CHEMOTHERAPY OF COLORECTAL CANCER

B K Smruti
Medical Oncologist and Haemato - Oncologist, Bombay Hospital and Post Graduate Institute of Medical Science, Marine Lines, Mumbai.

Surgery is the cornerstone of treatment of colorectal cancer since most patients present with resectable disease. Due to the presence of micrometastasis at presentation one third of the patients develop recurrent or metastatic disease despite adequate local therapy. Chemotherapy given after curative surgery to erradicate these micrometastasis is termed as adjuvant treatment. Therapy is also given for metastasis.

ADJUVANT THERAPY

"Who Should Receive It?"

The benefit of adjuvant therapy is more pronounced in those who are at a high risk of relapse. The need for this therapy is determined by

Pathologic stage of resected specimen[1] : The decision about adjuvant therapy is made after surgery on the basis of histopathology report and surgical findings. Stage A and B1 (Stage I) is cured by surgery and do not require chemotherapy. However Stage II (B2 - 3 : invasion through bowel wall) and Stage III (Stage C i.e. lymph node metastasis), the survival drops with surgery alone to 70% and 25-60% respectively. Chemotherapy is recommended for Dukes B2[2] and C and for tumours causing obstruction perforation or invading adjacent organ which have a high incidence of metastasis.

Location of tumour : Colonic tumours which lie about the peritoneal reflection predominantly have liver metastasis rather than local recurrences and hence require adjuvant chemotherapy. Rectal cancer which lies below the peritoneal reflection has a propensity for loco-regional failure requiring local radiotherapy and chemotherapy.

Other biologic factors : The importance of ploidy thymidylate synthase express on clinical decision making is uncertain.

Adjuvant Chemotherapy of Colonic Cancer

This is restricted to 5-Flurouracil. Till recently due to paucity of other active agents, the focus has been on augmenting the efficacy of 5-Flurouracil (5-Fu) with levamisole and leucovorin (folinic acid) which potentiate its activity.[3] The regimes recommended for Dukes B2 and C are as shown in Table 1. All the regimes are equally effective, the shorter duration 5-Fu and LV is the preferred regime.

TABLE 1

Adjuvant therapy of colon cancer

Schedule Duration

Leucovorin 20 mg/m2 IV Days 1-5, repeat at 4 weeks, 5-Fur425 mg/m2 IV 8 weeks and every 5 weeks for total 6 courses (6 months)
Leucovorin 500 mg/m2 2 hr. inf. Weekly x 6 2 weeks rest. 5-Fu500 mg/m2 IV push 1 hr after Leucovorin inf. Started 1 course - 4 courses
3.5-Fu 450 mg/m2 Day 1-5, 1 month rest then weekly 1 yr. Levamisole 50 mg TID x 3 days every 14 days x 1 year

Novel therapies with the new drugs which are presently used in metastatic disease (oral flurouracil formulations, irinotecan and oxaliplatin) in combination with 5-Fu are being investigated.

Toxicities

The main toxicities encountered are mucositis and diarrhoea. The diarrhoea is controlled with loperamide or diphenoxylate. In severe diarrhoea octreoide 50-100 Mg tid is used with intensive hydration. Myelosuppression is minimal seen more with the bolus regimes.

Adjuvant Chemotherapy of Rectal Cancer

Locoregional failure in 25 to 60% of patients undergoing curative resection is the dilemma in rectal cancer. Studies have shown that 5-Fu used as radiosensitiser with radiotherapy is better than radiotherapy alone.[4] The regimes as shown in Table 2 administer 5-Flurouracil (bolus or infusion) with leucovorin at the start and conclusion of radiotherapy followed by 4 courses of 5-Flurouracil and leucovorin.

The same treatment can be given pre-operatively for locally advanced T3 tumours or resectable tumours not invading the sphinctre to enhance sphinctre preservation.

Chemotherapy of Metastatic Colorectal Cancer

The last ten years have witnessed the development of novel chemotherapeutic agents with significantly consistent antitumour activity in colorectal cancer (Table 2) with three of them being approved for metastatic disease. Their use as adjuvant therapy is being investigated.

Topoisomerase inhibitors (Irinotecan) : These produce DNA strand breaks by inhibiting the topoisomerase enzyme. Irinotecan is the most extensively evaluated. It is used in 5-Fu resistant colorectal cancer. It is being combined with other drugs such as oxaliplatin and 5-Fu. Dose 350 mg/m2 once in 3 weeks (90 minutes infusion).

Oxaliplatin : This platinum analogue is synergistic with 5-Fu even in tumours resistant to 5-Fu. It is combined with 5-Fu and leucovorin (LV) in FOLFOX regimes 1-7 with varying doses of the three drugs.[5] Doses : Oxaliplatin 85-100 mg/m2 with LV and 5-Fu.

Oral Formulations of 5-Fu which give prolonged exposure to 5-Fu (Capecitabine, Tegafur) without need for venous access are under investigations.

Thymidylate synthase (TS) inhibitors. These drugs inhibit the thymidylate synthase enzyme which is needed for DNA synthesis. Tomudex which belongs to this group is approved for treatment of colorectal cancer.

Hepatic arterial infusion : Hepatic metastasis with no extrahepatic disease can be treated with hepatic arterial infusion FUDR (Fluro-deoxyuridine) with a response rate of 50%. This is injected via a port with a catheter in the hepatic artery.

TABLE 2

Adjuvant therapy of rectal cancer

Schedule Duration

Radiotherapy + 5-Fu425 mg/m2 Concurrent with RT (1st 4 and last 4 day) LV 20 mg/m2 + 4 more courses post RT

CONCLUSION

The standard care in colorectal cancer for a long time has been restricted to 5-Fu and its modulators. More recently several novel chemotherapeutic agents have been identified with non-cross resistant antitumour activity which could expand the armamentarium of agents useful.

REFERENCES

Cohen AM, Shank B, Freidman MA. Colorectal cancer. In Devita VT Jr, Hellman S, Rosen Berg SA (eds) : Cancer Principles and practice, ed. 3, Philadelphia, JB Lippincott. 1989; 929-77.
Mamounas EP, Rochette H, Jones J, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dubes'B V/S Dubes C colon cancer - Results from 4 NSABP adjuvant studies (CO1, CO2, CO3, CO4). Proc Ann Soc Clin Oncl 1996; 15 : 205.
AbelAlla EE, Blair GE, Jones RA, et al. Mechanism of synergy of levamisole and flurouracil : Induction of human leucoyte antigen class I in a colorectal cancer cell line. J Natl Cancer Institute 1995; 87 : 489-96.
Gastrointestinal tumour study group. Survival after post-operative combination treatment of rectal carcinoma. N Engl J Med 1986; 315 : 1294.
Andre T, Bensmaine A, Louver C, et al. Addition of oxalipatin (Eloxatin) to the same leucovorin (LV) and 5-Flurouracil (5-FU) bimonthly regimens after progression in patients (Pts) with metastatic colorectal cancer (MCRC). Preliminary report. Proc Am Soc Clin Oncology 1997 (abstr.); 16 : 270-9.