Renal Cell Carcinoma 217

43. Renal Cell Carcinoma

43.1 Geneal considerations

Stage grouping

Stage T N M

I T1 N0 M0

II T2 N0 M0

III T1, 2 N1 M0

T 3 N0, 1 M0

IV T4 N0, 1 M0

any T N2 M0

any T any N M1

Radical nephrectomy (often with regional lymphadenectomy) is the standard of treatment of localized renal cell carcinoma. No clearly effective adjuvant therapy (neither chemotherapy, immunotherapy nor radiotherapy) has yet been identified.

Nephrectomy may also be indicated for metastatic disease for palliation of symptoms caused by the primary tumor and in combination with metastasectomy in patients with resectable metastases. Standard anticancer treatment such as radiotherapy, chemotherapy or hormonal therapy have very limited activity in metastatic renal cell carcinoma . Some progress came from immunologic therapies mainly with interferon alpha and interleukin-2 which demonstrate low but reproducible response rates in the 10 –20 % range and ( in case of interferon) a moderate survival advantage. Nephrectomy followed by interferon therapy resulted in longer survival than did interferon therapy alone in at least two randomized studies. Recently a number of investigational therapies including vaccination with dendritic cells/ tumor fusions and nonmyeloablative allogeneic stem cell transptantation (“ minitransplantation”) have also gained interest.

Literature: for review e.g.

AMATO, Semin. Oncol. 27 (2000): 177 – 186 (chemotherapy)

BERG et al, Semin. Oncol. 27 (2000): 234 – 239 (novel investigative approaches: retinoids, monoclonal antibodies , antiangiogenesis, and others)

BUKOWSKI, Semin. Urol. Oncol. 19 (2001): 148 – 154 (cytokine therapy) and Semin. Oncol. 27 (2000): 204 – 212 (cytokine combinatios)

CHILDS and DRACHENBERG, Curr. Opin. Urol. 11 (2001): 495- 502 (allogeneic stem cell transplantation )

FISHMAN et al, Expert Opin. Investig. Drugs 10 (2001): 1033- 1044

(novel therapies)

FLANIGAN and YONOVER, Curr. Oncol. Rep. 3 (2001): 424 – 432 (role

of resection)

GITLITZ et al, Semin. Urol. Oncol. 19 (2001): 141 – 147 (vaccine and

gene therapy )

GODLEY and TAYLOR, Curr. Opin. Oncol. 13 (2001): 199 – 203

HARTMANIN and BOKEMEYER, Anticancer Res. 19 (1999): 1541 –

1543 (chemotherapy)

HEINZER et al, World J. Urol. 19 (2001): 111- 119 (chemotherapy and chemoimmunotherapy)

MICKISCH, Onkologie 24 (2001): 122 – 126

MILLER, Urol. Int. 63 (1999): 6 – 9

MOTZER and RUSSO, J. Urol. 163 (2000): 408 – 417

NOVICK, Can. J. Urol. 7 (2000): 960 – 966 (management of localized

disease )

218 Renal Cell Carcinoma

43.2 Immunological therapy

43.2.1 Interferon alpha (IFN α)

Interferon alpha 5 –10 mio IU /m² s.c. or i.m. daily or 3 x weekly

Until tumor progression ( max 1 year in responders)

Literatrue: e.g.

FLANIGAN et al, N. Engl. J. Med. 345 (2001): 1655 – 1659 (randomized

study SWOG- 8949 comparing nephrectomy followed by interferon with

interferon alone)

FOSSA, Semin. Oncol. 27 (2000): 187 – 193 (review)

PASTORE et al, Cancer Invest. 19(2001): 281-291 (review)

RITCHIE et al, Lancet 353 (1999): 14 – 17 (randomized study of the

Medical Research Council Renal Cancer Collaborators demonstrating a

survival advantage of interferon over medroxyprogesterone acetate)

43.2.2 Interleukin – 2 ( IL – 2)

Interleukin-2 600000 i.v. (15 min inf) d 1– 5 (+ 11 – 15)

720000 IU/kg 3 x daily (ev. 8 h)

One or two cycles, or

Interleukin-2 9 –18 mio IU /d i.v. (cont inf) or s.c. for 5 d

To be repeated every 3 weeks. Patients who fail to respond after two treatment

courses have no benefit to further IL-2 therapy. Patients who exhibit objective

responses receive additional treatment courses until either CR or IL-2 intolerance

develops.

Literature: e.g.

LINDSEY et al, J. Clin. Oncol. 18 (2000): 1954 – 1959 (impact of the number of treatment courses on the clinical response )

MALAGUARNERA et al, Eur. J. Clin. Pharmacol. 57 (2001): 267 – 273 (meta analysis and review )

MARGOLIN, Semin. Oncol. 27 (2000); 194 – 203 (review)

SCHWARZENTRUBER, J. Immunother. 24 (2001): 287- 293 ( guidelines for administration)

43.2.3 Second- line treatment after failure of the other cytokine

Cross – over after failure of IL-2 or IFN α is poorly efficient.

Literature:

ESCUDIER et al, J. Clin. Oncol. 17 (1999): 2039 – 2043

43.2.4 Combination of interferon alpha and interleukin-2

Results of a phase III study demonstrate improved response rate and 1- year event-free survival for patients treated with combined IL-2 + INF α compared with either cytokine alone.

Literature: e.g.

BUKOWSKI, Semin. Oncol. 27 (2000): 204 – 212 (review)

NEGRIER et al, N. Engl. J. Med. 338 (1996): 1272 – 1279 ( IL-2 + IFN α

vs IL-2 vs IFN α)

43.3 Chemotherapy

Renal cell carcinoma is relatively chemoresistant. If at all, treatment may be attempted with vinblastin, 5 – fluorouracil (continuous infusion), or floxuridine (FUDR) (continuous infusion or circadian administration).

Literature: e.g.

AMATO, Semin. Oncol. 27 (2000): 177 – 186 (review)

&#HARTMANN and BOKEMEYER, Anticancer Res. 19 (1999): 1541-1543

(review)

Renal Cell Carcinoma 219

43.4 Combined use of cytokines and cytostatics

E.g.

Interferon alpha 3 mio IU s.c. or i.m. 3 x weekly (week 1) and

(9-) 18 mio IU s.c. for subsequent wks

Vinblastine 0.1 mg/kg i.v. (bolus) every 3 wks

Duration of treatment either 12 months, until development of PD, or for 3 months after first observation of a CR.

Literature:

PYRHÖNEN et al, J. Clin. Oncol. 17 ( 1999): 2859 – 2867 (randomized trial of vinblastine +/ - IFN α )