168                                                                                                        Lung Cancer, non-small cell (NSCLC)

 

31.                Lung Cancer, non small cell (NSCLC)

 

31.1        General considerations

 

Stage grouping

Stage 0                                      Tis                           N0                          M0

Stage Ia                                     T1                            N0                         M0

Stage Ib                                     T2                            N0                         M0

Stage IIa                                    T 1                           N1                         M0

Stage IIb                                    T2                            N1                         M0

                                                  T3                            N0                         M0

Stage IIIa                                   T3                            N1                         M0     

                                                  T 1 – 3                      N2                         M0

Stage IIIb                                   T 1 – 3                     N3                         M0

                                                   T4                            N0-3                     M0

Stage IV                                     any T                       any N                    M 1

 

Surgical resection is described as the preferred therapy for patients with respectable NSCLC (stage I, II and selected IIIa), although it fails to cure a considerable number of patients. Radiotherapy can be applied alternatively as a definitive treatment for medically inoperable disease in patients with early stage NSCLC and also post-operatively to enhance local tumor control. Studies exploring postoperative (adjuvant) chemotherapy so far have not demonstrated a positive impact on survival. On the other hand promising results were reported for a multimodality approach of induction (neoadjuvant) chemotherapy followed by surgery and/ or radiotherapy (first of all in patients with respectable stage III disease but now also under investigation in earlier stages).

 

For patients with non-resectable NSCLC ( stage IIIB/IV) in good clinical condition (WHO PS≤1) combination chemotherapy either alone or in association with radiotherapy is now established as first-line treatment , resulting in survival benefit, symptom reduction, and improved quality of life. For patients with PS > 1 and elderly patients single agent chemotherapy results in better palliation than palliative care (incl. radiation) alone. At progression after (platinum-based) front-line chemotherapy docetaxel seems to result in a small survival benefit compared to supportive care alone.

 

Literature: for review e.g.

            BONOMI, Semin. Oncol. 28 (Suppl 14) (2001): 45 – 49 (novel treatment 

            approaches)

            BUNN, Oncology 15 (Suppl 6) (2001) : 26 – 32

            DEPIERRE et al, Cancer Treat, Rev. 27 (2001): 119 – 127 (preoperative 

            chemotherapy)

            FOSSELLA, Curr. Oncol.  Rep. 2 (2000): 96 – 101 (second- line 

            chemotherapy)

GANDARA et al, Semin. Oncol. 28 (Suppl 9 ) (2001): 26 – 32  (chemoradiotherapy for stage III NSCLC)

GRIDELLI, Crit. Rev. Oncol. Hematol. 35 (2000): 219 – 225 (chemotherapy in elderly patients)

HAURA, Cancer Control 8 (2001): 326-336 (review of current randomized trials in advanced NSCLC)

HUISMAN et al, J. Clin. Oncol. 18 (2000); 3722-3730 (second-line chemotherapy)

KHURI et al, Ann. Oncol. 12 (2001): 739 – 744

 

Lung Cancer, non-small cell (NSCLC)                                                                                                                   169

 

KOTAS et al, Lung Cancer 33 (Suppl 1) (2001): 61-64 (sequential chemoradiotherapy for locally advanced NSCLC)

                        MANEGOLD, Lung Cancer 34 (Suppl 2) (2001) : 165 – 170          

                        (chemotherapy) and Oncology 15 (Suppl 6)  (2001): 46 – 51 

                        (chemotherapy in elderly patients)

MEERT et al, Anticancer Res. 19 (1999) ; 4379-4390 (systematic review of phase II and III studies with new drugs)

NICUM and CULLEN, Anticancer Drugs 11(2000): 603-607 (chemotherapy vs palliativecare)

NOVELLO and LeCHEVALIER, Eur. J.Cancer 38(2002): 292-299(chemoradiotherapy for locally advanced NSCLC )

NON-SMALL-CELL LUNG CANCER COLLABORATIVE GROUP, Br. Med. J.311(1995): 899-904 (meta-analysis of chemotherapy vs palliative care)

NON-SMALL-CELL LUNG CANCER EXPERT PANEL, J.Clin. Oncol. 15(1997) :2996-3018(ASCO clinical practice guidelines for the treatment of unresectable NSCLC)

PISTERS, Semin. Oncol. 28(Suppl 14) (2001) : 23-28(adjuvant and neoadjuvant therapy for early stage NSCLC )

ROSELL et al , Semin. Oncol . 28 (Suppl 2 ) (2001) : 28-34 (molecular markers )

SMYTHE.Cancer Control 8(2001) : 318-325 (stage I and II NSCLC )

SORENSON et al, Acta Oncol. 40 (2001) : 327-339 (systematic overview of chemotherapy )

SWEENEY and SANDLER , Invest . N. Drugs 18 (2000) : 157-186 ) chemotherapy)

SWISHER and ROTH, Curr. Rep. 2(2000): 64-70 (gene therapy)

THATCHER, Lung Cancer 34 (Suppl 2) (2001) :171-175 (chemotherapy)

Van ZANDWIJK, Lung Cancer 34 (Supple 2) (2001) : 145-150 (neoadjuvant strategies)

 

31.2              Single agent chemotherapy

 

31.2.1        Docetaxel

                  Literature : for review e.g.

                         COMER  and GOA , Drugs Aging 17 (2000) :53-80

                         GREEN, Anticancer Drugs 12 (Suppl 1) (2001) : 11-16

                          LA NGER , Invest. New Drugs 18 (2000) : 17-28

                          MILLER and  KRIS , Semin. Oncol. 27(Suppl 3) (2001) : 3-10

                          SHEPHERD et al, Semin. Oncol. 28(Suppl 2) (2001) :4 - 9

 

Docetaxel                75*or 100 mg/m2**                   i.v. (1 h inf)                    d 1

   To be repeated every 3 weeks

   *    For chemotherapy- pretreated patients

   **  For chemotherapy- naive patients

 

    Literature:

          FOSELLA et al, J. Clin. Oncol. 18(2000) : 2354 – 2362

          SHEPHERD et al, J. Clin. Oncol. 18(2000) : 2095 – 2103

 

31.2.2           Gemcitabine

Literature : for review e.g.

       JOHNSON, Oncology 15 (Suppl 6) (2001) : 33-39

       KELLY, Ann. Oncol. 10 (Suppl 5) (1999) : 53-56

       MANEGOLD et al, Invest. New Drugs 18 (2000) : 29-42

 

Gemcitabine            1000-1250 mg/m2               i.v. (30 min inf)            d 1,8,15

   To be repeated every 4 weeks

170                                                                                                          Lung Cancer, non small cell (NSCLC)

            Literature:

                        ANDERSON et al, j. Clin. Oncol. 12 (1994): 1821 – 1826

                        GATZEMEIER et al, Eur. J. Cancer 32 A(1996): 243-248

 

31.2.3.                       Vinorelbine

Literature: for review e.g.

            GRALLA et al, Ann. Oncol. 10 (Suppl 5) (1999): 41-45

            WOZNIAk, Semin. Oncol. 26 (Suppl 16) (1999): 62 – 66

Vinorelbine                30 mg/m2               i.v. (20 min inf)                    d 1, 8, 15

To be repeated every 4 weeks

Literature:

         LeCHEVALIER et al, J. Clin. Oncol. 12 (1994): 360-367 (randomized 

         study of vinorelbine vs vinorelbine + cisplatin vs vindesine + cisplatin)

 

31.3           Combination chemotherapy

31.3.1.                           Platinum-based regimens

31.3.1.1.  MIC

Mitomycin                     6 mg/m2                    i.v. (bolus)                           d 1

Ifosfamide                      3000 mg/m2              i.v. (3 h inf)                         d 1

                                                                        With mesna uroprotection

Cisplatin                        50 mg/m2                  i.v. (1 h inf)                          d 1

            To be repeated every 3 weeks (max 4 courses)

            Literature:

CULLEN et al, J. Clin. Oncol. 17 (1999): 3188-3194 (report of two randomized, parallel trials to determine the effect of added  chemotherapy on duration and quality of life in localized, unresectable, and extensive NSCLC)

ROSELL et al, N. Engl. J. Med. 330 (1994): 153-158 (randomized trial of neoadjuvant MIC followed by surgery vs surgery alone)

          or

Mitomycin                        6 mg/m2                    i.v. (bolus)                           d 1

Ifosfamide                         3000 mg/m2              i.v. (3 h inf)                         d 1

                                                                            With mesna uroprotection

Cisplatin                           100 mg/m2                  i.v. (1 h inf)                        d 1

To be repeated every 3 weeks (max 6 courses)

Literature:

            CRINO et al, Ann. Oncol. 8 (1997): 709 – 711

31.3.1.2     Cisplatin + Etoposide

 Literature: for review

        ARDIZZONI et al, Ann. Oncol. 10 (Suppl 5) (1999): 13 – 17

This second-geneation regimen may still represent a reasonable choice for patients with stage IV NSCLC when cost issues are of concern. It is also an option when no clear distinction between small cell and non-small cell histology can be made. E.g.

 

Lung Cancer, non –small cell (NSCLC)                                                                                                      171

Cisplatin                      75 mg/m2                    i.v. (1 h inf)                        d 1

Etoposide                     100 mg/m2                  i.v.(45 min inf)                  d 1-3

To be repeated every 3 weeks

Literature:

            BONOMI et al, J. Clin. Oncol. 18 (2000): 623-631

31.3.1.3  Cisplatin + Vinorelbine

Cisplatin                   120 mg/m2                 i.v. (1 h inf)                        d 1 + 29

                                                                                                      Then every 6 wks

Vinorelbine               30 mg/m2                  i.v.(20 min inf)                  d 1, 8, 15…..

           

            or

Vinorelbine               25 mg/m2                  i.v.                                  d 1, 8, 15

Cisplatin                   100 mg/m2                 i.v.                                  d 1

To be repeated every 4 weeks ( in the absence of progression or intolerable toxicity for a minimum of 6 cycles)

 

Literature:

KELLY et al, J. Clin. Oncol. 19 (2001) : 3210-3218 (randomized phase III trial of the SWOG of paclitaxel + carboplatin vs vinorelbine + cisplatin)

31.3.1.4  NIP (VIP)

Vinorelbine                   25 mg/m2                 i.v.(slow bolus)                   d 1+ 8

Ifosfamide                    3000 mg/m2              i.v. ( 2 h inf)                        d 1

                                                                       With mesna uroprotection

Cisplatin                      80 mg/m2                  i.v. (1 h inf)                          d 1

To be repeated every 3 weeks (for IIIb NSCLC 3 courses as induction followed by radiotherapy in case of CR, PR, or SD: 2 Gy/d, 5 d/week, total dose 60 Gy starting 4-6 weeks after the end of induction chemotherapy)

           

            Literature:

                        BALDINI et al, Ann. Oncol. 7 (1996): 747-749 and Semin. Oncol. 27  

                        (Suppl 1) (2000): 28-32

 

31.3.1.5  Paclitaxel + Cisplatin

Paclitaxel                           175 mg/m2                  i.v. (3 h inf)                       d 1

Cisplatin                           80 mg/m2                     i.v. (1 h inf)                        d 1

            To be repeated every 3 weeks

 

            Literature:

                        GIACCONE et al, J. Clin . Oncol. 16 (1998): 2133-2141 (randomized   

                        study of the EORTC comparing  paclitaxel + cisplatin  and cisplatin +  

                        teniposide)

  

172                                                                                                          Lung Cancer, non small cell (NSCLC)

            or

Paclitaxel                          135 mg/m2                  i.v. (24 h inf)                       d 1

Cisplatin                           75 mg/m2                     i.v. (1 h inf)                        d 1

            To be repeated every 3 weeks

 

            Literature:

SCHILLER et al, N. Engl. J. Med. 346 (2002); 92-98 (randomized comparison of four chemotherapy  regimens by the ECOG)

31.3.1.6  Paclitaxel + Carboplatin

Literature: for review e.g.

            BONOMI, Semin. Oncol. 26 (Suppl 2) (1999): 55-59

Paclitaxel                           225 mg/m2                  i.v. (3 h inf)                       d 1

Carboplatin                        AUC = 6                     i.v. (15min inf)                  d 1

To be repeated every 3 weeks ( in the absence of progression or intolerable toxicity for a minimum of 6 cycles)

 

Literature:

SCHILLER et al, N. Engl. J. Med. 346 (2002):  92-98 (randomized comparison of four chemotherapy regimens by the ECOG)

            KELLY et al, J. Clin. Oncol. 19 (2001): 3210-3218 (randomized phase III 

            trial of the SWOG of paclitaxel + carboplatin vs vinorelbine + cisplatin)

31.3.1.7  Docetaxel  + Cisplatin

    Literature : for review e.g.

            BELANI and  LYNCH, Semin. Oncol. 28 (Suppl 2) (2001): 10 – 14

Docetaxel                         75 mg/m2                    i.v.                            d 1

Cisplatin                           75 mg/m2                    i.v.                            d 1

To be repeated every 3 weeks

 

Literature:

SCHILLER et al, N. Engl. J. Med. 346 (2002) : 92-98 (randomized comparison of four chemotherapy regimens by the ECOG)

 

or

Docetaxel                  75 mg/m2                  i.v. (1 h inf)             d 1

Cisplatin                   100 mg/m2                i.v. ( 1 h inf)             d 1 (1 h after DOC)

To be repeated every 3 weeks for 3 cycles, then every 6 weeks.

 

Literature:

            LeCHEVALIER et al, Eur. J. Cancer 34 (1998): 2032- 2036

 

Lung Cancer, non –small cell (NSCLC)                                                                                                      173

31.3.1.8   Gemcitabine + Cisplatin

                Literature: for review e.g.

                        CARTEI et al, Ann. Oncol. 10 (Suppl 5) (1999): 57 – 62

Gemcitabine             1000mg/m2            i.v. (30-60 min inf)              d 1, 8., 15

Cisplatin                  100 mg/m2              i.v. ( 30-120 min inf)           d 1  1** or 2*

To be repeated every 4 weeks

 

            Literature:

                *  CRINO et al, J. Clin. Oncol. 17 (1999): 3522-3530 ( randomized phase II  

                     study of  GC vs  MIC)

                ** SANDLER et al, J. Clin. Oncol. 18 ( 2000) : 122 – 130 ( phase III  

                     international trial of GC vs cisplatin )

                     SCHILLER et al, N. Engl. J. Med. 346 (2002): 92-98 (randomized

                    comparision of four chemotherapy regimens by the ECOG)

 

31.3.2         Non- platinum combinations

    The following regimens are only examples for a relatively new development.

 

31.3.2.1  Gemcitabine + Vinorelbine

Gemcitabine                  1200mg/m2            i.v.                                       d 1+ 8

Vinorelbine                    30 mg/m2              i.v.                                       d 1 + 8

To be repeated every 3 weeks ( for a maximum of 6 cycles)

Literature:

FRASCI et  al, J. Clin. 18 (2000): 2529-2536 (randomized comparison of gemcitabine + vinorelbine vs vinorelbine alone in elderly patients with advanced NSCLC)

31.3.2.2.GIN

Gemcitabine                  1000mg/m2            i.v. (2 h inf)                         d 1 and

                                       800 mg/m2             i.v. (2 h inf)                        d 4 

Ifosfamide                      3000 mg/m2           i.v. (2 h inf)                        d 1

                                                                     With mesna uroprotection

Vinorelbine                    25 mg/m2               i.v. (slow bolus)                 d 1 and

                                       20 mg/m2               i.v. (slow bolus)                  d 4

            To be repeated every 3 week

            Literature:

                        BALDINI et al, Br. J. Cancer 85 (2001) : 1452 – 1455

 

31.4                Selective inhibition of the epidermal growth factor receptor tyrosine kinase Gefitinib ( Iressa)

Gefitinib                  250mg/d                            p.o.

Salvage treatment after ( platinum – based) chemotherapy.

 

Note: Gefitinib has the potential to cause severe acute interstitial pneumonia, especiallity in patients with previous thoracic irradiation and poor performance status.

174                                                                                                          Lung Cancer, non small cell (NSCLC)

 Literature:

            FUKUKOA et al, Proc. Am. Soc. Clin. Oncol. 22 (2002) : 298a (final results form 

            study IDEAL 1)

            INOUE et al, Lancet 361 (2003): 137 – 139 (severe acute interstitial pneumonia)

            KRIS et al, Proc. Am. Soc. Clin. Oncol. 22 (2002): 292a ( results from study  

            IDEAL 2)