Combined Chemotherapy and Radiation in NSCLC.

Where do we put the chemo?

Jeremy Kilburn, MD

November 8, 2011

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…

Should radiation be delivered alone or with chemotherapy?

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.

Should radiation be delivered before (sequential) or during (concurrent) radiation?

• 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.

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.

Local Regional Control is improved. Absolute diff6% at 3 yrs. (35% vs 28.9%)

Distant Failure is not affected.40% at 3 yrs.

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.

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%

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

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.

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.”

Previous trials treated elective nodes, but can this be safely omitted and thus spare toxicity?

• 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.

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

Results41 mos FU• 32 pts suffered

failures in ENI areas. (6.1%)

• 2 yr Control Rates• Primary 51%• EN area 92%

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)

• 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)

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.

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.

• 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

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

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.

Is there a role for Induction Chemotherapy with concurrent chemoradiotherapy?

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)

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%

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

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.

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.

• CALGB 39801. Randomized Phase III• Concurrent chemoradiotherapy plus or

minus induction chemotherapy.• 366 pts• Stage IIIA, IIIB

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.

Results• Reponse to induction…

• PR 31%• Stable 39%• Progression 6%

Toxicity-Induction Rx

Toxicity- Concurrent Therapy

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%

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.”

Can we improve survival by the addition of consolidative chemo?

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.

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.

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

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?

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.

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.