Evidence Of A Survival Benefit For Adjuvant Chemotherapy In Colorectal Cancer

The efficacy of adjuvant therapy for carcinoma of the colon is now well established. Drugs known to be effective in treating metastatic disease (see Chapter 17) have been used in the adjuvant setting to seek improved survival.

The first large, prospective randomized trial to demonstrate a survival benefit was the National Adjuvant Breast and Bowel Project (NSABP) study protocol C-01 (3). This compared the combination of 5-fluorouracil (5-FU), semustine, and vincristine all given postoperatively for eight, 10-weekly cycles; Bacillus Calmette Guerin (BCG) treatment; and surgery alone; in patients in Dukes' B and C categories. This revealed a small improvement in overall survival (OS) with the 5-FU combination; 1166 patients entered this trial between 1977 and 1983—379 were in the arm receiving CT, 394 were in the observation arm, and 393 patients received BCG therapy. There was an overall improvement of disease free survival (DFS) (p = 0.02) and survival (67% vs. 59%; p=0.05) in favor of the CT-treated group. At five years of follow up, patients treated with surgery alone were at 1.29 times the risk of developing treatment failure and 1.31 times the likelihood of dying as were those patients treated with combination adjuvant CT.

A subsequent Intergroup study 0035 established the efficacy of adjuvant 5-FU-based CT. This trial therefore assessed 1296 patients with resected Dukes' B or C colon cancer, randomizing them to no further treatment or to treatment with 5-FU plus levamisole (an antihelminthic drug with poorly described "immunomodulating" properties) for 12 months. The regime used was fluorouracil, 450 mg/m2/day x 5 then weekly, and levamisole 50 mg tid po, days 1-3 every week for one year. Some of those patients with Dukes' C cancer were also randomized to a further arm of treatment with levamisole alone for 12 months. Nine hundred and twenty-nine eligible patients were followed for five years or more. The initial report was published in 1990 (4) and the results for Dukes' C (stage III) patients were later confirmed in a 1995 publication (5). These showed that treatment with surgery and the combination of 5-FU and levamisole to those

FIGURE 1 Recurrence-free interval according to treatment arm. Patients who died without recurrence have been censored. Abbreviation: 5-FU, fluorouracil. Source: From Ref. 5.

patients with stage III disease decreased the risk of cancer recurrence by 41% (p < 0.0001) after a median follow up of three years, and the overall death rate was decreased by 33% (p=0.006). The five-year DFS with fluorouracil and levamisole was 61% and OS was 60% compared with 44% DFS and 47% OS with observation only (Figs. 1, 2). In retrospect, a trial arm with fluoro-uracil alone will have been helpful for interpretation of the data.

Patients with Dukes' B (stage II) disease showed a trend toward reduction in the rate of disease recurrence in the 5-FU plus levamisole arm compared to the surgery-alone arm, but there was no difference in OS at a median follow up of seven years. Levamisole therapy alone had no impact on DFS or OS. The overall results of The Intergroup 0035 study (INT0035) therefore established the role of postoperative CT for stage III patients, and following National Institute of Health's (NIH) consensus statement in 1990, this became the standard of care for such patients in America.

A number of studies at about this time demonstrated the combination of 5-FU and folinic acid (FA) to be superior to fluorouracil alone in treating patients with advanced colorectal carcinoma (6), and this combination was subsequently taken into the adjuvant arena. The NSABP protocol C-03 (7) demonstrated that a 5-FU/FA combination (a treatment schedule of eight cycles of a high-dose leucovorin (LV), weekly regime given for six of eight weeks) was superior to methyl-CCNU, vincristine, and 5-FU (MOF, five, 10-weekly cycles) in Dukes' B and C colon cancer patients, providing three-year DFS and OS advantages of 73% versus 64% (P=0.0004) and 84% versus 77% (P=0.003), respectively. (Adjuvant MOF therapy had previously been shown to have a slight advantage over surgery alone.)

Large studies comparing CT to a control group who received no postsurgery treatment were also performed by the North Central Cancer Treatment Group (NCCTG) (8) and

Liver Abdominal Lungs Local Retro- Other regional peritoneal metastatic nodes sites

Site of initial recurrence

Liver Abdominal Lungs Local Retro- Other regional peritoneal metastatic nodes sites

Site of initial recurrence

FIGURE 2 Survival according to treatment arm. Abbreviation: 5-FU, fluorouracil. Source: From Ref. 5.

the International Multicenter Pooled Analysis of Colorectal Cancer Trials (IMPACT) Collaborative Group (9).

The IMPACT study was a pooled analysis of three randomized trials [GIVIO, National Cancer Institute of Canada-Cancer Treatment Group (NCIC-CTG), and FFCD] comparing postoperative treatment with high-dose 5-FU and FA (370- to 400-mg/m2 5-FU and FA 200 mg/m2 daily for five days, every 28 days for six cycles) with surgery alone. One thousand five hundred and twenty-six patients with Dukes' B (56%) and C (44%) disease were entered with 1493 eligible for analysis. Chemotherapy was seen to reduce mortality and recurrences, increasing the three-year, event-free survival from 62% to 71% (P=0.0001) and OS from 78% to 83% (P=0.018).

The NCCTG study was performed to compare the classical Mayo regimen of 5-FU (425 mg/m2) and LV (20 mg/m2) to observation alone after surgery in patients with Dukes' B and C disease. Due to the emergence of the results of the INT0035 study, this trial was stopped prematurely. Only 309 patients were enrolled—290 of these patients had Dukes' C disease, and their five-year survival was increased from 63% to 74%. These studies therefore gave evidence that adjuvant therapy following primary surgical treatment offers benefits compared to observation alone.

It will seem on theoretical grounds that the earlier the treatment is commenced after surgery, the more likely it is to be successful. However, there is no evidence to support this, and although oncologists recommend it, there may be a window of up to three months after surgery to introduce adjuvant therapy. In practice, it is usual to aim to commence treatment within four to six weeks of surgery. Appropriate candidates are identified by close cooperation between surgeons, oncologists, and other members of the multidisciplinary team.

Was this article helpful?

0 0

Post a comment