4. Radiation Alone vs Chemo and Radiation
Study-Phase III Chemotherapy Results
Le Chavalier et al. 1991 3 months of induction and MS 10 vs 12
(French Group). JNCI. adjuvant Vindesine, mos.
n=353 cyclophosphamide, Improved DM
Cisplatin, Lomustine. rate.
Schaake-Konig et al. Concurrent daily Cis 3 yr OS 2% vs
1992. (EORTC) NEJM. 16%.
n=331
CALGB 8433. Dillman et 2 cycles of induction MS 9.6 vs 13.7
al. 1996. JNCI. n=153 cisplatin/Vinblastine. mos.
RTOG 8808. Sause et al. 2 cycles of induction MS 11.4 vs
2000. Chest. n=490 Cisplatin/Vinblastine 13.2 mos
All studies confirmed benefit of combined treatment.
MS 9-12 mos versus 12-14 mos.
5. Should radiation be delivered
before (sequential) or during
(concurrent) radiation?
6. • 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.
7.
8. Overall Survival Favors Concurrent Therapy
Absolute 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.
10. 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.
11. 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%
12. Methods
ARM 1
Sequential Cis/Vinblastine
Conventional Daily Radiation
ARM 2
Concurrent Cis/Vinblastine
Conventional Daily Radiation
ARM 3
Concurrent Cis/Vinblastine
Hyperfractionated Radiation
• 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.
13. 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 5 yr
p=.046 OS
Patterns of Failure Analysis. Arm 1 14.6 mos 10%
No statistical Differences. Arm 2 17.0 mos 16%
Arm 3 15.6 mos 13%
14. 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.”
15. Previous trials treated elective
nodes, but can this be safely
omitted and thus spare toxicity?
16. • 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.
17. 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
18. Results
41 mos FU
• 32 pts suffered
failures in ENI areas.
(6.1%)
• 2 yr Control Rates
• Primary 51%
• EN area 92%
19. 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)
20. • 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)
21. 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
• Involved Field • Elective Nodal
Irradiation Irradiation
• 1.8 to 2 Gy to 68 to VERSUS • 60 to 64 Gy
74 Gy for IFI. • Same GTV.
• GTV=pre-chemo • Mediastinum and
volume and LN’s > Ipsi hilum to 44 Gy.
1 cm. • Re-Scan and boost
16-20 Gy.
22. 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.
23. Results
• Follow up. CT scans at 3 and 6 mos
and then CXR q 3 mos.
• 5 yr OS. Overall Survival
• 25.1% vs 18.3%. NS
MS-20 mos vs 15 mos
• Overall Response Rate
• 90% vs 79%. p=.032
24. 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
25. 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.
26. Is there a role for
Induction Chemotherapy with
concurrent chemoradiotherapy?
27. 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)
28. 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
Sequential Induction→Concurrent Concurrent →Consolidation
I
Treatment compliance no different in three Groups. ~70%
29. Results Survival OS PFS
• 276 pts
• Med FU 40 mos Arm 1 13.0 mos 9 mos
• Primary Endpoint-Med OS Arm 2 12.7 mos 6.7 mos
• Closed early after results of RTOG
94-10 were made available. Arm 3 16.3 mos 8.7 mos
Sequential vs Historical Control Concurrent vs Historical Control
Induction-Concurrent vs Historical Control
30. 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.
31. 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.
32. • CALGB 39801. Randomized Phase III
• Concurrent chemoradiotherapy plus or
minus induction chemotherapy.
• 366 pts
• Stage IIIA, IIIB
33. 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.
35. Results OS Dist Gr 3/4 Gr 3/4
(p=.3) Failures Esophagiti Dyspnea
s
Arm 1 12 mos n=86 32% 14%
(30%/2%)
Arm 2 14 mos n=84 36% 19%
(28%/8%)
Survival-Subgroup
Survival-ITT Analysis
Survival
Survival 16 vs 14 mos
12 vs 14 mos
36. 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.”
37. Can we improve survival
by the addition of
consolidative chemo?
38. 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.
39. 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.
40. Results-Med FU 42 Mos.
• Closed after 203 pts for evidence of futility.
Grade 3 to 5 Non-Hem Toxicity • 28.8% of pts required
hospitalization during
consolidation
compared to 8.1% in
observation arm.
Overall Survival
PFS
MS 21.7 vs 21.2 mos.
41. 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?
42. 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.
43. 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.
