EN area 92%
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Conclusions
• Use of IFRT does not lead to significant amount of nodal failures in untreated regions.
• Acceptable method which allows for dose escalation while minimizing toxicity. (although no toxicity data provided in paper)
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• Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Jinan, Shandong Province, China; and Tianjin Medical University, Tianjin City, China.
• Impetus to avoid ENI in this trial based on theory of dose escalation and avoidance of pulmonary and esophageal toxicity.
• This is balanced by concern for nodal recurrences in untreated regions.
• Single Center Randomized Phase III. n=200. Primary Endpoint-LC
• (CT Staging, NO PET)
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Methods• 1997-2001.• 200 pts. Stage IIIA/B Non Resectable• 2 Cycles of q 21 day induction chemo
• Cisplatin 25 mg/m2, Days 1-3 • Etoposide 75mg/m2, Days 1-5.
• 3D-CRT delivered concurrently with cycle 3
Randomized
VERSUS
• Elective Nodal Irradiation
• 60 to 64 Gy• Same GTV. • Mediastinum and
Ipsi hilum to 44 Gy. • Re-Scan and boost
16-20 Gy.
• Involved Field Irradiation
• 1.8 to 2 Gy to 68 to 74 Gy for IFI.
• GTV=pre-chemo volume and LN’s > 1 cm.
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Results-IFI vs ENI. Med FU 27 mos
• Toxicity:• Radiation Pneumonitis
• 17% vs 29%. p=.044
• Similar results in esophagitis and radiation pericarditis, although not SS.
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• Follow up. CT scans at 3 and 6 mos
and then CXR q 3 mos. • 5 yr OS.
• 25.1% vs 18.3%. NS
• Overall Response Rate• 90% vs 79%. p=.032
Results
Overall Survival
MS-20 mos vs 15 mos
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Patterns of Failure-IFI vs ENI
• Med PFS• 17 mos vs 11.5 mos. p=.15.
• 5 yr LC. PRIMARY ENDPOINT• 51% vs 36%. p=.032.
• Failure in Elective nodal regions.• 7% vs 4%.
• Involved Field failure was main relapse site in both arms.• 5 yr LC 62% vs 45%. p=0.16
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Conclusions• Improved overall response and local control achieved
with involved field irradiation. • Allowed for dose escalated RT to be delivered.
• Of course, was the escalated RT responsible for the improved response and LC rates? • (RTOG 0617)
• LC rates were still the major site of failure in both arms.
• My interpretation…• Although LC favored IFI arm, this study
simply justifies the omission of ENI. • In other words, we don’t see increased
failures in elective nodal regions or diminished survival.
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Is there a role for Induction Chemotherapy with concurrent chemoradiotherapy?
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LAMP (Locally Advanced Multimodality Protocol)
• Randomized Phase II• Optimal sequencing of and integration of
paclitaxel/carboplatin with standard daily thoracic radiation.
• Stage III unresected NSCLC• Results compared to historical RTOG data
• RTOG 88-08 (Cisplatin/Vinblastine)
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Methods• Stage IIIA and IIIB• Same Radiation-63 Gy in 34 Fx’s.
• 45 Gy in 25 Fx’s to initial fields.• Boost nodal and primary disease to 63 Gy
• 18 Gy in 9 Fx’s• Post Chemo volumes in Arms 1/2.
• All Staged w/ CT
I
Sequential Induction→Concurrent Concurrent →Consolidation
Treatment compliance no different in three Groups. ~70%
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Results• 276 pts• Med FU 40 mos• Primary Endpoint-Med OS• Closed early after results of RTOG
94-10 were made available.
Sequential vs Historical Control
Induction-Concurrent vs Historical Control
Survival OS PFS
Arm 1 13.0 mos 9 mos
Arm 2 12.7 mos 6.7 mos
Arm 3 16.3 mos 8.7 mos
Concurrent vs Historical Control
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Toxicity• Grade 3/4 Toxicity during induction
• Granulocytopenia in ~35%• Grade 3/4 Toxicity during Radiation
• Esophagitis• Arm 1-3%• Arm 2-19% (ENI)• Arm 3-28%
• 3 Grade 5 Toxicities due to infection. • 1 in Arm 2, 2 in Arm 3.
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Conclusions
• Although study not powered to detect survival advantage with concurrent chemoradiation, authors noted a trend towards improved survival.
• This improvement must be balanced with an increased rate of Grade 3 esophagitis.
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• CALGB 39801. Randomized Phase III• Concurrent chemoradiotherapy plus or
minus induction chemotherapy.• 366 pts• Stage IIIA, IIIB
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Methods
• Radiation• Prechemo volume for both arms• Initial field to 44 Gy: ipsi hilum and
mediastinum.• Boost 22 Gy: ipsi hilum and
reduced mediastinum avoiding cord.
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Results• Reponse to induction…
• PR 31%• Stable 39%• Progression 6%
Toxicity-Induction Rx
Toxicity- Concurrent Therapy
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Results
Survival 12 vs 14 mos
Survival 16 vs 14 mos
Survival-ITT AnalysisSurvival-Subgroup
OS (p=.3)
Dist Failures
Gr 3/4 Esophagitis
Gr 3/4 Dyspnea
Arm 1 12 mos n=86 32% (30%/2%)
14%
Arm 2 14 mos n=84 36% (28%/8%)
19%
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Conclusions
• Study failed to show an advantage to induction chemotherapy.
• Addition of induction chemotherapy to concurrent chemoRT adds toxicity without affecting survival.
• “CALGB 39801 reaffirms the status of early concomitant chemoradiotherapy as current standard therapy for patients with unresectable stage IIIB NSCLC.”
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Can we improve survival by the addition of consolidative chemo?
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Hoosier Oncology Group. Phase III • Test whether survival in SWOG 9504 was due to
consolidative chemo.• Gandara_2003_JCO
• Phase II. Cis/Etop c XRT to 61 Gy. Consolidative Docetaxel x 3 cycles.
• Showed improved OS compared to historical control (SWOG 9019 without consolidative chemo)
• MS 26 vs 15 mos.
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Methods
• 203 pts randomly assigned after cis/etop and concurrent radiation to 59.4 Gy (45 Gy to mediastinum and 14.4 Gy boost to gross disease) to…• Consolidative Docetaxel 75 mg/m2 q 21 days x 3
cycles.• VS
• Observation
• Hoosier Oncology Group• Community based cooperative group.
• Trial later joined by US Oncology.
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Results-Med FU 42 Mos. • Closed after 203 pts for evidence of futility.
MS 21.7 vs 21.2 mos.
Overall Survival
Grade 3 to 5 Non-Hem Toxicity • 28.8% of pts required hospitalization during consolidation compared to 8.1% in observation arm.
PFS
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Conclusions• “Consolidation docetaxel after PE/XRT results in
increased toxicities but does not further improve survival compared with PE/XRT alone.”• Favorable survival compared to previous studies.
• 22 mos median survival. • 3 year OS 30.2%.
• Why did the Ph III fail to confirm results of SWOG 9504?
• More strict critiera for pulm fxn?• Differences in amount of drug delivered or
observed toxicities? • Real lack of benefit?
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What are the current trials doing?
• RTOG 0617 (prior to Hoosier Onc Group)• 60 vs 74 Gy c/ concurrent carbo/Taxol
• XRT Sensitizing chemo doses. Carbo AUC 2, Paclitaxel 45 mg/m2
• Plus or minus Cetuximab• Includes 2 cycles of consolidative chemo.
• CALGB 30605• Poor Risk Stage III NSCLC. PS 2 pts OR
PS 0-1 w > 10% wt loss • Induction Carbo/Abraxane x 2 cycles. • Radiation at Day 43 c daily Erlotinib.
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Conclusions…Combined Chemotherapy and Radiation in NSCLC.
Where do we put the chemo? Depends…• In healthy Stage IIIA/B non-resectable pts
• Concurrent with radiation.• Confers ~5% survival advantage compared to
chemotherapy alone. • No role for induction or adjuvant chemotherapy.
• In poor PS pts• Consider strategy employed in CALGB 30605.
• In healthy Stage IIIB with C/L hilar, SCV disease, or disease too large to encompass in radiation field.
• Induction chemo followed by concurrent radiation and chemo to post chemo volume.