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                                    Protocol 01063

                A phase III randomised study comparing
       concomitant radiochemotherapy with cisplatin and docetaxel
               as induction versus consolidation treatment
                     in patients with locally advanced
                 unresectable non-small cell lung cancer

Writing committee:    T Berghmans, J.P. Sculier and P. Van Houtte

Study coordinator :   T. Berghmans

Data Manager :        N. Leclercq

Statistician :        M. Paesmans

Final version :       June 2006

Ethical committee :

Activated :


1.   Group

2.   Background

3.   Study objectives

4.   Study population

5.   Study design

6.   Investigations

7.   Chemotherapy treatment plan

8.   Radiochemotherapy treatment plan

9.   Trial quality control

10. Drug procurement, preparation and storage

11. Side effects

12. Dose adaptation plan

13. Criteria of evaluation

14. Off treatment regimen and off study definitions and procedures

15. Entry and randomisation procedures

16. Data management and trial coordination

17. Ethical considerations

18. Statistical considerations
19. Publication and authorship
20. Bibliography
Appendix I :       Performance scale (Karnofsky)

Appendix II :      WHO toxicity criteria

Appendix III :     Staging classification

Appendix IV :      The World Medical Association Declaration of Helsinski


Participating centers and members:

Bruxelles                     Institut Jules Bordet            J.P. Sculier, M. Paesmans, P.
                                                               Van Houtte, E. Markiewicz,
                                                               T. Berghmans, C. Mascaux,
                                                               A.P. Meert, M. Roelandts, M
                              Hôpital Brugmann                 A. Drowart, P. Prigogine
                              Hôpital St Pierre                R. Sergijsels, V. Ninane, T.
                                                               Bosschaerts, S Alard
                              Hôpital Erasme                   V. Richard, S Luce
Gilly                         Hôpital Saint-Joseph             B. Colinet
Montignies-le-Tilleul         C.H.U. A. Vesale                 D. Brohée
Mouscron                      CH Mouscron                      C. Tulippe
Baudour, Tournai, Ath         RHMS                             P Ravez, V. Richard
Verviers                      C.H. Peltzer-La Tourelle         Y. Bonduelle, I. Louviaux
Mons                          Hôpital Ambroise Paré            P. Wackenier, S Holbrechts, P
Namur                         Clinique St Luc                  O. Van Cutsem
Lille                         Hôpital A. Calmette              J.J. Lafitte, A. Scherpereel
Arras                         CH d’Arras                       J. Amourette
Douai                         C.H. de Douai                    M.C. Florin, E. Maetz
Tourcoing                     CH de Tourcoing                  X. Ficheroulle
Valence                       Hospital de Sagunto              V. Giner Marco
Athens                        Hellenic Cancer Institute – St   A. Efremidis, G. Koumakis,
                              Savas Oncology Hospital          G Pissakas


      Recent progresses have been obtained in the treatment of non-small cell lung cancer (NSCLC)
by the development of active chemotherapy, mainly with regimens including cisplatin (1). A
survival benefit has been shown in advanced, locoregional unresectable and resectable diseases, as
pointed by some meta-analyses {Berghmans, 2005 67 /id;1995 5 /id;Sculier, 2005 72 /id}. In
patients with unresectable locally advanced NSCLC, the traditional therapeutic approach consisting
in chest irradiation has changed in the nineties and today a combined modality approach is
      Induction chemotherapy followed by chest irradiation has been shown to result in better
survival than radiotherapy alone. The 14 randomised trials (5-21) performed on this question are
summarised in table 1. All but three used cisplatin-based chemotherapy, combined with at least
another active drug in 8 cases. Four of the studies reported statistically significant results in favour
of the combined approach. A recent meta-analysis of the ELCWP (22), including most of these
studies (fig 1) has concluded to a beneficial effect of chemotherapy with a HR (hazard ratio) = 0.78
(95 % confidence interval or CI : 0.71-0.86).
      Only two trials assessed the effect of adding chemotherapy after radiotherapy (table 2). Both
were negative. Lad et al (23) included patients with an incomplete resection of the tumour after
surgery. Johnson et al (24) compared the addition of a single agent chemotherapy (vindesine) to
radiotherapy. These 2 trials are too different to allow meaningful conclusions.
      So far the trials that we have analysed have tested sequential treatment modalities
administration. Chemotherapy and radiotherapy can also be administered concomitantly
(concurrently). Eleven trials (25-35) have been published comparing radiotherapy alone to
concurrent chemoradiotherapy. They are summarised in Table 3. These studies have mainly
exploited the radiosensitisation properties of the platinum derivatives (cisplatin in 6 and carboplatin
in 5). There was no chemotherapy administration after the chemoradiotherapy. Four of these studies
have shown a statistically significant survival improvement when chemotherapy was present. The
ELCWP meta-analysis (22), including the first 8 trials (fig 2), also showed a significant benefit with
a HR of 0.79 (95 % CI : 0.70-0.89). This was confirmed in a further Cochrane meta-analysis (36).
The risk of death at two years was reduced (relative risk [RR] 0.93; 95% CI 0.88-0.98; p = 0.01)
with the concurrent treatment.
     Six randomised trials (four phase III and two phase II) compared concurrent
chemoradiotherapy to a sequential approach with chemotherapy followed by chest irradiation
(Table 4) (37-41). In the first one published by Japanese authors (37), 320 patients were
administered two cycles of chemotherapy consisting in cisplatin, vindesine, and mitomycin. In the
concomitant arm, radiotherapy began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions
per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the
sequential arm, radiotherapy was initiated after completing chemotherapy for a total dose of 56 Gy
(2 Gy per fraction and 5 fractions per week for a total of 28 fractions). The median survival duration
was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with
those receiving sequential therapy (13.3 months) (P = 0.04). Two-, 3-, 4-, and 5-year survival rates
in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in
the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). A randomised phase II trial
compared twice a day radiotherapy with concomitant chemotherapy to sequential induction
chemotherapy followed by once-a-day irradiation sensitised by cisplatin (38). No statistically
significant survival difference was observed. In a third study (39), four cycles of cisplatin and
vinorelbine with concurrent radiotherapy beginning at cycle 2 were compared to four cycles of the
same chemotherapy as induction followed by radiotherapy. A significant survival advantage was
associated with the concomitant chemoradiotherapy (median survival times of 16.6 versus 12.9
months; p = 0.02). In a fourth study, concomitant radiochemotherapy with cisplatin and etoposide
was followed by two cycles of consolidation chemotherapy with cisplatin and vinorelbine and
compared to sequential induction chemotherapy followed by radiotherapy (40). There was no
statistically significant survival difference between the two arms. Belani et al (41) addressed the
question of the timing of chemoradiotherapy in a three-arms trial comparing induction
chemotherapy followed by radiotherapy, induction chemoradiotherapy with consolidation
chemotherapy and induction chemotherapy with consolidation chemoradiotherapy. The
chemotherapy regimen was carboplatin plus paclitaxel. Median survival time was slightly increased
with induction chemoradiotherapy (16.3 months) in comparison with the sequential (13 months) or
the consolidation chemoradiotherapy arms (12.7 months). Nevertheless, no statistical analysis was
reported. Lastly, the RTOG (42) reported in 2000, in an unpublished study, better survival times
with concurrent once-a-day radiotherapy in comparison with a sequential approach. The
chemotherapy regimen was cisplatin plus vinblastine. In a Cochrane meta-analysis, three
randomised trials of concurrent versus sequential radiochemotherapy were pooled (36). The risk of
death was significantly reduced at two years with the concurrent treatment (RR 0.86; 95% CI 0.78-
0.95; p = 0.003). These results were incorporated in the recently available guidelines of the
European Lung Cancer Working Party (ELCWP) (
      If cisplatin is still considered as the central agent in the chemotherapy of NSCLC as illustrated
in a recent meta-analysis (43), new active drugs are now available. These agents are gemcitabine (a
pyrimidine analogous antimetabolite like cytarabine), the taxans paclitaxel and docetaxel (inhibitors
of the depolymerisation of the tubulin molecules of the microtubules, leading to growth arrest in the
G2/M phase of the cell cycle), the camptothecin derivatives irinotecan (CPT-11) and topotecan

(DNA topoisomerase I inhibitors) and vinorelbine (a vinca-alcaloid inhibiting tubulin
polymerisation). They have allowed to significantly increase the number of active drugs in this
disease (31). Gemcitabine, vinorelbine and docetaxel are today commercially available for the
treatment of NSCLC in all the countries of the institutions participating to the ELCWP.
     Gemcitabine, vinorelbine and docetaxel have demonstrated radiosensitising properties.
However, gemcitabine must be used cautiously when administered concurrently with radiotherapy
due to dose-related, possibly life-threatening complications (44) although interesting activity was
noted when given at low dose (45;46). Gemcitabine administration is not allowed in France if
concurrent to irradiation. Further, in a recently published randomised phase III trial including
advanced and metastatic patients, cisplatin plus taxotere was associated with better survival and
reduced toxicity in comparison with cisplatin plus vinorelbine (47).
     Some phase I and II published studies established the activity and the good toxicity profile of
concurrent docetaxel and radiotherapy (Tables 5-6). The recommended dose of docetaxel is
between 20 and 30 mg/m²/week (48-54). The principal dose-limiting toxicity was grade 3
oesophagitis, occurring in one third of the patients. Except in two studies performed by the same
group (49;52), grade 3-4 radiation pneumonitis was infrequently observed (2-7%). In other studies,
docetaxel was combined with platinum derivatives and administered concomitantly with
radiotherapy (55-63). The carboplatin, docetaxel, radiotherapy combination presented with
potentially severe radiation pneumonitis (9% and 17%) (55;61). This complication was infrequently
observed when docetaxel was given with cisplatin without any increase in the frequency of grade 3
oesophagitis that ranged between 11% and 31% (Tables 5-6). Response rates (37-79%) and median
survival times (10.5 to more than 23.4 months) appeared interesting. Recommended doses of
cisplatin ranged between 20 and 25 mg/m²/week or 40 mg/m² (days 1, 8, 29 and 36) for each drug.
This last schedule was associated with more profound neutropenia (60%) than the weekly regimens
     There are few data assessing concomitant chemoradiotherapy with platinum derivatives and
docetaxel before or after a chemotherapy regimen including the same drugs. Two studies
demonstrated the feasibility of the induction or the consolidation chemoradiotherapy with
carboplatin and docetaxel (59;61) (Tables 5-6). Two phase I studies, only presented as abstracts,
assessed cisplatin-docetaxel induction chemoradiotherapy followed either by docetaxel alone or
cisplatin plus docetaxel. In the first phase I (64), docetaxel (20 mg/m²) and cisplatin (25 mg/m²)
were given weekly with radiotherapy (66 Gy) followed by docetaxel 75 mg/m² twice (dose was
further reduced to 60 mg/m² due to grade 3-4 toxicities). Grade 3 oesophagitis and pneumonitis
were observed in 46% and 23%. The authors concluded that this combined treatment can be safely
administered in good performance status patients. In the second phase I (65), only 3 patients were

included due to excessive toxicity during concomitant chemoradiotherapy but cisplatin was given
once every 3 weeks at 75 mg/m², a schedule fairly different from the published studies reported in
the Tables 5-6, with weekly docetaxel 20 mg/m²; the severity of the toxicity was not reported. In a
phase II study, induction chemoradiotherapy with biweekly cisplatin and docetaxel (40 mg/m² both)
followed by the same consolidation chemotherapy schedule demonstrated impressive response rate
(78%) with limited oesophageal (8%) and lung (2%) grade 3 or more toxicities (66). The feasibility
of concomitant chemoradiotherapy with docetaxel after two courses of induction cisplatin plus
docetaxel was demonstrated in a phase II randomised study (54). Toxicity was minimal. Lastly, in a
phase II unpublished trial (67), induction chemotherapy with cisplatin and docetaxel (75 mg/m²
both) was given twice with the third similar course administered concomitantly with radiotherapy.
The authors confirmed the activity and the tolerability of concomitant cisplatin-docetaxel plus
radiotherapy with 11% grade III oesophagitis and 15% grade II-III pneumonitis with one patient
dying 3 months after therapy.
      In advanced and metastatic NSCLC, the use of higher dose cisplatin was not associated with
increased survival in comparison with standard dose (50-60 mg/m²) (68-71) but demonstrated
increased chronic renal, auditive and neurologic toxicity (72). Based on all these considerations, we
have decided to use standard dose cisplatin (60 mg/m²) plus docetaxel (75 mg/m²) as chemotherapy
alone regimen and to administer cisplatin and docetaxel weekly at the doses of 20 mg/m²/week
concurrently with radiotherapy, so that in a 3-weekly cycle the dose of cisplatin remained constant.
As there is no enough convincing argument that hyperfractionated radiotherapy will improve
survival when administered concomitantly with chemotherapy, we propose to use conventional
irradiation for a total dose of 66 Gy, 2 Gy per fraction and 5 doses per week. In a previous study of
concurrent chemoradiotherapy including cisplatin, gemcitabine and vinorelbine (46), we observed
that lung toxicity was inversely correlated with the V20 (volume of normal lungs receiving a dose
in excess of 20 Gy) and we recommend that the V20 was no more than 30%. We decided to begin
the treatment schedule with a first course of chemotherapy before the two second courses of
induction chemotherapy or the induction chemoradiotherapy. This decision was taken after a survey
performed among the members of the ELCWP showing that for practical reasons, it is unlikely in
half of the centres to obtain radiotherapy appointment in a short delay of time (less than 15 days).
This attitude allows to plan the radiotherapy according to the protocol.
     The purpose of the present phase III trial will be to assess           if induction concurrent
chemoradiotherapy followed by consolidation chemotherapy will improve survival in comparison
with the same chemotherapy given as induction followed by consolidation concurrent
chemoradiotherapy, the regimen of chemotherapy consisting in a combination of cisplatin with a
second-generation agent, docetaxel.

Table 1: Trials comparing induction chemotherapy followed by chest irradiation to
radiotherapy alone.

Reference               Chemotherapy     RT             Control arm               Chemotherapy arm        P
                                         Gy     N pts      MST        5 years   n pts   MST      5 yrs
Mattson, 1988 (14)          CAP          55     119       311 d                 119     332 d             NS

Van Houtte, 1988        CDDP-VP16-       55      32        11 m                  27     11 m              NS
(20)                        VDS
Dillman, 1990 &          CDDP-VBL        60      77        10 m        6%        78     14 m     17 %    0.01
1996 (9;10)
Morton, 1991 (16)          MACC          50      58       313 d        7%        56     317 d    5%      0.69
Le Chevalier, 1991      CDDP-VDS-        65     177        10 m                 176     12 m             0.02
& 1992 (12;13)           CCNU-CPA
Gregor, 1993 (11)        CDDP-VDS        50      39        53 w                  39     52 w              ?
Crino, 1993 (7)         CDDP-VP16        56      33        36 w        0%        33     52 w     9%      0.11
Wolf, 1994 (21)           Ifo-VDS        50      41        9m                    37     14 m             0.016
Sause, 1995              CDDP-VBL        60     149        11 m                 151     14 m             0.007
Planting, 1996 (17)      CDDP-VDS        55      33        12 m                  37     12 m             0.28
Brodin, 1996 (6)        CDDP-VP16        56     154        10 m        1%       163     11 m     3%      0.16
Cullen, 1999 (8)            MIP          > 40   223        10 m                 223     12 m             0.14
Mattson, 2003 (15)        Docetaxel       ?     140       12.6 m                134     14.8 m            NS
Beslija, 2005 (5)     CDDP-Gemcitabine   63      30        10 m                  30     12.5 m           0.07

RT : radiotherapy ; n pts : number of patients ; MST: median survival time; CAP : cisplatin +
adriamycine + cyclophosphamide ; CDDP : cisplatin ; VP16 : etoposide ; VDS : vindesine ; VBL :
vinblastine ; MACC : methotrexate + adriamycine + cyclophosphamide + CCNU ; CPA :
cyclophosphamide ; Ifo : ifosfamide ; MIP : mitomycin C + ifosfamide + cisplatin

Figure 1 : Meta-analysis of the randomised trials published until 1999 comparing
chemotherapy followed by chest radiotherapy to radiotherapy alone.

       Table 2: Trials comparing to chest irradiation alone irradiation followed by chemotherapy;

Reference      Chemotherapy          RT                 Control arm                 Chemotherapy arm      P
                                                n pts     MST         5 yrs   N pts    MST       5 yrs
Lad, 1994          CAP          incompl. Res.    86       20 m                 78      13 m              0.133
(23)                             + 2 x 20 Gy
Johnson,           VDS             60 Gy        106       8.6 m       3%      107      9.4 m     3%      0.56
1990 (24)

       RT : radiotherapy ; n pts : number of patients ; MST : median survival time; CAP : cisplatin +
       adriamycine + cyclophosphamide ;VDS : vindésine ; incompl res.: incomplete resection

Table 3: Trials comparing to chest irradiation alone concurrent chemoradiotherapy

Reference               Chemotherapy         RT           Control arm          Chemotherapy arm          P
                                              Gy      n pts  MST      5 yrs   n pts  MST      5 yrs
Soresi, 1998 (25)           CDDP             50.4      50    11 m              45    16 m              0.18
                         15 mg/m2/w
Schaake-Koning,            I. CDDP           30+25    108                      98                      0.048
1992 (26)                30 mg/m2 /w

                            II. CDDP                                          102
                           6 mg/m2/d
Trovo, 1992 (27)              CDDP            45       88     10 m             85     10 m             0.89
                           6 mg/m2/w
Blanke, 1995 (28)             CDDP           60-65    111    46 wk    2%      104    43 wk     5%      0.35
                          70 mg/m2/3 w
Jeremic, 1995 (29)           CBDCA           64.8      61     8m       5%      52    18 m     21 %    0.003
                         100 mg J1+2/w       2x/j
                             + VP16
                         100 mg J1-3/w
                             CBDCA                                             56     13 m    16 %     0.17
                       200 mg J1+2/2 w
                             + VP16
                        100 mg J1-5/2 w
Jeremic, 1996 (30)     CBDCA 50 mg/d          69.6     66     14 m             65     22 m             0.02
                        + VP16 50 mg/d        2x/j
Bonner, 1998 (31)         CDDP-VP16          30 x 2    33                      32                        ?
                                2x            2x/d
Ball, 1999 (32)              CBDCA             60      53                      54                        ?
                         70 mg/m2 d1-5
                             CBDCA            60       46                      51                        ?
                         70 mg/m2 d1-5       2x/d
Clamon, 1999 (33)    CBDCA 100 mg/m²/w        60      120     13 m            130     13 m              NS
                      (after two induction
                     cycles of CDDP-VBL)
Groen, 2004 (34)      CBDCA 20 mg/m²/d        60       78    11.7 m            82    11.8 m             NS
Cakir, 2004 (35)     CDDP 20 mg/m²/d1-5       64       88              2%      88             10%     0.0002
                                                                      (3y)                    (3y)

RT : radiotherapy ; n pts : number of patients ; MST: median survival time; CDDP : cisplatin ;
CBDCA : carboplatin ; VP16 : etoposide

Figure 2 : Meta-analysis of the randomised trials published until 1999 comparing concurrent
chemoradiotherapy to chest radiotherapy alone.

Table 4: Randomised trials comparing sequential to concurrent chemoradiotherapy

References        Treatment                           N      RR     MST        5yrs    P
Furuse,      1999 CDDP-MMC-VDS + RT (56Gy)            156    89%    16.5 m     15.8% 0.04
(37)              CDDP-MMC-VDS  RT (56Gy)            158    66%    13.3 m     8.9%
Curran,      2000 CDDP-VBL  RT (60Gy)                              14.6 m     10%     0.04
(42)              CDDP-VBL + RT (60Gy)                              17 m       16%
                  CDDP-VP16 + RT (69.6Gy bid)                       15.6 m
Komaki,      2002 CDDP-VP16 + RT (69.6Gy bid)         81     71%    15.5 m     16%     0.39
(38)              CDDP-VBLx2  RT (63 Gy) + CDDP      81     73%    16.4 m     13%
Zatloukal, 2004 CDDP-VNR x 4 + RT (60Gy cycle 2)      52     80%    16.6 m             0.02
(39)            CDDP-VNR x4  RT (60Gy)               50     47%    12.9 m
Fournel,     2005 CDDP-VP16 + RT (66Gy)  CDDP- 100          40%    16.3 m             0.24
(40)              VNR x2
                  CDDP-VNR x3  RT (66Gy)       101          50%    14.5 m
Belani,      2005 PAC-CBDCA x2  RT (63Gy)   91                     13 m
(41)              PAC-CBDCA x2  PAC-CBDCA + 74                     12.7 m
                  RT (63Gy)
                  PAC-CBDCA + RT (63Gy)  PAC- 92                   16.3 m
                  CBDCA x2
RT: radiotherapy; RR: response rate; N: number of patients; MST: median survival time; CDDP:
cisplatin; MMC: mitomycin; VDS: vindesine; VBL: vinblastine; VNR: vinorelbine; PAC:
paclitaxel; CBDCA: carboplatin

Table 5: Phase I studies assessing radiotherapy with docetaxel alone or in combination in non-small cell lung cancer

Reference                 Treatment                         N            RR     ≥Grade        3 Recommended dose of chemotherapy
Mauer, 1998 (48)          DOC + RT 60Gy                     20           47% Oeso 39%            DOC 20 mg/m²/w
                                                                             Lung 7%
                                                                                PMN 25%
Koukourakis, 1999 (49)    DOC + RT 60Gy                     9            77% Oeso 33%            DOC 15 mg/m²/twice a week
                                                                             Lung 20%
Choy, 2001 (55)           DOC + RT 60 Gy                    15           60% Oeso 31%            DOC 20 mg/m²/w + CBDCA AUC2/w
                          DOC-CBDCA + RT 60 Gy              9                Lung 17%
                                                                             PMN 19%
Wu, 2002 (56)             DOC-CDDP + RT 63Gy                18           75% Oeso 11%            DOC 20 mg/m²/w + CDDP 20 mg/m²/w
                                                                                PMN 6%
Varveris, 2003 (57)       DOC-CDDP + RT 69.6Gy bid          9    (+10 78% Oeso 55%               DOC 10 mg/m²/w (day 4) + CDDP 10 mg/m²/w
                                                            ORL)          PMN 17%                (day 1)
Mudad, 2003 (58)          DOC-CDDP + RT 60Gy                19           37% Oeso 31%            DOC 25 mg/m²/w + CDDP 25 mg/m²/w
Wirth, 2003 (59)          DOC-CBDCA x2  idem + RT 29                    39% Oeso 24%            DOC 30 mg/m²/w + CBDCA AUC2/w
                          54Gy                                               PMN 3%
Schwarzenberger,      2004 DOC + RT 50Gy                    26           68% -                   -
N: number of patients; RR: response rate; DOC: docetaxel; Oeso: oesophagitis; PMN: grade 3-4 neutropenia; RT: radiotherapy; CBDCA: carboplatin;
CDDP: cisplatin

Table 6: Phase I/II and II studies assessing radiotherapy with docetaxel alone or in combination in non-small cell lung cancer

Reference           Phase Treatment                                N    RR    MST     ≥Grade 3 toxicity   Recommended dose of chemotherapy
Koukourakis, 1998 I/II     DOC + RT 64Gy                           30 77% 7.5m        Oeso 20%            DOC 30 mg/m²/w
(51)                                                                                  Lung 3%
                                                                                      PMN 17%
Koukourakis, 1999 II       DOC + RT                                35 80% 12m         Oeso 34%            DOC 30 mg/m²/w
(52)                                                                                  Lung 11%
Koukourakis, 2002 I/II     DOC-Caelyx-Ami + RT 64Gy                25 75% 9m          Oeso 36%            DOC 30 mg/m²/w + Caelyx 25
(73)                                                                                                      mg/m²/w
Kiura, 2003 (60)    I/II   DOC-CDDP + RT 60Gy                      75 75% +23m        Oeso 19%            DOC 40 mg/m² + CDDP 40 mg/m²
                                                                                      Lung 5%             days 1-8-29-36
                                                                                      PMN 60%
Sakai, 2004 (61)    II     DOC-CBDCA + RT 60Gy  DOC- 33 91% 27m                      Oeso 3%             DOC 30       mg/m²/2w   +   CBDCA
                           CBDCA x2                                                   Lung 9%             AUC3/2w
                                                                                      PMN 6%
Vergnenegre, 2005 II       CDDP-VNR x2  DOC + RT 66Gy             40 46% 13m         Oeso 22%            DOC 25 mg/m²/w
(62)                                                                                  Lung 7%
Brunsvig,     2005 I/II    DOC + RT                                42 46% 13.6m Oeso 9.5%                 DOC 30 mg/m²/days 1-8-22-29
(53)                                                                                  Lung 2%
                                                                                      PMN 2%
Iwasaki, 2006 (66) II      DOC-CDDP + RT 60Gy DOC-CDDP 46 78% 19.1m Oeso 8%                              DOC 40 mg/m²/2w + CDDP 40
                           x2                                        Lung 2%                              mg/m²/2w
                                                                     PMN 70%
Yamamoto,     2006 I/II    DOC-CDDP + RT                           21                                     DOC 20 mg/m²/w + CDDP 25
(63)                                                                                                      mg/m²/w

Scagliotti,   2006 II      DOC-CDDP x 2  DOC + RT 60Gy 43 58% 14.9m Oeso 17%/0%                          DOC 20 mg/m²/w
(54)                       DOC-CDDP x 2  RT 60 Gy      46 48% 14m   Lung 5%/7%
N: number of patients; RR: response rate; DOC: docetaxel; Oeso: oesophagitis; PMN: grade 3-4 neutropenia; RT: radiotherapy; CBDCA: carboplatin;
CDDP: cisplatin; Ami: amifostine; VNR: vinorelbine


     Primary endpoint :

         to determine if induction concurrent chemoradiotherapy followed by consolidation
chemotherapy will improve survival in comparison to induction chemotherapy followed by
consolidation concurrent chemoradiotherapy in patients with unresectable locally advanced non-
small cell lung cancer.

     Secondary endpoints :

     -   to determine the objective response rate between the two therapeutic approaches
     -   to determine the toxicity between the two therapeutic approaches
     -   to determine the local control rate obtained in each arm


4.1 Criteria of eligibility include :

-    Histological or cytological diagnosis of non-small cell carcinoma of the lung
-    Initially unresectable non-metastatic stage III disease
-    Availability for participating in the detailed follow-up of the protocol
-    Presence of an evaluable or measurable lesion
-    Written informed consent
-    No functional or anatomical contraindication to chest irradiation
-    Irradiation technically possible according to the protocol guidelines (see section 8)

4.2 Criteria of ineligibility include :

-    Prior treatment with chemotherapy, radiotherapy or surgery
-    Performance status < 60 on the Karnofsky scale
-    A history of prior malignant tumour, except non-melanoma skin cancer or in situ carcinoma of
         the cervix or cured malignant tumour (more than 5 year disease-free interval)
-    Neutrophils < 2,000/mm³
-    Platelet cells < 100,000/mm3
-    Serum bilirubin > 1.5 mg/100 ml
-    Hepatic disease contra-indicating the administration of docetaxel and/or GOT or GPT ≥ 2.5x
     the normal value and/or alkaline phosphatase ≥ 5x the normal value
-    Serum creatinine > 1.5 mg/100 ml and/or creatinine clearance < 60 ml/min

-     Recent myocardial infarction (less than 3 months prior to date of diagnosis) or uncontrolled
    angina pectoris
-   Congestive cardiac failure or cardiac arrhythmia requiring medical treatment
-   Uncontrolled infectious disease
-   Symptomatic polyneuropathy
-   Auditive impairment contra-indicating cisplatin administration
-   Serious medical or psychological factors which may prevent adherence to the treatment
-   Malignant pleural or pericardial effusion
-   Homolateral supraclavicular lymph node excepting upper lobe lesion
-     Heterolateral supraclavicular lymph node
-     Known hypersensitivity to docetaxel or cisplatin
-     Pregnancy or for pre-menopausal patient, incapacity to use adequate contraceptive method
-     Aberrations from the radiotherapy guidelines according to the study protocol (see section 8)

Patients will be randomised before any treatment between the two following arms:
ARM A : One course of chemotherapy with cisplatin and docetaxel followed by induction
chemoradiotherapy followed by two courses of consolidation chemotherapy (to be started on day
ARM B : Three courses of induction chemotherapy followed by consolidation chemoradiotherapy
(to be started on day 64)

Chemotherapy regimen (DP):           Cisplatin 60 mg/m² on day 1
                                     Docetaxel 75 mg/m² on day 1
                                     Duration of one cycle: 3 weeks
Concurrent chemoradiotherapy:        Radiotherapy 66 Gy in 2 Gy/ fraction, 5 fractions/wk (6.5
                                     Cisplatin 20 mg/m²/week, 6 times, beginning on day 1 of
                                     Docetaxel 20 mg/m²/week, 6 times, beginning on day 1 of

The final response will be assessed by a complete work-up four weeks after the completion of the
whole therapeutic program: two situations are possible:
1. the patient has an objective response or no change: treatment is stopped and patient is followed.

2. local progression without distant metastases or distant metastases are documented : the patient
   will be off trial.
In any case, follow-up will continue until death.

                                     STUDY SCHEDULE

                                Registration and randomisation

Day                       Arm A                                     Arm B

1                              Cisplatin 60 mg/m² + Docetaxel 75 mg/m²

              Induction radiochemotherapy                   Induction chemotherapy
22-66    chest irradiation (66 Gy;2Gy/d;5d/wk)

22       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²   Cisplatin 60 mg/m² + Docetaxel 75 mg/m²

29       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

36       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

43       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²   Cisplatin 60 mg/m² + Docetaxel 75 mg/m²

50       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

57       Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

               Consolidation chemotherapy              Consolidation radiochemotherapy

64-108                                             Chest irradiation (66 Gy;2Gy/d;5d/wk)

64                                                 Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

71       Cisplatin 60 mg/m² + Docetaxel 75 mg/m²   Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

78                                                 Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

85                                                 Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

92       Cisplatin 60 mg/m² + Docetaxel 75 mg/m²   Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

99                                                 Cisplatin 20 mg/m² + Docetaxel 20 mg/m²

136                               FINAL RESPONSE ASSESSMENT


Initial investigations :

- History and physical examination
- Weight, height, surface area and record of performance status.
- Biological tests including haemoglobin, white blood cell count, differential count, platelet count;
uraemia and serum creatinine; serum bilirubin, alkaline phosphatase, SGOT, SGPT; calcium,
magnesium, uric acid, electrolytes.
- Chest X-ray (P.A. and lateral).
- Chest CT scan, and if indicated, NMR scan.
- Bronchoscopy with biopsy.
- Electrocardiogram.
- Bone isotopic scintigraphy (with X rays of suspected lesions).
- CT Scan or echography of the liver and adrenals.
If a PET scan is performed, bone isotopic scintigraphy can be avoided and abdominal CT scan or
echography will be performed in case of positive lesions.
- Brain NMR or CT Scan.
- Pulmonary function tests.
- Except for bulky involvement, mediastinoscopy (or EBUS or EUS) in case of mediastinal nodes
larger than 10 mm on CT scan or in case of positive PET scan.

During treatment

1. Weekly : haemoglobin, white blood cell count, differential count, platelet count; uraemia and
   serum creatinine
2. Before each new course of chemotherapy and at day 1 and 22 of the chemoradiotherapy: history
    and physical examination; weight, height, surface area and record of performance status;
    biological tests as initially; chest X-ray (P.A. and lateral) and electrocardiogram.

Final evaluation
Same investigations as initially, except 12. Bronchoscopy and pulmonary function tests are optional
but bronchoscopy is mandatory to confirm complete remission.

Follow-up after treatment
The patient should be seen, after discontinuation of therapy, at least every 2 months for the first six
months and thereafter every 3 months. The schedule can be alternated for individual patients when
necessary. At each visit, biological tests and chest X-ray (P.A. and lateral) should be performed.
Chest CT scan should be checked every 6 months.


DP will be given at the following dosages, with the suggested following antiemetic policy:

Time (hours)       Drug                     Route Dosage                             Duration of
0                  Tropisetron              iv       5 mg in 50 ml NaCl 0.9%         5 min
5 min              Furosemide               iv       20 mg                           bolus
5 min              1l NaCl 0.9%             iv                                       2 hrs
2h                 Docetaxel                iv       75 mg/m² in 250 ml NaCl 1 hr
3h                 Cisplatin                iv       60 mg/m² in 250 ml NaCl 3%      30 min
3h30               Furosemide               iv       20 mg                           bolus
3h30               1l NaCl 0.9% + 1.5g iv                                            2 hrs
5 h 30                                             End of iv therapy
24 h               Tropisetron              po       5 mg
48 h               Tropisetron              po       5 mg
72 h               Tropisetron              po       5 mg
96 h               Tropisetron            Po      5 mg
Pre-medication: dexamethasone 8 mg (or an equivalent dosage of methylprednisolone) per os T-12h
and T -6h
After chemotherapy: dexamethasone 8 mg (or an equivalent dosage of methylprednisolone) per os
T+12h, T+24h, T+36h and T+48h


1. Patient’s positioning
Patients should undergo initial simulation according to the following guidelines :
- in supine position
- with arms above the head
- with an immobilization device to secure the same position during all planning and treatment
2. Patients data acquisition
The planning CT scan should be performed in the same treatment position as the simulation or the
treatment, with a flat table top using 3-5 mm thick cuts through the tumour volume and 10 mm
through all the normal lung parenchyma. After acquisition, transfer and reconstruction, the different
normal structures (lung, heart, oesophagus, spinal cord) and the gross tumour volume should be
outlined. After CT, all fields may be verified using the simulation, or a virtual simulation is
allowed, but DRR should be available for review.
3. Volumes definition
3.a Definition of volumes
As a general rule, no attempt will be made to electively irradiate mediastinal or hilar nodes. The
volumes should be delineated according to the following recommendations:
- The gross tumour volume (GTV) will be defined as the primary tumour and lymph nodes larger
than 1 cm in short axis dimension, plus any abnormal findings in fiberbronchoscopy,
mediastinoscopy, EBUS or PET scan. If a node larger than 1 cm is negative at biopsy, it should be
considered as negative.
- The clinical target volume (CTV) will encompass regions at risk of microscopic extension: a
margin of 5 mm should be added to the GTV
- The planning target volume (PTV) will be defined as the CTV plus a margin to take into account
beam, patient set-up uncertainties and tumour movements. This margin should certainly not be
more than 2 cm but should be adapted taking into account the location and the tumour movements.
- Post-chemotherapy GTV will be used for patients treated with induction chemotherapy.
PET-CT treatment planning (if possible) should be encouraged.
3.b.Organs at risk
The different organs should be delineated: spinal cord, oesophagus, heart, lung parenchyma. Acute
and late toxicity should be assessed and recorded according to the table:

- Dose calculation for organs at risk
Maximal tolerated dose
Maximal tolerated dose
Spinal cord                                  50 Gy
Heart                     V < 30%            55 Gy
                          V > 30%            40 Gy
Oesophagus                Length < 8 cm      65 Gy
                          Length > 15 cm 50 Gy
Lung                      V20                30%

- The following doses should be reported:
        Lung V20 Mean lung dose
        Heart Maximal dose, the V30%,
        Spinal cord: the maximal dose
        Oesophagus: the maximal dose, the length receiving more than 65 Gy, 50 Gy
4.. Dose computation
A treatment planning system capable of 3 D dose computation must be available. Dose distribution
should be obtained in 3 D with Dose Volume Histogram (DVH). All treatment plans should include
corrections for lung inhomogeneity
5. Equipment and tools
Patients should be treated using a linear accelerator. The technique should be individualized
according to the guidelines. All fields should be treated daily and verified at least at the beginning
of the radiation and at least once during radiation.
6. Dose specification
Dose prescription will follow the ICRU recommendations : located near or at the centre of the
planning target volume on or near the isocentre.
7. Dose recording
The following dose values should be recorded:
- The prescription point dose
- The minimum and maximum dose in the PTV
- Average dose in the PTV
GTV and PTV volume should be recorded
8. Dose of radiotherapy
The delivered dose should be 66 Gy. The treatment will be delivered using 2 Gy per fraction, 5
fractions per week.

Days 1-8-15-22-29-36: Cisplatin + Docetaxel

Time (hours)      Drug                    Route Dosage                           Duration of
0                 Tropisetron             iv       5 mg in 50 ml NaCl 0.9%       5 min
5 min             Furosemide              Iv       20 mg                         bolus
5 min             1l NaCl 0.9%            iv                                     1 hrs
30 min            Docetaxel               iv       20 mg/m² in 250 ml NaCl 30 min
1h                Cisplatin               iv       20 mg/m² in 250 ml NaCl 3%    30 min
1 h 30            Furosemide              Iv       20 mg                         bolus
1 h 30            1l NaCl 0.9% + 1.5g iv                                         2 hrs
3 h 30                                          End of iv therapy
24 h               Tropisetron            po      5 mg
Pre-medication: dexamethasone 8 mg (or an equivalent dosage of methylprednisolone) per os T-12h
and T -6h
After chemotherapy: dexamethasone 8 mg (or an equivalent dosage of methylprednisolone) per os
T+12h, T+24h


Each patient record will be reviewed for evaluation and response in regular meetings of the Group.
Patient’s original record including radiological documents have to be available at this time.


Each drug may have different commercial names and pharmaceutical presentations according to the
country. Investigators have to get local information.

10.1. Cisplatin :
    How supplied : 10 mg - 25 mg - 50 mg vials as a lyophilisate powder
    Storage : the product remains stable in a cool (+ 4°C) and dark place for 18 months
    Reconstitution : with sterile water (1 mg/1 ml)
    Stability after reconstitution :
               - 1 h at light and room temperature
               - 8 h at dark and room temperature
               - in refrigerator : risk of crystallisation
       Procurement : commercially available.

10.2 Docetaxel (TaxotereR)
  How supplied: Injection, solution [concentrate]: 20 mg/0.5 ml (0.5 ml, 2 ml) [diluent contains
     ethanol 13%]
  Storage: store intact vials at 2°C to 25°C and protect from light
  Reconstitution: intact vials of solution should be further diluted with 13% (w/w) ethanol/water
     to a final concentration of 10 mg/ml. Do not shake. Initial diluted solution is stable for 8 hours
     at room temperature or under refrigeration. Docetaxel dose should be further diluted with 0.9%
        sodium chloride or 5% dextrose in water to a final concentration of 0.3-0.9 mg/ml and must be
        prepared in a glass bottle, polypropylene, or polyolefin plastic bag to prevent leaching of
        plasticizers. The manufacturer recommends using within 4 hours. According to other
        references, diluted solutions are stable for up to 4 weeks at room temperature 15°C to 25°C in
        polyolefin containers.
       Administration:      administer     IV     infusion    over    1-hour   through     nonsorbing
        (nonpolyvinylchloride) tubing; in-line filter is not necessary. When administered as sequential
        infusions, taxane derivatives should be administered before platinum derivatives (cisplatin,
        carboplatin) to limit myelosuppression and to enhance efficacy.
       Procurement : commercially available.


11.1. Cisplatin :
   10%:
     -   Dermato1ogic: Mild alopecia
     -   Gastrointestinal: Cisplatin is one of the most emetogenic agents used in cancer
         chemotherapy; nausea and vomiting occur in 76% to 100% of patients and is dose-related.
         Prophylactic antiemetics should always be prescribed; nausea and vomiting may last up to
         1 week after therapy.
     -   Haematological: Myelosuppressive: Mild with moderate doses, mild to moderate with
         high-dose therapy WBC: Mild
         Platelets: Mild Onset: 10 days
         Nadir: 14-23 days
         Recovery: 21-39 days
     -   Nephrotoxicity: Re1ated to elimination, protein binding, and uptake of cisplatin. Two
         types of nephrotoxicity: Acute renal failure and chronic renal insufficiency.
         Acute renal failure and azotemia is a dose-dependent process and can be minimised with
         proper administration and prophylaxis. Damage to the proximal tubules by unbound
         cisplatin is suspected to cause the toxicity .It is manifested as increased BUN/creatinine,
         oliguria, protein wasting, and potassium, calcium, and magnesium wasting.
         Chronic renal dysfunction can develop in patients receiving multiple courses of cisp1atin.
         Slow release of tissue-bound cisplatin may contribute to chronic nephrotoxicity.
         Manifestations of this toxicity are varied, and can include sodium and water wasting,
         nephropathy, hyperuricemia, decreased C1cr, and magnesium wasting.
         Recommendations for minimising nephrotoxicity inc1ude: Prepare cisplatin in saline-
         containing vehicles Infuse dose over 24 hours
         Vigorous hydration (125-150 ml/hour) before, during, and after cisplatin administration
         Simultaneous administration of either mannitol or furosemide. Pretreatment with
         Avoid other nephrotoxic agents (aminoglycosides, amphotericin, etc)
     -   Neurotoxicity: Peripheral neuropathy is dose- and duration-dependent. The mechanism is
         through axonal degeneration with subsequent damage to the long sensory nerves. Toxicity
         can first be noted at cumulative doses of200 mg/m2, with measurable toxicity at
         cumulative doses >350 mg/m2. This process is irreversible and progressive with continued

     -   Ototoxicity: Ototoxicity occurs in 10% to 30%, and is manifested as high frequency
         hearing loss. Baseline audiography should be performed. Ototoxicity is especially
         pronounced in children.
     -   Hepatic: Elevation of liver enzymes

   1% to 10%:
     -   Extravasation: May cause thrombophlebitis and tissue damage if infiltrated; may use
         sodium thiosulfate as antidote, but consult hospital policy for guidelines irritant

   <1%:
     -   Anaphylactic reaction occurs within minutes after intravenous or intraperitoneal
         administration and can be controlled with epinephrine, antihistamines, and steroids
     -   Cardiovascular: Bradycardia, arrhythmias, orthostatic hypotension
     -   Dermatological: Mild a1opecia
     -   Endocrine & metabolic: SIADH
     -   Local: Phlebitis, thromboph1ebitis
     -   Ocular: Optic neuritis, blurred vision, papilloedema
     -   Renal: Haemolytic uremic syndrome
     -   Miscellaneous: Mouth sores

11.2. Docetaxel:
      >10%:
     -   Cardiovascular: Fluid retention, including peripheral oedema, pleural effusions, and ascites
         (33% to 47%); may be more common at cumulative doses> or =400 mg/ml. Up to 64% in
         breast cancer patients with dexamethasone premedication.
     -   Dermatologic: Alopecia (56% to 76%); nail disorder (Il % to 31 %, banding, onycholysis,
         hypo- or hyperpigmentation)
     -   Gastrointestinal: Mucositis/stomatitis (26% to 42%, severe in 6% to 7%), may be dose-
         limiting (premedication may reduce frequency and severity); nausea and vomiting (40% to
         80%, severe in 1 % to 5%); diarrhoea (33% to 43%)
     -   Haematology: Myelosuppression, neutropenia (75% to 85%), thrombocytopenia, anaemia
           o Onset: 4-7 days
           o Nadir: 5-9 days
           o Recovery: 21 days
     -   Hepatic: Transaminase levels increased (18%)

        -    Neuromuscular & skeletal: Neurosensory changes (paresthesia, dysesthesia, pain) noted in
             23% to 49% (severe in up to 6%). Motor neuropathy (including weakness) noted in as
             many as 16% of lung cancer patients (severe in up to 5%). Neuropathy may be more
             common at higher cumulative docetaxel dosages or with prior cisplatin therapy.
        -    Miscellaneous: Hypersensitivity reactions (6% to 13%; angioedema, rash, flushing, fever,
             hypotension); frequency substantially reduced by premedication with dexamethasone
             starting one clay prior to docetaxel administration.

           1% to 10%:
        -    Cardiovascular: Hypotension (3%)
        -    Dermatologie: Rash and skin eruptions (6%)
        -    Gastrointestinal: Taste perversion (6%)
        -    Hepatic: Bilirubin increased (9%)
        -    Neuromuscular & skeletal: Myalgia (6% to 91%), arthralgia (3% to 9%)
        -    Miscellaneous: Infusion site reactions (up to 4%)

            <1 %, postrnarketing and/or case reports (Limited to important or life-threatening): Atrial
             fibrillation, acute respiratory distress syndrome (ARDS), dehydration, erythema
             multiforme, gastrointestinal haemorrhage, gastrointestinal obstruction, gastrointestinal
             perforation, hepatitis, ileus, interstitial pneumonia, ischemic colitis, lachrymal duct
             obstruction, MI, neutropenic enterocolitis, pulmonary oedema, pulmonary embolism,
             radiation recall, seizures, Stevens-Johnson syndrome

11.3. Chest radiotherapy
 Radiation dermatitis
   Rib fractures (late effect)
   Pleural effusion
   Pericarditis
   Radiation pneumonitis and fibrosis:
1. Symptoms of radiation pneumonitis usually have an insidious onset and include the following:
        -    .A non productive cough may occur early.
        -    Dyspnoea may only occur with exertion, or can be described as an inability to take a deep
        -    Fever is usually low grade, but may be more pronounced in severe cases.

     -   Chest pain may be pleuritic or substernal and can represent pleuritis, oesophageal
         pathology, or rib fracture.
     -   Malaise and weight loss may be observed.
2. Physical signs include the following:
     -   Rales or a pleural rub may be heard, or in some cases auscultation can be normal.
     -   Dullness to percussion may be detected as a result of a small pleural effusion in about 10
         percent of patients. Effusions often cause no symptoms and may spontaneously remit. In
         contrast to malignant effusions, radiation-induced effusions do not increase in size after a
         period of observed stability .
     -   Skin erythema may outline the radiation port but is not predictive of the occurrence or the
         severity of radiation pneumonitis.
     -   Tachypnea, cyanosis, or signs of pulmonary hypertension may be seen in more severe
3. Chest radiographic abnormalities following thoracic irradiation need to be distinguished from
    other pulmonary maladies, such as infection, lymphangitic or direct extension of tumour, drug-
    induced pneumonitis, haemorrhage, and cardiogenic oedema.
     -   Chest roentgenograms may be normal in symptomatic subjects during the subacute phase
         of radiation pneumonitis.
     -   Perivascular haziness is an early radiation-induced abnormality on chest roentgenogram,
         often progressing to patchy alveolar filling densities.
     -   Films taken during the chronic phase of radiation pneumonitis may show volume loss with
         coarse reticular or dense opacities.
     -   A straight fine effect, which does not conform to anatomical units but rather to the
         confines of the radiation port, is often seen and is virtually diagnostic of radiation-induced
         lung injury (show radiograph).
     -   Modest pleural effusions and rib fractures may be seen, but lymphadenopathy does not
         occur .
     -   Chest CT is more sensitive than the chest roentgenogram in detecting subtle lung injury
         following radiation treatment . The non anatomic straight edge effect described above is
         also evident on CT.
   Oesophagitis: Patients undergoing palliative or radical radiotherapy for thoracic tumours are at
    risk for developing oesophagitis and oesophageal strictures. In the acute setting, patients may
    develop oesophagitis resulting in dysphagia and odynophagia. In some patients, chronic (>two
    months after radiotherapy) radiation oesophagitis develops, which may present as oesophageal
    ulcerations or strictures resulting from chronic ischemia and radiation fibrosis . The incidence of

   strictures after radiation is variable depending upon the type and dose of radiation, but can be as
   high as 44 percent. In one report, the median time from radiotherapy to the development of
   dysphagia was 14 weeks. The location of the strictures depends upon the site of maximal
   radiation injury. Another potential cause of dysphagia in patients who have received thoracic
   radiation is a motility disorder. However, one report demonstrated that radiotherapy had only a
   minimal effect on esophageal motility or transit.


12.1 Myelotoxicity :
a) chemotherapy alone:
      - If neutrophils count is < 1,500/mm3 and/or platelets < 100,000/mm3 on day 22, treatment
         is postponed by one or two weeks
                                              3                                       3
      - If neutrophils nadir is < 500/mm and/or platelets nadir is < 25,000/mm , doses of
         cytostatic agents are reduced to 75 % for the subsequent course of chemotherapy alone
         (full doses of weekly chemotherapy as scheduled in the protocol will be administered; see
         12.1.b), even if full recovery has occurred at time of treatment
     - If myelosuppression persists on day 36, the patient is off chemotherapy and proposed for
        radiotherapy (if not yet received) without concurrent chemotherapy.

b) chemoradiotherapy: (58)
      - If neutrophils count is < 1,500/mm3 and/or platelets < 100,000/mm3 on day 1 of the
         concurrent chemoradiotherapy, the whole treatment (including radiotherapy) is postponed
         by maximum two weeks; if myelosuppression persists on day 36 of the last course of
         chemotherapy, the patient is proposed for radiotherapy without concurrent chemotherapy
      - Subsequent chemotherapy administration (on days 8-15-22-29-36) requires neutrophils >
         1,000/mm³ and platelets > 50,000/mm³. Radiotherapy is continuing.
     -   If < 250 neutrophils /mm³ or < 25,000 platelets /mm³, radiotherapy is delayed until the
         count increases to > 250/mm³ and 25,000/mm³.

12.2 Nephrotoxicity :
a) chemotherapy alone:
     - If serum creatinine peak is 1.5-3.0 mg/dl with return to normal value, the dose of CDDP is
reduced by 50 % except if creatinine clearance is > 60 ml/min
     - If serum creatinine peak has exceeded 3.0 mg/dl, CDDP administration is stopped (even if
return to normal value)
     - If serum creatinine is not in the normal range on day 28, the patient is off chemotherapy
          and proposed for radiotherapy with docetaxel alone (if not yet received)
b) chemoradiotherapy: (58)

     -      If serum creatinine peak is 1.5-3.0 mg/dl, CDDP is omitted until recovery (creatinine < 1.5
mg/dl) and docetaxel is pursued; after recovery, the dose of CDDP is reduced by 50 %, except if
creatinine clearance is > 60 ml/min, during chemoradiotherapy and, in arm A, during consolidation
     - If serum creatinine peak has exceeded 3.0 mg/dl, CDDP administration is stopped (even if
return to normal value) and radiotherapy will continue with docetaxel weekly

12.3 Neurotoxicity :
    In case of WHO grade > II neurotoxicity (peripheral polyneuropathy), the patient is off
    chemotherapy and proposed for radiotherapy alone (if not yet received)

12.4 Otoxicity :
    If hearing loss becomes evident clinically, CDDP administration is stopped.

12.5 Anemia :
    If haemoglobin level is < 12 g/dl, it is proposed to administer erythropoietin to the patient until
    the end of the whole treatment.

12.6 Oesophagitis:
    Chemoradiation will be interrupted only in case of severe (grade ≥ III) oesophagitis non
    responding to best supportive care (including major analgesics and optimal nutrition)

12.7 Radiation pneumonitis

    Irradiation will be stopped only in case of severe (grade ≥ III) pneumonitis
    In case of grade III or more lung toxicity, concomitant chemotherapy will be omitted until

12.8. Liver toxicity
         If the bilirubin is above the upper limit of normal (ULN), docetaxel is omitted.
         The dose of docetaxel is reduced to 75% for transaminases between 2.5 and 5 times the ULN
         and was held if >5X the ULN


Response will be evaluated by a complete restaging four weeks after the end of the whole treatment.
However, patients who will not receive it because of early tumour progression or too high toxicity
will be considered as failures to treatment. The duration of overall response is the period between
the day of randomisation and the date of first progression. Survival will be dated from the first day

of registration. All patients have to be followed until death, including non evaluable and non
eligible patients.

Measurability of the disease :
1. Are considered measurable, lesions which are measurable in two perpendicular diameters:
            - lung tumour surrounded by aerated lung
            - a superficial subclavicular lymph node with positive fine needle biopsy
2. Are considered evaluable, lesions that are not measurable in two perpendicular diameters :
            - a lung tumour not completely surrounded by aerated lung
            - a deep lymph node
             - a bronchial lesion evaluable by endoscopy.

Response criteria :

1.   Complete response :
     complete disappearance of all tumour lesions, for a duration of at least 4 weeks.
2.   Partial response :
     defined as a decrease of > 50 % in the sum of the product of cross-sectional diameters of well-
     outlined lesions or > 50 % decrease of poorly-outlined lesions for at least 3 weeks in the
     absence of progressive disease elsewhere or occurrence of new lesions elsewhere. In evaluable
     lesion, this decrease will be estimated and in measurable disease, it will be measured.
     Patients with a complete clinical response but a positive control bronchoscopy with biopsy will
     be considered partial responders.
3.   Progressive disease :
     > 25 % increase in the product of cross-sectional diameters of one or more outlined lesions or
     the occurrence of new lesions irrespective of response elsewhere.
4.   Stable disease :
     This include all patients who have reductions of < 50 % or increases of < 25 % in the sum of
     well-outlined lesions whether progressing or improving, for a period of at least 3 weeks.
5.   For each patient, response evaluation will be controlled by at least 5 investigators of the group
     independent from the institution where the patient has been treated.

Death :
 - Early death :
    death due to progression of disease prior to time of response evaluation.
 - Toxic death :
     death occurring as a result of drug toxicity.


A. Treatment regimen - definition :
    A progressive course of treatment and follow up, modified for toxicity and supplemented by
    supportive therapy, as indicated in this protocol.

B. Off treatment regimen - definition :
    A patient is off treatment regimen when it is not longer possible to continue treatment in
    accordance with the protocol, including the case wherein a patient refuses treatment. Follow up

C. Off trial - definition and reporting :
    Patients can only be withdrawn from the trial for one of the following reasons and after an
    appropriate form has been sent to the coordinating centre.
            1 Initial ineligibility discovered after registration.
              Cite reason by letter. To be followed until death.
            2 Death. Submit form 7.
            3 Patient refuses follow up. Report by letter the stated and apparent reasons.


     A. Registration and randomisation :
     All eligible patients enrolled on the study by a participating institution will be registered and
     randomised by calling the data manager at (32)2.539.04.96 between 9 and 12 a.m. The
     following information will be required :
               - trial code or protocol number
               - treatment centre
               - patient's name, birthday and P.S.
               - diagnosis of local pathologist (squamous cell, adenocarcinoma, large cell or other)
                - clinical TNM staging. (See appendix III)
                - neutrophil count

     B. Stratification :
       Stratification will be done by :
         1 centre
         2 gender
         3 PS < 70 vs > 80
         4 Stage (IIIA vs IIIB)
         5 Neutrophil count (< 7500 vs > 7500)


The study coordinator is Dr T. Berghmans (tel. : 32-2.541.31.91) and the data manager is Mrs N.
Leclercq (Institut Jules Bordet, rue Héger-Bordet 1, 1000 Bruxelles, tel. : 32-2.539.04.96).

              The following forms have to be submitted :

                           Forms                         To be submitted
form A              Current tumour status                at the registration and at each
form 2              Registration report                  at the time of initial location together
                                                         with form A
form 3              Form 3                               after final evaluation
form B              Chemotherapy report                  after each course of chemotherapy
form 4              Radiotherapy report                  after radiotherapy
form 5              Post-treatment follow up or failure every 3 months following the end of
                    report                              the chemotherapy or at progression of
                                                        the disease
form 7              Final report                         on death of the patient
form 10             Serious adverse events report        at occurrence of any serious adverse
                                                        event, to be submitted as soon as
                                                        possible to the data centre
* A serious adverse event is a life-threatening complication, patient' death or severe or permanent
disability. They may be unexpected or expected. If they are unexpected, they should be reported
to the data centre within 48 h open days. If they are expected, the report should be mailed to the
data centre within 15 days.
Expected serious adverse events that may occur during the present study are the followings:
1. Toxicity grade IV
         uncomplicated grade IV neutropenia
         uncomplicated grade IV thrombopenia
         uncomplicated grade IV anemia
         severe alopecia
2. Hospital admissions
         uncomplicated febrile neutropenia (not requiring ICU admission for life support techniques
         uncomplicated bleeding related to thrombopenia (not requiring ICU admission for life
              support techniques administration)
         renal failure due to treatment not requiring renal replacement therapy
         emesis requiring hospitalisation prolongation without shock and without renal failure

       encephalopathy related to cytotoxic administration requiring admission
       PAC complications (thrombosis, infection and others)
       anaemia requiring red cell transfusions
       mucositis/oesophagitis and/or diarrhoea requiring rehydration or enteral/parenteral nutrition
       infections not related to cancer and/or treatment
       cardiac failure and/or dysrhytmias not requiring ICU admission for life support techniques
       allergic reactions due to treatment not requiring ICU admission for life support techniques
       cellulitis and tissular necrosis due to extravasation of cytotoxic drugs requiring surgical
       pneumopathy related to irradiation, requiring corticosteroid administration, less than grade
            IV according to OMS toxicity scale, not requiring mechanistic ventilatory support
            and/or surgery
       headaches related to treatment administration, without neurological deficit
       vesical complication related to treatment administration not requiring surgery and/or ICU
            admission for life support techniques administration
       Hyponatremia related to chemotherapy administration, without severe neurological
            symptoms (convulsions, coma) and/or not requiring ICU admission for life support
            techniques administration
       Hypomagnesaemia related to chemotherapy administration
       Oedema and/or cavity effusions (pleural or pericardial effusions, ascites) due to
            chemotherapy administration, not life-threatening and/or requiring ICU admission for
            life support techniques administration
3. Serious events related to cancer
       haemoptysis related to lung cancer
       death by cancer progression
       admission due to cancer progression
       convulsions caused by brain metastasis
       venous thrombosis or pulmonary embolism without death
       fracture due to bone metastasis
       pain related to cancer
       compression due to epidural metastasis
       infection : zona, postobstructive pneumonia
       coagulation disorders related to cancer

4. Serious events related to comorbidity
       exacerbation of COPD during chemotherapy not requiring ICU admission for life support
                techniques administration
       venous thrombosis without death
       arterial vascular complication/thrombosis
5. Handicap
       Hypoacousia due to cisplatin
       Polyneuropathy due to cytotoxic agents


1.     The protocol will be approved by the ethical committees according to the European
directive 2001/20/CE and its transposition in the local legislation. In the different countries, the
approval by the ethical committee must be performed according to national legislation.

2.     Patients will be asked to agree to participate to the study. The outline of the trial will be
explained by the investigator and patient will have to give consent. Patient will be informed of the
modalities, anticipated benefits and possible hazards and discomforts in taking part in the trial. The
patient will be informed that the trial will comply with the principles present in the Declaration of
Helsinki. If     during the study, the patient wants to stop the treatment, this will be respected by the

3.     Patient consent will be noted in the hospital file and a signed informed consent must be
conserved by the local investigator.

4.     Every unexpected serious adverse event will be notified by the principal investigator to the
other participants, by e-mail, as soon as it will be known. Other adverse events will be reported
once a year during the annual assembly.

5.     The patient’s confidentiality has to be respected. Personal data and/or samples must be
anonymous. Only the local investigator will known the relationship between the patient’s code and
its personal sheet. This link will be destroyed after the end of the trial.


The primary endpoint of the study will be to compare the distributions of the survival duration
between the two arms. The sample size evaluation relies on the following assumptions :
       a) Using the survival data from a previous trial of the ELCWP (74), it is expected to reach a
2 year survival rate of 20% in the arm where treatment begins with three courses of chemotherapy;
       b) On the basis of the trial published by Furuse (37;74), it appears reasonable to expect an
increase of this 2 year survival rate to 35% in the arm with immediate concomitant
       c) If true in the patients population recruited by the ELCWP, this increase should be
detected by the present trial with a power of 80% and a type I error level of 5% using a two-sided
logrank test.
With these assumptions, the total number of events to be observed is 178 and should be achieved
with randomisation of 123 patients in each arm of the study.
An interim toxicity analysis will be performed after treatment completion of the first 40 randomised
patients, to confirm the tolerability reported in the phase I/II trials published in the literature (56-


Authors on publication include the study coordinator, the members of the writing committee, the
statistician and a member of each institution entering at least 10% of evaluable patients for abstracts
and 5% of evaluable patients for full papers. Authorship will also include the data manager for full
papers. All information generated by the study is full property of the European Lung Cancer
Working Party. No information may be used for publication or presentation without written
approval of the study coordinator and the chairman of the group.


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Appendix I : Performance scale (Karnofsky)

Able to carry on normal activity;  100 Normal; no complaints, no evidence
no special care is needed                of disease

                                             90   Able to carry on normal activity;
                                                  minor signs or symptoms of disease

                                         Normal activity with effort; some
                                         signs or symptoms of disease
Unable to work, able to live at     70 Care for self, unable to carry on
home, care for most personal needs;      normal activity or do active work
a varying amount of assistance is
                                    60 Requires occasional assistance,
                                                  but is able to care for most of his needs

                                         Requires considerable assistance, and
                                         frequent medical care
Unable to care for self; requires   40 Disabled; required special care and
equivalent of institutional or           assistance
hospital care; disease may be
progressing rapidly
                                             30   Severely disabled; hospitalisation is
                                                  indicated, although death not imminent

                                             20   Very sick; hospitalisation necessary,
                                                  active supportive treatment necessary

                                             10   Moribund; fatal process progressing

                                     0 Dead
(Cancer 1 : 634 (1948) )

Appendix II : WHO toxicity criteria

Cancer Clinical Trials

                                   COMMON TOXICITY CRITERIA


   Toxicity            0                1                  2                    3                      4

    WBC               4.0          3.0 - 3.9          2.0 - 2.9            1.0 - 1.9                < 1.0
    PLT              WNL          75.0 - normal       50.0 - 74.9          25.0 - 49.9               < 25.0
    Hgb              WNL          10.0 - normal       8.0 - 10.0            6.5 - 7.9                < 6.5
Granulocytes/         2.0          1.5 - 1.9          1.0 - 1.4            0.5 - 0.9                < 0.5
Lymphocytes           2.0           1.5 - 1.9          1.0 - 1.4            0.5 - 0.9                < 0.5
Hemorrhage           None            Mild, no      Gross,1 - 2 units     Gross,3 - 4 units      Massive, > 4 units
  (Clinical)                       transfusion      transfusion per      transfusion per     transfusion per episode
                                                         episode             episode
  Infection          None              Mild             Moderate              severe            Life-Threatening
   Nausea            None          Able to eat    Intake significantly    No significant               --
                                    reasonable     decreased but can          intake
                                      intake               eat
  Vomiting           None          1 episode in   2 - 5 episodes in 24   6 – 10 episodes   > 10 episodes in 24 hrs
                                      24 hrs               hrs              in 24 hrs      or requiring parenteral
   Diarrhea          None         Increase of 2 -   Increase of 4 - 6    Increase of 7 - 9    Increase of > 10
                                   3 stools/day      stools/day, or       stools/day, or    stools/day or grossly
                                   over pre-Rx nocturnal stools, or incontinence or          bloody diarrhea, or
                                                   moderate cramping severe cramping         need for parenteral
  Stomatitis         None            Painlesse     Painful erythema,          Painful      Requires parenteral or
                                      ulcers,     edema, or ulcers, but erythema, edema,       enteral support
                                   erythema, or          can eat          or ulcers, and
                                  mild soreness                             cannot eat
   Bilirubin         WNL                 -             < 1.5 x N           1.5 - 3.0 x N          > 3.0 x N
 Transaminase        WNL              2.5 x N        2.6 - 5.0 xN        5.1 - 20.0 x N         > 20.0 x N
  Alk Phos or        WNL             2.5 x N         2.6 - 5.0 xN        5.1 - 20.0 x N           > 20.0 x N
 Liver-clinical     No change           -                  -                 Precoma             Hepatic coma
                  from baseline

                         COMMON TOXICITY CRITERIA (continued)


  Toxicity       0                 1                         2                   3                 4

 Creatinine     WNL             <1.5 x N                1.5-3.0 x N          3.1-6.0 x N        >6.0 x N
 Proteinurie     no               1+ or                  2 - 3 + or        4 + or> 1.0 g/X     neprhotic
               change      < 0.3 gX or < 3 g/l        0.3-1.0gX or 3-        or > 10 g/l       syndrome
 Hematuria      Neg            Micro only             Gross, no clots       Gross + clots        requires
  Alopecia     No loss       Mild hair loss         Pronouced or total            -                 -
                                                          hair loss
 Pulmonary     None or    Asymptomatic, with            Dyspnea or           dyspnea at      dyspnea at rest
                 no       abnormality in PFT’s      significant exertion   normal level of
               change                                                          activity
  Cardiac       None         Asymptomatic,             Recurrent or           Requires           Requires
dysrhytmias              transient, requiring no       persistent, no         treatment      monitoring; or
                                 therapy             therapy required                        hypotension, or
                                                                                              tachycardia or
  Cardiac       None     Asymptomatic, decline       Asymptomatic,          Mild CHF,            Severe of
  function                 of resting ejection      decline of resting    responsive to      refractory CHF
                          fraction by less than    ejection fraction by       therapy
                         20% of baseline value      more than 20% of
                                                       baseline value
   Cardiac      None      Non-specific T wave       Asymptomatic ST      Angina without Acute myocardial
  Ischemia                       flattening       and T wave changes       evidence for        infarction
                                                  suggesting ischemia       infraction
  Cardiac       None           Asymptomatic         Pericarditis (rub,    Symptomatic        Tamponade ;
 Pericardial                    effusion, no         chest pain, ECG         effusion ;    drainage urgently
                          intervention required           changes)      drainage required       required
Hypertension   None or         Asymptomatic,            Recurrent or    Requires therapy Hypertensive crisis
                 no        transient increase by   persistent increase
               change     greater than 20mmHg         by greater than
                                  (D) or to        20mmHg (D) or to
                         > 150/100 if previously         150/100 if
                                   WNL.             previously WNL.
                          No treatment required        No treatment
Hypotension    None or    Changes requiring no         Requires fluid   Requires therapy Requires therapy
                 no          therapy (including   replacement or other          and       and hospitalization
               change       transient or thoastic     therapy but not    hospitalization   for > 48 hrs after
                                hypotension)          hospitalization    resolves within stopping the agent
                                                                             48 hrs of
                                                                           stopping the

                          COMMON TOXICITY CRITERIA (continued)


  Toxicity         0               1                     2                        3                     4

Neurosensory    None or    Mild paresthesias, Mild or moderate            Severe objective,             --
                  no      loss of deep tendon objective sensory            sensory loss or
                change          reflexes        loss;moderate             paresthesias that
                                                 paresthesias          interfere with function
Neuromotor      None or       Subjective       Mild objective           Objective weakness          Paralysis
                  no         weakness, no     weakness without           with impairment of
                change    objective findings      significant                  function
                                               impairment of
Neurocortical    None     Mild somnolence or Moderate somnolence        Severe somnolence,      Coma, seizures
                               agitation         or agitation           agitation, confusion,   toxic psychosis
                                                                       hallucinations, aphasia,
                                                                         or severe difficulty
  Neuro-         None           Slight           Intention tremor,        Locomotor ataxia        Cerebellar
 cerebellar                 incoordination,      dysmetria, slurred                                 necrosis
                            dysdiadokinesis     speech, nystagmus
  Neuro           No        Mild anxiety or     Moderate anxiety or      Severe anxiety or           Suicidal
  Mood          change        depression            depression              depression               ideation
  Neuro          None            Mild           Moderate or severe     Unrelenting and severe           --
 Headache                                          but transient
  Neuro         None or          Mild                Moderate                  Seevere            Ileus > 96 hrs
Constipation      no
   Neuro        None or     Asymptomatic              Tinnitus         Hearing loss interfering    Deafness not
  Hearing         no        hearing loss on                               with function but         correctable
                change     audiometry only                                correctable with
                                                                             hearing ald
   Neuro        None or          --                     --              Symptomatic subtotal        Blindness
   Vision         no                                                       loss of vision
    Skin        None or Scattered macular or   Scattered macular or        Generalized             Exfolliative
                  no     papular eruption or    papular eruption or    symptomatic macular,        dermatitis or
                change    erythema that is        erythema with         papular, or vesicular       ulcerating
                           asymptomatic          pruritus or other           eruption               dermatitis
                                               associated symptoms
  Allergy        None      Transient rash drug Urticaria, drug fever       Serum sickness,         Anaphylaxis
                          fever < 38°c, 100.4F  38°c, 100.4F, mild         bronchospasm
                                                  bronchospasm           req.parenteral meds
  Fever in       None         37.1 - 38.0C         38.1 - 40.0C                > 40.0C                > 40.0C
 absence of                   98.7 - 100.4F       100.5 - 104.0F               > 104.0F            (104.0F) for
  injection                                                             for less than 24 hours     more than 24
                                                                                                    hrs or fever
                                                                                                  by hypotension

                                COMMON TOXICITY CRITERIA (continued)


    Toxicity               0                      1                        2                       3                  4

           Local          None                 Pain               Pain and swelling         Ulceration          Plastic surgery
                                                                  with inflammation                                indicated
                                                                     or phlebitis
Weight gain/loss        < 5.0%              5.0 - 9.9%                10.0 - 19.9             20.0%                  --
Hyperglycemia            < 116              116 – 160                  161 - 250            251 – 500              <500 or
 Hypoglycemia             > 64                55 – 64                  40 - 54                30 – 39                <30
    Amylase              WNL                 < 1.5 x N              1.5 - 2.0 x N          2.1 - 5.0 x N           >5.1 x N
 Hypercalcemia           < 10.6             10.6 – 11.5              11.6 - 12.5            12.6 - 13.5             13.5
  Hypocalcemia           > 8.4               8.4 – 7.8                7.7 - 7.0              6.9 - 6.1               6.0
Hypomagnesemia           > 1.4               1.4 – 1.2                1.1 - 0.9              0.8 - 0.6               0.5
   Fibrinogen            WNL              0.99 - 0.75 x N          0.74 - 0.50 x N        0.49 - 0.25 x N          0.24 x N
Prothrombin time         WNL              1.01 - 1.25 x N          1.26 - 1.50 x N        1.51 - 2.00 x N         > 2.00 x N
     Partial             WNL              1.01 - 1.66 x N          1.67 - 2.33 x N        2.34 - 3.00 x N         > 3.00 x N

                        Common terminology criteria for adverse events v3.0 (CTCAE)

 Toxicity           0                 1                       2                       3                     4              5

Oesophagitis       None        Asymptomatic              Symptomatic;      Symptomatic and                 Life-          Death
                                 pathologic,                 altered        severely altered            threatening
                               radiographic or        eating/swallowing eating/swallowing              consequences
                                 endoscopic               (e.g. altered     (e.g. inadequate
                                findings only         dietary habits, oral   oral caloric or
                                                       supplements); IV fluid intake); IV
                                                      fluids indicated <       fluids, tube
                                                               24h          feeding or TPN
                                                                            indicated ≥ 24h
Pneumonitis        None        Asymptomatic,          Symptomatic, not       Symptomatic,                  Life-          Death
                                radiographic            interfering with    interfering with           threatening;
                                findings only                 ADL               ADL; O2                 ventilatory
                                                                                indicated                 support
  Cough            None        Symptomatic,           Symptomatic and          Symptomatic and               -              -
                               non-narcotic                 narcotic              significantly
                                medication               medication             interfering with
                                                           indicated             sleep or ADL
    Pain           None           Mild, not            Moderate pain;          Severe pain; pain        Disabling           -
                               interfering with       pain or analgesics          or analgesics
                                   function            interfering with             severely
                                                       functioning but          interfering with
                                                        not with ADL                  ADL
ADL : activities of daily living

Appendix III : Staging classification

A.        TNM :

T : primary tumour

      -    TX : Tumour proven by the presence of malignant cells in bronchopulmonary secretions
           but not visualised by roentgenography or bronchoscopy, or any tumour that cannot be
           assessed as in a pretreatment staging tumour .

      -    T0 : No evidence of primary tumour

      -    TIS : Carcinoma in situ

      -    T1 : A tumour that is 3.0 cm or less in greatest dimension, surrounded by lung or visceral
           pleura, and without evidence of invasion proximal to a lobar bronchus at bronchoscopy*

      -    T2 : A tumour more than 3.0 cm in greatest dimension, or a tumour of any size that either
           invades the visceral pleura or has associated atelectasis or obstructive pneumonitis
           extending to the hilar region. At bronchoscopy, the proximal extent of demonstrable
           tumour must be within a lobar bronchus or at least 2.0 cm distal to the carina. Any
           associated atelectasis or obstructive pneumonitis must involve less than an entire lung.

      -    T3 : A tumour of any size with direct extension into the chest wall (including superior
           sulcus tumours), diaphragm, or the mediastinal pleura or pericardium without involving
           the heart, great vessels, trachea, oesophagus, or vertebral body, or a tumour in the main
           bronchus within 2.0 cm of the carina without involving the carina.

      -    T4 : A tumour of any size with invasion of the mediastinum or involving heart, great
           vessels, trachea, oesophagus, vertebral body, or carina or with presence of malignant
           pleural effusion.**
NB :
* The uncommon superficial tumour of any size whose invasive component is limited to the
bronchial wall and that may extend proximal to the main bronchus is classified as T1.

** Most pleural effusions associated with lung cancer are due to tumour. There are, however, some
few patients in whom cytopathologic examination of pleural fluid (on more than one specimen) is
negative for tumour and the fluid is non bloody and is not an exsudate. When these elements and
clinical judgement dictate that the effusion is not related to the tumour, the cases should be staged
T1, T2 or T3, with effusion being excluded as a staging element.

N : regional lymph node

        -   N0 : No demonstrable metastasis to regional lymph nodes

        -   N1 : Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region, or both,
            including direct extension

        -   N2 : Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes

        -   N3 : Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes,
            or ipsilateral or contralateral scalene or supraclavicular lymph nodes.

M : distant metastasis

        -   M0 : No (known) distant metastasis

        -   M1 : Distant metastasis present - specify site(s).

B. AJCC/UICC 1997 Staging :

Stage                                 T                          N                    M
Occult carcinoma                     X                           0                    0
0                                    IS                          0                    0
IA                                    1                          0                    0
IB                                    2                          0                    0
IIA                                   1                          1                    0
IIB                                   2                          1                    0
                                      3                          0                    0
IIIA                                 1-3                         2                    0
                                      3                          1                    0
IIIB                                Any                          3                    0
                                      4                      any                      0
IV                                  Any                      any                      1

Appendix IV


Recommendations guiding physicians in biomedical research involving Human Subjects.
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, amended by the 29th
World Medical Assembly, Tokyo, Japan, October 1975, the 35th World Medical Assembly, Venice,
Italy, October 1983 and the 41st World Medical Assembly, Hong Kong, September 1989.


It is the mission of the physician to safeguard the health of the people. His or her knowledge and
conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician with the words,
"The health of my patient will be my first consideration," and The International Code of
Medical Ethics declares that, "A physician shall act only in the patient's interest when
providing medical care which might have the effects of weakening the physical and mental
condition of the patient".

The purpose of biomedical research involving human subjects must be to improve diagnostic,
therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of

In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards.
This applies especially to biomedical research.

Medical progress is based on research which ultimately must rest in part on experimentation
involving human subjects.

In the field of biomedical research, a fundamental distinction must be recognised between medical
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research,
the essential object of which is purely scientific and without implying direct diagnostic or
therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect the environment, and
the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied to human beings to
further scientific knowledge and to help suffering humanity, the World Medical Association has

prepared the following recommendations as a guide to every physician in biomedical research
involving human subjects. They should be kept under review in the future. It must be stressed that
the standards as drafted are only a guide to physicians all over the world. Physicians are not
relieved from criminal, civil and ethical responsibilities under the laws of their own countries.


1.     Biomedical research involving human subjects must conform to generally accepted
       scientific principles and should be based on adequately performed laboratory and
       animal experimentation and on a thorough knowledge of the science literature.

2.     The design and performance of each experimental procedure involving human
       subjects should be clearly formulated in an experimental protocol which should be
       transmitted    to    consideration,    comment      and    guidance     to     a specially
       appointed committee independent of the investigator and the sponsor, provided that
       this independent committee is in conformity with the laws and regulations of the
       country in which the research experiment is performed.

3.     Biomedical research involving human subjects should be conducted only by
       scientifically qualified persons and under the supervision of a clinically competent
       medical person. The responsibility for the human subject must always rest with a
       medically qualified person and never rest on the subject of the research, even
       though the subject has given his or her consent.

4.     Biomedical research involving human subjects cannot legitimately be carried out
       unless the importance of the objective is in proportion to the inherent risk to the

5.     Every biomedical research project involving human subjects should be preceded by
       careful assessment of predictable risks in comparison with foreseeable benefits to
       the subject or to others. Concern for the interests of the subject must always prevail
       over the interests of science and society.

6.     The right of the research subject to safeguard his or her integrity must always be
       respected. Every precaution should be taken to respect the privacy of the subject
       and to minimise the impact of the study on the subject's physical and mental
       integrity and on the personality of the subject.

7.     Physicians should abstain from engaging in research projects involving human
       subjects unless they are satisfied that the hazards involved are believed to be

      predictable.   Physicians should cease any investigation if the hazards are found to
      outweigh the potential benefits.

8.    In publication of the results of his or her research, the physician is obliged to
      preserve the accuracy of the results. Reports of experimentation not in accordance
      with the principles laid down in this Declaration should not be accepted for

9.    In any research on human beings, each potential subject must be adequately
      informed of the aims, methods, anticipated benefits and potential hazards of the
      study and the discomfort it may entail. He or she should be informed that he or she
      is at liberty to obtain from participation in the study and that he or she is free to
      withdraw his or her consent to participation in any time. The physician should then
      obtain the subject's freely-given informed consent, preferably in writing.

10.   When obtaining informed consent for the research project the physician should be
      particularly cautious if the subject is in a dependent relationship to him or her or
      may consent under duress. In that case, the informed consent should be obtained
      by a physician who is not engaged in the investigation and who is completely
      independent of this official relationship.

11.   In case of legal incompetence, informed consent should be obtained from the legal
      guardian in accordance with national legislation.       Where physical or mental
      incapacity makes it impossible to obtain informed consent, or when the subject is a
      minor, permission from the responsible relative replaces that of the subject in
      accordance with national legislation. Whenever the minor child is in fact able to give
      a consent, the minor's consent must be obtained in addition to the consent of the
      minor's legal guardian.

12.   The research protocol should always contain a statement of the ethical
      considerations involved and should indicate that the principles enunciated in the
      present Declaration are complied with.

      (Clinical Research)

1.    In the treatment of the sick person, the physician must be free to use a new
      diagnostic and therapeutic measure, if in his or her judgement it offers hope of saving
      life, re-establishing health or alleviating suffering.

2.     The potential benefits, hazards and discomfort of a new method should be weighted
       against the advantages of the best current diagnostic and therapeutic methods.

3.     In any medical study, every patient including those of a control group, if any should
       be assured of the best proven diagnostic and therapeutic methods.

4.     The refusal of the patient to participate in a study must never interfere with the
       physician-patient relationship.

5.     If the physician considers it essential not to obtain informed consent, the specific
       reasons for this proposal should be stated in the experimental protocol for
       transmission to the independent committee (1, 2).

6.     The physician can combine medical research with professional care, the objective
       being the acquisition of new medical knowledge, only to the extent that medical
       research is justified by its potential diagnostic or therapeutic value from the patient.

       (Non-clinical biomedical research)

1.     In the purely scientific application of medical research carried out on a human being,
       it is the duty of the physician to remain the protector of the life and health
       of that person on whom biomedical research is being carried out.

2.     The subjects should be voluntaries either healthy persons or patients for whom the
       experimental design is not related to the patient's illness.

3.     The investigator or the investigating team should discontinue the research if in
       his/her or their judgement it may, if continued, be harmful to the individual.

4.     In research on man, the interest of science and society should never take
       precedence over considerations related to the well-being of the subject.


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