21. Colorectal Carcinoma

21.1        General considerations

The primary treatment for patients with localized disease is surgical resection.

Adjuvant chemotherapy (colon) or chemo-and/or radiotherapy (rectum) is of some benefit to patients with node- positive (stage III resp. C) disease and arguably to high-risk node-negative (stage II resp. B2) disease (high-risk is defined in Dukes’B2 colon cancer by the existence of at least one of the following characteristics:tumor perforation, tumor adherence, invasion of adjacent organs, non-diploidy, venous, lymphatic or perineural invasion).

Palliative chemotherapy is effective in prolonging time to disease progression and survival in patients with metastatic/recurrent disease. Radiotherapy can also be given for symptom control in case of pelvic recurrences (which are more frequent in rectal than in colon cancer).

            Literature: for review e.g.

                        BUYSE et al, Lancet 356 (2000): 373-378 (meta-analysis of the relation between tumor

                        response to first-line chemotherapy and survival in advanced colorectal cancer).

                        CASSIDY, Semin. Oncol. 27 (Suppl 10) (2000): 83-87 (thymidylate synthanse inhibitors in

                        colorectal cancer.

COLORECTAL CANCER COLLABORATIVE GROUP, Br. Med. J. 321 (2000): 531-535 (review and meta- analysis of palliative chemotherapy for advanced colorectal cancer in comparison with supportive care)

                        CUNNINGHAM and JAMES, Eur. J. Cancer 37 (2001): 826-834 (oral fluoropy-rimidines)

JONKER et al, Br. J. Cancer 82 (2000): 1789-1794 (meta-analysis of survival benefit of chemotherapy in metastatic colorectal cancer)

                        MAC DONALD et al, Semin. Oncol. 28 (2001): 30 – 40 (adjuvant therapy of colon cancer)

SARGENT et al, N. Engl. J. Med. 345 (2001): 1091 – 1097 (pooled analysis of adjuvant chemotherapy in elderly patients)

                        Van CUTSEM et al, Eur. J. Cancer 37 (2001): 2302 – 2309

WOLMARK et al, Semin. Oncol. 28 (Suppl 1 ) (2001): 9 – 13 (overview of the National Surgical Adjuvant Breast and Bowel Project trials in colon cancer)

21.2        5-Fluorouracil (5-FU) + folinic acid

Folinic acid modulated 5 – FU is established in the adjuvant treatment of colon cancer and was shown to significantly improve response rates over 5 – FU alone in patients with advanced disease.

Literature: for review e.g.

            ADVANCED COLORECTAL CANCER META-ANALYSIS PROJECT, J. Clin. Oncol.

10 (1992): 896-903 (meta-analysis of trials of 5 – FU ± folinic acid) and J. Clin. Oncol. 16 (1998) : 301 – 308 (meta- analysis of trials comparing continuous infusion and bolus administration of 5 – FU)

INTERNATIONAL MULTICENTRE POOLED ANALYSIS OF COLON CANCER TRIALS (IMPACT) INVESTIGATORS, Lancet 345 (1995): 936 – 944 (pooled analysis of efficacy of adjuvant 5 – FU + folinic acid) and J. Clin. Oncol. 17 (1999): 1356 – 1363 (pooled analysis of adjuvant 5 – FU + folinic acid in Dukes’ B2 colon cancer)

SCHMOLL et al, Semin. Oncol. 26 (1999): 589 – 605

Various regimens have been developed and only a few representative examples are presented for 5 – FU bolus administration with low-dose (<25 mg/m²) and high- dose folinic acid as well as protracted infusion of 5 – FU with high-dose folinic acid.

21.2.1 “ Mayo Clinic” – regimen

To be repeated every 4 (cycles 1 – 3) – 5 (cycles 4 – 6 ) weeks

Literature:

            BUROKER et al. J. Clin. Oncol. 12 (1994): 14 – 20

O’CONNELL et al, J. Clin. Oncol. 15 (1997): 246 – 250 (controlled trial of adjuvant therapy for colon cancer)

POON et al, J. Clin. Oncol. 7 (1989): 1407 – 1418

TOMIAK et al, Am. J. Clin. Oncol, 23 (2000): 94 – 98 (retrospective analysis of toxicity in 134 patients)

21.2.2  “QUASAR” regimen            

            *Given as L- folinic acid which is pharmacologically equivalent to double the dose of D,L- folinic

            acid. Patients were also randomized between additional levamisole (50 mg t.i.d. for 3 days, repeated     at 2- weekly intervals for 12 courses) or placebo.

            The once weekly regimen was found to be much less toxic and about as effective as the four-weekly      schedule, Neither high-dose folinic acid nor additional  levamisole resulted in an extra benefit over             low-dose folinic acid alone.

            Literature:

                        KERR et al, Ann. Oncol. 11 (2000): 947 – 955

                        QUASAR COLLABORATIVE GROUP , Lancet 355 (2000): 1588 – 1596

21.2.3.                       “NSABP”- regimen

            To be repeated weekly for 6 doses. This cycle was repeated after a 2- week rest period (x 6).

            Literature:

WOLMARK et al, J. Clin. Oncol. 17 (1999): 3553 – 3559 (randomized 3- arm study C – 04 of the National Surgical Adjuvant Breast and Bowel project which compared the efficacy of 5 – FU + folinic acid, 5 – FU + levamisole and 5 – FU + folinic acid + levamisole as adjuvant therapy for Dukes’ B and C colon carcinoma)

21.2.4 “ de Gramont” – regimen

To be repeated every 2 weeks

Literature:

ANDRE et al, Semin. Oncol. 28 (Suppl 1) (2001): 35 – 40 (randomized adjuvant study comparing  the bimonthly de Gramont-regimen with a monthly regimen of 5 – FU + folinic acid)

De GRAMONT et al J. Clin. Oncol. 15 (1997): 808 – 815 (randomized French intergroup study comparing monthly low-dose folinic acid and 5 – FU bolus with bimonthly high-dose folinic acid and 5 – FU bolus + continuous infusion)

21.2.5 “ Ardalan” – regimen

To be repeated starting d 57

Literature:

            ARDALAN et al, J. Clin. Oncol. 9 (1991): 625 – 630

21.3        5 – FU + radiotherapy

The addition of radiotherapy to postoperative adjuvant chemotherapy in Dukes’ B and C rectal cancer may reduce the risk of locoregional relapse; e.g.

To be repeated weekly for 6 weeks. This cycle was repeated after a 2 – week rest period (x 6)

Radiation therapy was initiated between three and five weeks following completion of cycle one of chemotherapy. Total administered dose to the intersection of the radiation fields was 4,500 cGy in 25 fractions of 180 cGy per day (five days per week)> The boost volume was treated to a dose of 540 cGy in three fractions of 180 cGy per day)

Bolus infusions of 5 – FU (400 mg/m²) were given during each of the first three and last three days of radiation therapy.

            Literature:

WOLMARK et al, J. Natl, Cancer Inst. 92 (2000): 388 – 396 (NSABP protocol R-02 comparing postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum)

            Or

• with RT 4500 cGy (followed by boost 540 cGy to the tumor bed) over 6 weeks

Literature :

                  O’CONNELL et al, N. Engl. J. Med. 331 (1994) : 502 – 507

21.4        Irinotecan (CPT 11)

Literature : for review e.g.

            ROUGIER and MITRY, Semin. Oncol. 27 (Suppl 10 ) (2000): 138 – 143

            VANHOEFER et al, J. Clin. Oncol. 19 (2001): 1501 – 1518

21.4.1   Monotherapy

As second- line therapy after failure of 5 – FU- based therapy and as first – line therapy,

To be repeated every 6 weeks

Literature:

            CONTI et al, J. Clin. Oncol. 14 (1996): 709 – 715

            PITOT et al, J. Clin. Oncol.  15 (1997): 2910 – 2919

Or

To be repeated every 3 weeks

• In patients > 70 years old, or WHO performance status of 2

Literature :

CUNNINGHAM et al, Lancet 325 (1998): 1413 – 1418 (randomized trial or irinotecan + supportive care vs supportive care alone after 5 – FU failure)

IVESON et al, Eur. J. Cancer 35 (1999): 1796 – 1804 (cost – effectiveness analysis of irinotecan in second-line treatment compared with infusional 5 – FU based on the study reported by Van Cutsem et al, 1999)

ROUGIER et al, J. Clin. Oncol. 15 (1997): 251- 260 (phase II study incl. chemotherapy-naïve patients) and Lancet 325 (1998): 1407 – 1412 (randomized trial of irinotecan vs infusional 5 – FU after 5 – FU failure)

Van CUTSEM and BLIJHAM on behalf of the V302 Study Group , Semin. Oncol. 26 (Suppl 5) (1999): 13- 20 (randomized trial of irinotecan vs infusional 5 – FU in metastatic colorectal cancer following failure on first-line 5 – FU)

Van CUTSEM et al, Eur. J.Cancer 35 (1999): 54 – 59 (multicenter phase II study of irinotecan in colorectal cancer truly resistant to 5 – FU)

Colorectal Carcinoma                                                                                         131

21.4.2                         Combination  therapy

21.4.2.1                  Irinotecan + 5-FU/folinic acid

To be repeated every 6 weeks

Literature:

SALTZ et al, N. Engl. J.Med.343 (2000):905-914(randomized phase lll  trial in which the combination was compared with the Mayo Clinic bolus 5-FU/folinic acid regimen  and with irinotecan monotherapy as a  Firs-line therapy for metastatic colorectal cancer)

            Or

Treatment was given until disease  progressed or until unacceptable toxicity developed or consent was withdrawn.

Literature:

DOUILLARD et al, Lancet 355 (2000):1041-1047 (phase lll multicenter randomized trial to assess the addition of  irinotecan  to 5-FU/ folinic acid for metastatic colorectal cancer)

21.4.2.2                  Irinotecan + oxaliplatin

          As  second-line therapy for 5-FU pretreated patients.

To be repeated every 3 weeks

Literature:

BECOUARN et al, J. Clin. Oncol. 19(2001):4195-4201

Or

To be repeated every 4 weeks. With G-CSF support!

Literature:

SCHEITHAUER  et al, J . Clin. Oncol.17(1999): 902-906

132                                                                                                                                Colorectal Carcinoma

21.5                 Oxaliplatin

 Literature: for review e.g.

                         ARMAND et al, Semin. Oncol.27(Suppl 10)(2000):96-104

CVITKOVIC  and BEKRADDA, Semin.Oncol.26(1999): 647-662

21.5.1                         Monotherapy

           As second –line therapy after failure  of 5-FU-based therapy and as              

           first-line therapy.

To be repeated every 3 weeks

Literature:

  BECOUARN et al,J.Clin.Oncol.16(1998):2739-2744

   DIAZ-RUBIO et al, Ann.Oncol.9 (1998): 105-108

21.5.2                         Combination therapy

21.5.2.1                  Oxaliplatin + 5FU/ folinic acid

FOLFOX  4

To be repeated every 2 weeks

Literature:

  De GRAMONT  et al, J.Clin.Oncol. 18(2000): 2938-2947(phase lll study of 5-FU/folinic acid with or without oxaliplatin as first-line treatment in advanced  colorectal cancer).

Or

FOLFOX 6

To be repeated every 2 weeks

Literature:

MAINDRAULT- GOEBEL et al, Ann. Oncol.11 (2000): 1477-1483 (comparison  of  FOLFOX 2,3, and  6 regimens)

Or

Chronomodulated regiment

To be repeated every 3 weeks

·        Administered using a multichannel, programmable pump; peak delivery rate  0.4:00h.

Colorectal Carcinoma                                                                                         133

Literature:

   GIACCHETTI  et al,J. Clin.Oncol. 18(2000):136-147(phase lll study of oxaliplatin added to chronomodulated – 5 FU/folinic  acid as first-line treatment of metastatic colorectal cancer)

21.5.2.2           Oxaliplatin + irinotecan

                         See 21.4.2.2.

21.6                  Raltitrexed

To be repeated every 3 weeks

Literature:

COCCONI  et al, J. Clin.Oncol.16(1998):2943-2952(randomized multicenter trial of raltitexed  vs 5-FU/high- dose folinic acid)

CUNNINGHAM  et al, Ann.Oncol.7 (1996):961-965(randomized trial  comparing raltitrexed with 5-FU/folinic acid  in advanced colorectal cancer) and Eur.J.Cancer 38(2002):478-486(review of phase ll and lll trials)

21.7                 Capecitabine   

Literature: for review

    SEITZ, Semin.Oncol,28(Suppl  1)(2001): 41-44

To be repeated every3 weeks

 *For  practical reasons, capecitabine doses are rounded to the nearest dose that could be administered with a combination of 500 mg and 150 mg tablets. Given at approx.12-h intervals.

Literature:

HOFF et al , J. Clin. Oncol.19 (2001) : 2282-2292 (phase lll study                 comparing  capecitabine with 5-FU/folinic acid as first-line treatment  in metastatic colorectal cancer)

TWELVES  et al,Eur .J. Cancer 37(2001):597-604(medical resource use compared with 5-FU/folinic  acid in a phase lll study [van Cutsem et al])

Van CUTSEM et al,J.Clin.Oncol. 19(2001): 4097-4106 (phase lll study comparing capecitabine with 5-FU/folinic acid)

21.8                                    UFT      

(Combination of tegafur  with uracil at a molar ratio of  1:4,100 mg  tegafur + 224mg uracil)

UFT + Folinic acid

For first-line chemotherapy of metastatic colorectal cancer  .

Literature: for review

    MINSKY,Int.J.Cancer(Radiat. Oncol.Invest.)96(2001):1-10

To be repeated every 5 weeks

*  The  UFT  dose refers to the tegafur component(max 600mg/d).

**Preferably 8-hourly, one hour before or after meals. UFT and folinic acid should be taken at the same time.

Literature:

134                                                                                                                                    Colorectal Carcinoma

                       CARMICHAEL et.al,J.Clin.Oncol.20(2002):3617-       

                       3627(randomized comparison of UFT/folinic  acid vs 5-  

                       FU/folinic acid for metastatic colorectal cancer)

            DOUILLARD et al,J.Clin.Oncol.20(2002): 3605-3616  

            (multicenter phase III study of UFT/folinic acid vs. 5-FU/folinic 

            acid for metastatic colorectal cancer)

            PAZDUR et al, Proc.Am. Soc. Clin.Oncol. 18(1999):263 (abstract   

            1009)(multicenter phase lll study of UFT or 5-FU both plus  folinic     

            acid for  metastatic colorectal  cancer)

21.9                                  Monoclonal antibody  17-1A(Edrecolomab)

Literature: for review

      HALLER, Semin.Oncol. 28(Suppl)(2001):25-30

Edrecolomab is used for adjuvant therapy following resection of stage lll (and ll)

colorectal cancer (still experimental).

Literature:

RIETHMULLER  et al,Lancet  343(1994):1177-1183(randomized trial of  edrecolomab vs  observation for resected Dukes’s C colorectal cancer) and J. Clin.Oncol.16(1998):1788-1794 (seven year outcome of the randomized trial).

21.10                                Non-resectable liver metastases

Metastases confined to the liver can be treated with 5-FU/follinic acid given either by  intravenous or by hepatic arterial infusion(HAI) or with  5-fluoro-2deoxyuridine (FUDR) given by HAI.Although HAI produced high response rates in a number of  randomized studies it can not be recommended  for routine therapeutic use as this time, because of the complexicity of the  technical procedure.

Literature:

            KEMENY, Semin.Oncol.27 (Suppl 10) (2000): 126-131(review)

            LORENZ and MULLER,J.Clin.Oncol.18(2000):243-254  

            (randomized multicenter trial of the German Cooperative Group on  

            Liver Metastases comparing 5-FU/folinic acid i.v. and HAI and 

            FUDR via HAI)

            META-ANALYSIS GROUP IN CANCER ,J.Natl.Cancer inst.               

            88 (1996): 252-258 (role of HAI ) and J.Clin.Oncol.16(1998):301- 

            308 (bolus vs continuous infusion of 5-FU) THIRION et 

            al,Ann.Oncol.10(1999):1317-1320(re-analysis of 22 trials and four 

            meta-analyses re.survival impact of chemotherapy  in patients    

            with  colorectal metastases confined fo the  liver).