Controvertial issues in non-small cell lung cancer Consolidation by pptfiles

VIEWS: 16 PAGES: 31

									Turkish Thoracic Society, 27. 12. 2007



Controversial issues in non-small cell lung cancer

              Consolidation Therapy in
                Radiochemotherapy

                      Rudolf M. Huber




Universität München                      Pneumologie
                                    NSCLC - Prognosis
(%)

100

 90       IA           IB       II A           II B           II B     III A           III A       III B           III B       IV
 80

 70
                                                                                                                     5-year survival
 60

 50

 40

 30

 20

 10

  0
          0




                                0




                                                          0
                   0




                                           0




                                                                                                                           1
                                                                     0




                                                                                                 0



                                                                                                               0
                                                                                   0
      M




                            M




                                                      M
                   M




                                         M




                                                                                                                           M
                                                                  1M




                                                                                               M



                                                                                                           M
                                                                               M
      0




                            1




                                                      0
               0




                                       1




                                                                                                                       x
                                                                                             2



                                                                                                           3
                                                                               2
                                                                 N
  N




                            N




                                                  N
               N




                                       N




                                                                                                                      N
                                                                                          0-



                                                                                                          N
                                                                              N
                                                                T3
T1




                       T1




                                                T3
              T2




                                    T2




                                                                                                                    Tx
                                                                                         N



                                                                                                      -3
                                                                          -3


                                                                                       T4



                                                                                                     T1
                                                                         T1
Radical Radiotherapy Versus
 Radio- Plus Chemotherapy
    Based on Cisplatin




                        a6080
      Non-small cell lung cancer:
       Therapy options RT / CT
sequential RCT



concomitant RCT
                                  RT
                          hyperfractionated?

Induction ® conc. RCT




Conc. RCT®Consolidation
Induction Chemotherapy vs. Radiotherapy Alone


                                    Med Surv 5-J-Surv
                         RT 60 Gy      9.6 M. 6%
                         VBL-P 2 Zyklen 13.7 M. 17%
                         + RT 60 Gy




6298
     Regionally Advanced
     Unresectable NSCLC
Final Results of Phase III Trial RTOG 8808
                                       *



                      *
                          2 cycles of cisplatin, vinblastine




                    Sause W ea. Chest 117 (2000)




                                                     a6577
     Regionally Advanced
     Unresectable NSCLC
Final Results of Phase III Trial RTOG 8808

 Patients < 60 years old
                                             *



                           *
                               2 cycles of cisplatin, vinblastine



                      Sause W ea. Chest 117 (2000)




                                                          a6578
 Inoperable Non Small Cell Lung Cancer
 Radiotherapy and Simultaneous Cisplatin
                    100 -
                                     Radiotherapy
                     90 -
                                     Radiotherapy + cisplatin weekly
                     80 -
                                     Radiotherapy + cisplatin daily
                     70 -
                     60 -
     Survival (%)
                     50 -
                     40 -
                     30 -
                     20 -
                     10 -
                      0-


                        0    1   2      3        4
                                 Year of Study
NEJM 326 (1992), 524 - 530                                      6484
SEQUENTIAL vs. SIMULTANEOUS CT-RT
               n = 320
Furuse-Trial   inoperable stage III


                                      OR    Median     5 YS
                                            survival
MVP 2 cycles induction                66%   13.3 m.     9%
+ RT 56 Gy
  vs                            p=              p=
                                0.0002          0.04


2 x (MVP 2 cycles                     84%   16.5 m.    16%
   + RT 28 Gy simultaneous)



                                                       Furuse, JCO 1999
        Inoperable Stage III NSCLC
Recurrence Patterns after Chemoradiotherapy




      Local-                             Distant
     Regional                  4%        Relapse
     Relapse
                                          56%
         33%




Furuse K et al. JCO 17:2692-2699, 1999
       RTOG 94-10 Curran et al. Astro 2003                               n=597

   Induction                                                   A 30 %
     versus                           Esophagitis G3 or higher B 48 %
  concurrent                                                   C 62 %
      RCT          MST        4y     Induction-CT                Concurrent CT-RT
                   (months)


                                                         RT 2 Gy/T
VBL
+ CDDP* (n= 198) 14.6 12 % 2 cycles /
                           3 Weeks
                                                          (60Gy)


VBL
                                                      RT 2 Gy/d (60Gy)
                    17        21 %
+ CDDP* (n= 195)                                        2 cycles / 3 Weeks


oral VP16                                             RT 2 x 1.2 Gy/d (69,6Gy)
                 15.3 17 %
+ CDDP* (n= 204)                                        2 cycles / 3 Weeks

  Minimum pot.follow up 15 months
                                               Sause et al. Oral communication, ASTRO 2003
      Amount of Chemotherapy in
        Radiochemotherapy
• Simultaneous radiochemotherapy seems to be
  more efficacious than induction chemotherapy
• For systemic disease or adjuvant therapy we use
  at least four cycles of full dose chemotherapy
• Do we need more chemotherapy for radio-
  chemotherapy, too?
• Is the amount of chemotherapy more relevant
  than the sequence?
                    Study Protocol
 NSCLC III A/B, inoperable                   Induction chemotherapy:
                                                2 cycles every 3 weeks
                                     Paclitaxel 200 mg/m² + Carboplatin AUC 6



                       No progressive disease? Operable?


                                                  Experimental Arm:
              Standard Arm:
                                                      Radiotherapy +
             Radiotherapy alone
                                               Simultaneous Chemotherapy:
             60-66Gy, 6.5 weeks
                                               Paclitaxel 60 mg/m² weekly


                                  Final evaluation
                         3 months after the end of therapy

BROCAT CTRT 99/97            Follow-up every 3 months
Induction Chemotherapy and Simultaneous
Radiochemotherapy or Radiotherapy Alone
    in Inoperable NSCLC (IIIA/IIIB)

Huber RM ea. JCO 2006
               Pattern of recurrences
 • In the simultaneous          Simulta-   Radiotherap
                                neous      y
   arm there are less
   (local and distal)    Local 41.4        41.9
   recurrences: 62.1 vs.
   83.8 % (p<0.001)      Distal 44.8       44.1

                         Both 13.8         14.0


Huber RM ea. JCO 2006
BROCAT study CTRT 99/97 Survival




                 60 pts. (37 %) got
                 2nd-line chemo-
                 therapy: RT 41.2
                 %, CTRT 30.8 %




                 Huber RM ea. JCO 2006
BROCAT study CTRT 99/97 Disease-free Survival




                            Huber RM ea. JCO 2006
BROCAT study CTRT 99/97 Survival of
  patients with CR/PR after induction




         Multivariate analysis: independent factor




                          Huber RM ea. JCO 2006
        Induction vs. Consolidation
    Chemotherapy in Radiochemotherapy
                                         GFPC-GLOT-IFCT 02–01
                                         Randomized phase II trial




                         N = 133. From 05/2002 to 03/2005




Fournel P ea. ASCO 2006: 7049
        Induction vs. Consolidation
    Chemotherapy in Radiochemotherapy
  GFPC-GLOT-IFCT 02–01 Randomized phase II trial
                          Overall Survival




                                Toxicities and OR comparable




Fournel P ea. ASCO 2006: 7049
                          InCoDoR           Huber RM ea. WCLC 2005
      Response rates after CTRT with docetaxel–cisplatin




Response rates after 4 weeks of docetaxel consolidation therapy
                                                        *
 * 60 mg/m2 d 71 and 92
  Consolidation Chemotherapy
         SWOG Phase II Trials
 9019 N = 50                9504 N = 83
                            pStage IIIB
  pStage IIIB



Cisplatin/VP16         Cisplatin/VP16
     XRT                    XRT


Cisplatin/VP-16              Docetaxel
                      75 mg/m2 cycle 1 then 100 mg/m2 cycles 2-3
 Consolidation Docetaxel After Concurrent
   Chemoradiotherapy in IIIB NSCLC
                      Phase II SWOG Study S9504




Gandara DR et al. JCO 21 (2003)                   b6300
         Consolidation chemotherapy
             HOG LUN 01-24
             Unresectable, Stage IIIA-IIIB NSCLC;
          ECOG PS 0-1; <5% Weight Loss in Prior 3 mo

                      ChemoRT Induction
                 Cisplatin 50 mg/m2 d 1,8,29,36
              Etoposide 50 mg/m2 IV d 1-5 & 29-33
               Concurrent RT 59.4 Gy (1.8 Gy/fr)

                             CR, PR, or SD;
                             ECOG PS 0-2


                              Randomize         4–8 weeks after end of induction


Docetaxel 75 mg/m2 q 3 wk ´ 3                      Observation

          Primary endpoint: 50% improvement in overall survival ?
        Consolidation chemotherapy
      HOG LUN01–24 – Interim analysis
       •   A preliminary analysis of the differences in
           toxicities between PE/XRT with or without
           consolidation D was performed.




  • 241 pts. enrolled, 163 pts. randomized
Bedano P ea. ASCO 2006: 7043
        Consolidation chemotherapy
      HOG LUN01–24 – Interim analysis
       •   45 % on docetaxel consolidation therapy
           had at least one G 3/4 toxicity
       •   Only 29 % got the planned 3 cycles
       •   41 % got less than 2 cycles
       •   22 % had dose modifications
       •   32 % required G-CSF
       •   5 % required blood transfusions
       •   20 % had hospitalization
       •   5.5 % treatment related deaths

Bedano P ea. ASCO 2006: 7043
            Consolidation chemotherapy
               Grade 3/4 Toxicities




Bedano P ea. ASCO 2006: 7043
 Simultaneous CRT +/- Consolidation with
 Vinorelbine oral + CDDP in stage III NSCLC
• A phase I/III study conducted in Germany
    searching for the best CT-RT sequence in IIIA/B pts
•   Questions:
     – Can induction CT with RT (CT-RT) followed by the same
       consolidation (CT-RT->CT) be better than CT-RT alone ?
1st step: Phase I* with escalating doses of Vinorelbine oral
          (40-60 mg/m²) and fractionated doses CDDP in
          combination with standard RT (5 centres)

2nd step: Phase III comparing consolidation CT vs control
          in patients not progressing during induction CT-RT
* Flentje et al, ASCO 2005
Treatment Schedule Phase I
Simultaneous CRT +/- Consolidation with
Vinorelbine oral + CDDP in stage III NSCLC
             Radiotherapy 66 Gy                                     Arm A: consolidation CT + BSC
                    6.5 weeks
                                                                          Cycle 3    Cycle 4
              Cycle 1       Cycle 2



                                                                     1     8   15   22   29 36 43
                                                       R
                                                                         CDDP 80 mg/m² d1, 22
       21    0/1   8   15 22 29   36   43   50 57                        NAVELBINE® ORAL 60 mg/m² d1, 8
                                                                                       80 mg/m² d22, 29
                                              6 weeks
                   Cisplatin                max. 8 weeks
                                                                     Arm B: BSC alone
                   20 mg/m² day 1 -4
                                                                         Cycle 3    Cycle 4
                   NAVELBINE® ORAL
                   50 mg/m²
      Screening                                                      1     8   15   22   29 36   43

  Study Registration
                                                                         End of treatment
                                                    for both Arms
                                                                          Tumor Assessment
      Radiochemotherapy of the locally
       advanced NSCLC - questions
•   How much chemotherapy is needed
•   Best sequence of radiotherapy and chemotherapy
•   Chemotherapy combinations in the different
    settings
•   Modifications of radiotherapy, higher radiation
    dosages
•   Benefit for older patients and patients with poor
    PS
•   Management of the non haematological toxicity
RCT works. Consolidation is an option. Need
for further randomised trials

								
To top