Elsevier

Cancer Treatment Reviews

Volume 28, Issue 5, October 2002, Pages 223-236
Cancer Treatment Reviews

ANTI–TUMOUR TREATMENT
Adjuvant therapy in colon cancer: current status and future directions

https://doi.org/10.1016/S0305-7372(02)00047-6Get rights and content

Abstract

The role of adjuvant chemotherapy in patients with stage III colon cancer is now well established and 5-FU/LV should be the reference regimen to which new drugs are tested against in the adjuvant setting. In stage II colon cancer, because the risk of recurrence is lower, any absolute benefit of chemotherapy is likely to be less than in stage III disease. The studies performed so far have been generally underpowered to detect what might be a clinically significant effect on survival. Molecular profiling of tumours may identify individuals more likely to benefit from adjuvant therapy and tailor individual treatment in the future. After potential curative treatment for localised colon cancer, about two out of five patients will experience disease recurrence, but the most effective strategies for follow-up remain to be established. New drugs such as irinotecan, oxaliplatin and oral fluoropyrimidines may offer improved efficacy or patients’ convenience in the adjuvant setting and their impact on survival will be evaluated in the recently closed large randomised studies. This review summarises the current status of adjuvant therapy in colon cancer and describes the future directions for research.

Introduction

Every year about 1 million new cases of colorectal cancers (CRC) are diagnosed world-wide with 500,000 patients dying from the disease (1). About 75–80% of patients with colon cancer present with localised disease. However, despite curative surgery, nearly 40% of patients still experience disease relapse leading to significant morbidity and eventually mortality. Much interest has been generated in the last few decades in adjuvant treatment that would eliminate microscopic disease, thus preventing recurrent disease. Whereas radiotherapy is often considered as part of the adjuvant treatment in rectal cancer, it has not been shown to improve outcome in colon cancer (2).

Approximately 35% of patients with resectable colon cancer have stage III disease (3). The role of adjuvant chemotherapy in this group of patients has been supported by a series of large randomised studies performed by National Surgical Adjuvant Breast and Bowel Project (NSABP) and National Cancer Institute sponsored co-operative groups (Table 1) [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Encouraged by the initial results from the NCCTG (North Central Cancer Treatment Group), 5-FU/levamisole was shown to increase disease-free survival (DFS) and overall survival (OS) in the confirmatory United States (US) Intergroup-0035 study with mature results showing 40% reduction in recurrence and 33% reduction in mortality (6). This led to the recommendations from the National Institute of Health consensus conference for this drug combination to be given as adjuvant therapy in patients with stage III colon cancer (14). 5-FU/levamisole became the standard of care in the United States and formed the control arm in many studies conducted in the 1990s.

5-FU and leucovorin (LV) has been used in various doses and schedules in advanced colorectal cancer. This combination produced significantly superior response rate over 5-FU monotherapy although without any discernible survival difference (15). The efficacy of 5-FU/LV as adjuvant therapy has been confirmed in Intergroup-0085 (7), NSABP C-03 (11) and IMPACT-1 (4) studies. In addition, this combination has also been tested against 5-FU/levamisole as well as the addition of levamisole or interferon α-2a (IFN) to 5-FU/LV. Evidence emerging from these studies shows that: (a) 5-FU/low dose LV (20 mg/m2) is equivalent to 5-FU/high dose LV (200–500 mg/m2); (b) 5-FU/LV given for 6 months is as good as given for 12 months; (c) there is no significant difference between the two most commonly used bolus 5-FU/LV dose schedules – Mayo Clinic regimen (5-FU 425 mg/m2 and LV 20 mg/m2 days 1–5 every 4 weeks for six cycles) or Roswell Park regimen (5-FU 500 mg/m2 and LV 500 mg/m2 weekly × 6 every 8 weeks for three to four cycles); (d) 5-FU/levamisole given for 6 months is inferior to the same treatment given for 12 months and (e) interferon produced no additional survival benefit at the expense of excessive toxicities.

Although the use of adjuvant therapy was widely disseminated between 1989 and 1990 in the US (16), there remained some uncertainties in Europe. Several studies that were reported in the last two years were originally initiated in the 1990s and were mainly conducted in Europe – some of which were aimed to replicate the results achieved in the US (Table 1). In the Netherlands Adjuvant Colon Cancer Project (NACCP) study, 1029 patients were randomised to receive 12 months of adjuvant 5-FU/levamisole or observation (17). This study confirmed the survival benefit of adjuvant therapy with a 27% reduction in odds of death in stage III disease. Apart from overall survival, adjuvant chemotherapy also resulted in significantly better recurrence-free survival.

Another study in Germany randomised 702 patients with stage III disease to receive either 5-FU/levamisole or 5-FU/LV (100 mg/m2) (18). 5-FU/LV given for 12 months showed a better overall and disease free survival despite a higher incidence of gastrointestinal toxicity. In another three-arm German study, patients were compared between 5-FU/levamisole with the addition of either LV (200 mg/m2) or interferon (19). The addition of LV to 5-FU/levamisole resulted in a better 4-year survival whereas the addition of interferon did not influence survival but resulted in much greater grade 3 and 4 toxicities than either 5-FU/levamisole or 5-FU/levamisole/LV.

The QUASAR (Quick And Simple And Reliable) study was the largest adjuvant study conducted to date (20). 4927 patients were recruited with 95% of patients entered from the United Kingdom. In a two × two factorial design, patients were randomised to receive 5-FU with either high-dose (175 mg fixed dose) or low dose (25 mg fixed dose) LV and with either levamisole or placebo. No differences in survival or recurrence were observed between high or low dose LV. However more recurrences and borderline worse survival occurred in the levamisole arm compared to placebo. Therefore, results from QUASAR, Intergroup-0089 and the previously mentioned German study (19) suggested that although 5-FU/levamisole/LV may be superior to 5-FU/levamisole, it does not confer any benefits over 5-FU/LV. Toxicities between high and low dose LV were similar in the QUASAR trial although treatment with levamisole resulted in more dermatological toxicities than placebo. Treatment related mortality occurred in 0.1% of patients confirming these adjuvant chemotherapy regimens are safe in large-scale phase III studies.

To have a pragmatic approach and maximise recruitment in QUASAR, patients could receive their chemotherapy either on weekly or 4-weekly schedules in a non-randomised fashion. In a separate analysis, weekly chemotherapy resulted in no difference in recurrence rates and survival compared with 4-weekly chemotherapy although toxicities including diarrhoea, stomatitis, neutropenia and dermatological were much more pronounced in the 4-weekly schedule (21). Despite greater toxicities, the proportions of patients receiving the planned course of 5-FU treatment were similar in the 4-weekly schedule. However, there are caveats in concluding the weekly schedule is more desirable. Firstly, this is a non-randomised comparison between weekly and 4-weekly treatment although the baseline clinical characteristics appeared to be balanced. Secondly, only brief details of serious toxic effects were collected annually in all randomised patients and detailed treatment toxicities were available for only about 600 out of 4927 patients, therefore a difference in toxicity reporting pattern between the two treatment schedules could potentially exist.

Although adjuvant chemotherapy is now an established treatment option with stage III colon cancer, elderly patients are much less likely to receive chemotherapy. In a recent US study of 6262 patients aged 65 years or older with resected stage III colon cancer using population data linking Surveillance Epidemiology and End Results (SEER) with the Medicare database, age at diagnosis was the strongest determinant of whether adjuvant chemotherapy was offered to the patient (22). Although overall 55% of patient received adjuvant treatment, a steep decline in the proportion of patients receiving adjuvant chemotherapy with increasing age was evident decreasing from 78% of patients aged 65–69 years to 11% of those aged 85–89 patients. Apart from age, black ethnicity and lower socioeconomic status were also associated with less utilization of adjuvant chemotherapy. Two other recent population based US studies including 4706 and 4998 patients found broadly similar results [16], [23].

However, in a recent pooled analysis of 3351 patients enrolled in randomised trials, the elderly benefited the same as their younger counterparts (24), – an effect also seen in the general population receiving treatment outside clinical trials (25). Moreover, advancing age was not found to correlate with increasing incidences of grade 3–4 nausea or vomiting, stomatitis or diarrhoea in patients treated with fluorouracil based chemotherapy although more leucopenia occurred with increasing age (24). Therefore chronological age should not be used as the sole reason for withholding adjuvant chemotherapy. In another pooled analysis of 6632 patients taking part in NSABP C-01 to 05 trials in which 10% of patients were African–Americans, a 21% excess risk of overall mortality was seen in this ethnic group even though African–Americans and Caucasians had largely similar demographic and clinical characteristics (26). However, only a non-significant 8% excess risk of colon cancer recurrence was noted in African–American suggesting non-cancer related deaths may contribute to the shorter overall survival times among African–Americans. The benefit of adjuvant chemotherapy therefore extends to this ethnic group and should be actively offered to these patients. Further research is required to evaluate reasons for the apparent inequalities in the delivery of adjuvant chemotherapy in the elderly, ethnic minority and lower socio-economic groups.

Approximately 50% of patients with resectable colon cancer have stage II disease (3). However, adjuvant therapy in patients with stage II (Dukes’ B) colon cancer remains controversial with no international consensus. Two large analyses addressed this issue [27], [28]. The NSABP used results from C-01, C-02, C-03 and C-04 to compare the relative efficacy of adjuvant chemotherapy in patients with stage II and stage III colon cancer (28). When these four trials were examined independently, a similar benefit from treatment was seen in stage II and stage III, but the number of patients with stage II cancer was too limited to rule out a difference in treatment effect according to staging. In addition, the NSABP also examined the trials collectively by creating two comparison groups: the first group consisted of all patients with the superior treatment in each of the four trials and the second consisted of patients on the inferior treatment. Using this methodology, the results were pooled in 1565 stage II patients and a reduction in mortality and recurrence were seen with adjuvant chemotherapy. However, the treatment received in these four trials varied widely. In contrast, the IMPACT B2 study pooled results from five trials including 1006 patients with Dukes’ B2 colon cancer and the results did not support the use of 5-FU/LV as a standard adjuvant treatment for such patients (27). This study showed no differences in 5-year OS rate (80% in control group vs. 82% in 5-FU/LV group; Hazard Ratio[HR]: 0.86; 90% confidence interval [CI]: 0.68–1.07; p=0.130) and event free survival (73% in control group vs. 76% in 5-FU/LV group; HR: 0.88; 90% CI: 0.72–1.07; p=0.137). However, the statistical power was not great enough to detect reliably a true but small difference in survival between observation and adjuvant chemotherapy.

More recently, the Dutch NACCP study has reported a beneficial effect of adjuvant chemotherapy in stage II patients (17). In addition to the expected benefit in stage III, this study also showed a 19% reduction in death from 468 patients with stage II disease. Although the prognosis is significantly different for stage II and stage III, the size of reduction in odds of death by treatment was similar.

In another US study linking the SEER population data and Medicare database on 3725 patients with resected stage II colon cancer, 31% of the cohort received adjuvant chemotherapy and no survival advantage was seen with adjuvant treatment (HR: 0.93; 95% CI: 0.81–1.07) (29).

Taken together, the value of adjuvant chemotherapy for Dukes’ B/stage II disease is not yet proven, but relatively few patients have been randomised. Small treatment differences can only be detected reliably with many more patients. To detect an absolute risk reduction of 4% at 5 years, 4700 patients will be required (30). In individual stage II patients without other medical contraindications, adjuvant treatment with 6 months of 5-FU/leucovorin could be offered after a careful discussion with the patient who should understand that such adjuvant treatment is not definitely proven and that any benefit is likely to be small. However, in patients with high-risk characteristics such as intestinal obstruction, perforation, T4 tumours, poorly differentiated tumours, extramural venous or lymphatic invasion or perineural invasion and no other medical contraindications, adjuvant therapy can reasonably be offered to them.

Another important pathological consideration that needs to be taken account as to whether adjuvant therapy should be offered to patients is the number of lymph node harvested during resection. When the Italian INTACC (Intergruppo Nazionale Terpia Adiuvante Colon Carcinoma)-01 and 02 studies were analysed, surgical and pathological details were available in 3248 patients (1635 stage II and 1613 stage III patients) (31). The number of lymph nodes harvested during resection and examined by pathologists strongly correlated with both relapse free and overall survival in patients with stage II colon cancer. An 8% absolute survival advantage at 5 year was detected for patients with at least 18 lymph nodes recovered compared to those with ⩽7 lymph nodes. Patients with ⩽7 collected nodes might be inadequately staged and therefore might not be truly stage II patients. These patients should be evaluated differently for adjuvant chemotherapy.

Prolonged infusion of 5-FU results in less haematological toxicity and a small but statistically significant survival advantage over bolus regimens in advanced colorectal cancer (32), thus providing the rationale to investigate infused 5-FU as adjuvant therapy. Three months of protracted venous infusion (PVI) 5-FU produced similar overall and relapse free survival compared with 6 months of bolus 5-FU/LV in a recent UK study (33). Significantly less diarrhoea, stomatitis, neutropenia, anaemia and alopecia occurred with PVI 5-FU. A French study coordinated by GERCOR (Group d’Etude et de Recherche Clinique en Oncologie Radiotherapies) compared 2-weekly infused 5-FU/LV with 4-weekly bolus 5-FU/LV with a second randomisation to either 24 or 36 weeks of treatment. 905 patients recruited from 1996 to 1999 showed that 2-weekly treatment was less toxic than monthly treatment with lower incidences of neutropenia, diarrhoea and mucositis. No differences in DFS were seen between the treatment arms (HR: 1.042; 95% CI: 0.814–1.335) or between different durations of treatment (HR: 0.942; 95% CI: 0.735–1.21) (34). In the Intergroup-0153 study, continuous infusion of 5-FU with levamisole was compared to bolus 5-FU/LV and levamisole (35). The study was closed prematurely after 1078 patients had been recruited when an interim analysis showed no survival advantage in the continuous infusion arm and this was unlikely to happen even if the accrual goal of 1800 patients was reached.

Given that the current studies do not support a dramatic survival benefit of bolus 5-FU/LV over infused 5-FU or vice versa and these dose schedules show different toxicity profiles, it is reasonable to consider infused 5-FU to be used in place of bolus 5-FU/leucovorin depending on treating clinicians’ and patients’ preference. Two-weekly infused 5-FU/LV has been adopted as the control arm when comparing with the addition of irinotecan or oxaliplatin to infused 2-weekly 5-FU/LV in two large European studies.

Oral fluoropyrimidines have been increasingly incorporated in the treatment paradigms of advanced colorectal cancer. Capecitabine has been shown to have equivalent survival to bolus 5-FU/LV in advanced colorectal cancer [36], [37]. Oral tegafur (UFT) and uracil plus LV have also been shown to have similar survival to bolus 5-FU/LV in advanced colorectal cancer [38], [39]. In the adjuvant setting, capecitabine is being tested against bolus intravenous 5-FU/LV in 1956 stage III patients with colon cancer. NSABP C-06 recruited 1608 patients in a trial that was designed to compare treatment using UFT/LV against bolus 5-FU/LV. Accrual has finished in both studies and efficacy results are expected in the next couple of years. Table 2 shows recently completed or on-going studies of adjuvant therapy in colon cancer.

Irinotecan has been shown to improve survival in both first and second line settings in advanced colorectal cancer [40], [41], [42], [43]. Its role in adjuvant treatment is tested in two large studies – CALGB (Cancer and Leukemia Group B) C89803 and PETACC-3. However, in April 2001, an unexpected number of deaths occurred within the first 60 days of study entry in N9741, an Intergroup randomised study using irinotecan and bolus 5-FU/LV in recurrent and metastatic colorectal cancer, and a review of early death rate in C89803 concurred with the result. The patients (2.2%) in study C89803 receiving irinotecan and bolus 5-FU/LV experienced early deaths as opposed to a treatment-related mortality of 0–0.8% in recently reported colon cancer adjuvant studies. In relation to other arms of the studies, irinotecan and bolus 5-FU/LV had a 3-fold increased rate of treatment induced or treatment exacerbated deaths (44). In the PETACC-3 study where 2-weekly infused 5-FU/LV is used instead of a bolus schedule, no excessive treatment related deaths are thus far reported.

Oxaliplatin is a third generation platinum compound that has shown promise in advanced colorectal cancer [45], [46] and is used widely in Europe. A European study (MOSAIC) recruited 2248 stage II and III colon cancer patients and preliminary data confirm the safety of oxaliplatin/infused 5-FU/LV as adjuvant treatment (47). NSABP C-07 is still on-going testing the adjuvant role of oxaliplatin/bolus 5-FU/LV and aims to recruit 2472 patients.

Recently concerns have been raised over the safety of irinotecan when given in combination to bolus 5-FU/LV (IFL regimen). Higher than expected 60-day all cause mortality rates were noted in two US randomised trials in adjuvant and metastatic colorectal cancer – CALGB C89803 and Intergroup N9741 (44). This has been attributed to a gastrointestinal syndrome characterised by diarrhoea, nausea and vomiting, dehydration coupled with febrile neutropenia and electrolyte imbalances and a vascular syndrome characterised by acute, fatal myocardial infarction, cerebrovascular accident and pulmonary embolism. Arterial and venous thrombotic events were not in general associated with irinotecan when tested in the advanced disease setting. However, when the data in the European advanced colorectal cancer study were reviewed, a higher than expected thromboembolic events were evident (48). In the US Intergroup N9741 trial, the treatment arm consisting of oxaliplatin/bolus 5-FU/LV was also associated with excessive treatment related deaths and was closed due to safety.

However, infused schedules of 5-FU/LV with irinotecan or oxaliplatin have not been shown to cause excessive treatment related mortality. The evolution of combining irinotecan or oxaliplatin with 5-FU/LV appeared to have followed different avenues in the US and in Europe. Whereas a bolus schedule of 5-FU/LV given weekly is favoured in the US, a continuous infusion schedule given weekly or every 2 weeks is more in vogue in Europe. Treatment related death with irinotecan and bolus 5-FU/LV is concerning and is even more unacceptable in the adjuvant setting. It is possible that the bolus schedule is not the optimum partner with irinotecan and oxaliplatin, both of which can cause considerable side effects if supportive measures are not instituted immediately at the onset of toxicity. Oral fluoropyrimidines such as capecitabine and UFT have been shown to have a more favourable toxicity profile than bolus 5-FU/LV [36], [37], [38] although no direct comparisons with continuous infusion have been made. The efficacy of oral fluoropyrimidines with irinotecan or oxaliplatin has been demonstrated in phase II studies in metastatic colorectal cancer [49], [50]. These agents may prove in the future the bridge between bolus and infused schedules when combining with irinotecan and oxaliplatin.

Edrecolomab is a monoclonal antibody against human tumour associated antigen Ep-CAM (also known as 17-1A). In a German study comparing edrecolomab monotherapy with observation in 189 stage III colorectal cancer patients, edrecolomab monotherapy resulted in significantly better overall and disease free survival (51). Two large phase III studies have been reported. The first 3-arm randomised study of 2761 stage III colon cancer patients showed that edrecolomab monotherapy was inferior to either 5-FU/LV or 5-FU/LV/edrecolomab whilst there were no differences in OS and DFS between 5-FU/LV and 5-FU/LV/edrecolomab (52). A second study randomised 1839 patients to receive fluorouracil based chemotherapy with or without edrecolomab. A significant survival benefit favoured the addition of edrecolomab although an absolute survival benefit of only 2.7% in 3-year OS was seen (53). Combining edrecolomab with 5-FU based treatment did not alter the incidences of 5-FU related toxicities.

As there are great uncertainties of the benefit of adjuvant chemotherapy to individual patients, molecular markers that can reliably provide prognostic information and predict benefit from treatment are much needed, especially in patients with stage II disease. Approximately 10–15% of all colorectal cancers are characterised by microsatellite instability (MSI) – a hallmark of a DNA mismatch repair defect. Patients with stage III colon cancer receiving fluorouracil based chemotherapy in whom the tumours showed high level of microsatellite instability have been found to have a lower risk of cancer recurrence (54) and better survival (55). However, both studies used data derived from a non-randomised patient population.

More recently, a molecular analysis of 570 tissue specimen from North American and European randomised studies was performed (56). In these studies, patients with stage II and III colon cancer were randomised to receive either adjuvant fluorouracil-based chemotherapy or observation. In the absence of fluorouracil-based chemotherapy, MSI tumours had a better 5 year overall survival compared to microsatellite stable (MSS) tumours (p=0.004), but no survival advantage was seen in the presence of fluorouracil based chemotherapy. Indeed, in patients with MSS tumours, adjuvant chemotherapy had a significant beneficial impact on survival whereas for adjuvant patients with MSI tumours therapy resulted in a trend towards worse outcome compared to those under observation. However, as MSI tumours only accounted for 16.7% of all specimens, patients with MSI tumours who received adjuvant chemotherapy constituted a small subgroup of the whole cohort.

In another study of 460 patients treated with fluorouracil-based chemotherapy, loss of heterozygosity at chromosome 18q and microsatellite stability were independent predictive markers for recurrences. In addition, allelic loss of 18q was also associated with a near 2-fold increase in risk of death whilst microsatellite stability was associated with a borderline significant increased risk of death (57). At a population level outside clinical trials, MSI was also found to be associated with a better prognosis in patients with colon cancer. Reductions of about 60% for colon cancer related mortality and about 45% from all cause mortality were found with MSI tumours.

Other molecular markers that are under investigations include tumour thymidylate synthase (TS) expression and p53 status. Uncertainty still exists with regard to the value of TS expression in resected colon cancer. Three large studies attempted to address this issue, but came to different conclusions [58], [59], [60] (Table 3). In future, a predictive model using a panel of molecular markers may be able to more accurately identify the subgroup of patients who would benefit most from adjuvant treatment.

The aim of follow up for patients with resected stage II and III colon cancer is to detect resectable local recurrences or metastases confined to a single organ such as liver and lung. Aggressive surgical approaches to metastatic disease are increasingly practiced as a proportion of patients can enjoy long term survival. However, the value of follow-up after curative resection of colon cancer has been much debated. A recent systematic review and meta-analysis of five randomised studies examined the benefit of intensive follow up strategies after curative resection in 1342 patients with colorectal cancer (61). Intensive follow-up was associated with a reduction in all cause mortality (RR: 0.81; 95% CI: 0.70–0.94; p=0.007), an earlier detection of all recurrences (8.5 months earlier) and an increased detection rate for isolated local recurrences. However, the definition of intensive follow-up differed in these trials.

In a separate meta-analysis, data regarding detection rates of recurrences by follow-up, investigations and treatment for recurrences obtained from both uncontrolled and randomised studies were pooled (3). Overall, 37.5% of patients would have a recurrence within 5 years with approximately 1 in 8 patients experiencing local recurrence, 1 in 5 developing liver metastases and 1 in 12 developing pulmonary metastases. However, the type of surveillance tests used during follow up of colon cancer patients and the interval with which these tests are required remains to be established. For local recurrence, the best false vs. true positive (FP/TP) ratio was obtained with endoscopy and endoscopic ultrasound. For liver metastases, ultrasound and CT scanning of liver and CEA testing had the best FP/TP ratio. Diagnostic accuracy of tests for pulmonary metastases suffered from a paucity of data. In the course of follow-up, many false positive tests will occur triggering further testing to eliminate uncertainty about the presence or absence of recurrence and will therefore incur considerable cost.

After recurrences are detected, a large proportion of patients would not be able to undergo radical resection. Overall only 2.4% of patients with local recurrence, 3.1% of patients with pulmonary metastases and 2.4% with other non-hepatic recurrences are 5 year survivors. If liver is the solitary site of recurrence, 5-year survival rate after surgical resection varies from 20% to 45% (62). With the advent of neoadjuvant irinotecan or oxaliplatin based chemotherapy resulting in significant tumour shrinkage, more patients could now undergo potentially curative resection of hepatic metastases, thereby improving survival.

In an ECOG (Eastern Cooperative Oncology Group) study following patients on INT- 0089 study, 96 out of 421 patients with recurrent diseases underwent potentially curative surgical resection (63). The first test to detect recurrence was CEA measurement (n=30), chest X-ray (n=12) colonoscopy (n=14). Symptoms as the first sign of resectable recurrences were recorded in 24 patients whereas routine physical examination alone detected none of the recurrences. In a separate report of colonoscopy screening in this same cohort of patients, 42 cases of second primary invasive colon cancer were found with a cumulative incidence of 1.5% at 5 years (64). When compared to the general population, the incidence rate was higher in this cohort and many colorectal cancers were diagnosed within a relatively short period after patients’ most recent colonic surveillance. However, whether more frequent surveillance would have decreased the incidence of a second primary colorectal cancer and led to earlier diagnosis was not addressed in this study. In another study conduced in the Netherlands, 213 out of 496 patients developed recurrent disease and the recurrences were identified by liver ultrasound or CT (n=14), evaluation of symptoms (n=12), colonoscopy (n=8), CEA measurement (n=3), chest radiograph (n=2) and physical examination (n=1) (65).

Given the data regarding the accuracy of diagnostic tests and the probability of curative resection of recurrences, it has been estimated that 370 positive follow-up tests would be required. Out of these tests, 26 would be true positive test results identifying 11 patients that could be operated upon for recurrence and only 6 would be resected with curative intent. Four of these patients would undergo R0 resection with only one alive at 5 years after R0 resection. Therefore to provide one more colorectal cancer patient with long term survival through follow up, 369 tests and 10 operations would be done where either no gains or indeed harm are done (3).

In the US and Europe, different follow-up guidelines have been developed advocating the use of CEA, colonoscopy and liver imaging to detect recurrences. The ideal surveillance strategy would be one that detects recurrent colon cancer at a time when it is surgically resectable, at low cost and with minimal psychological stress. A randomised study of different surveillance strategies may be required and it is likely to involve thousands of patients, but survival, quality of life and economic implications will all need to be addressed in such a study.

Section snippets

Conclusion

In patients with stage III colon cancer, the role of adjuvant therapy is now established. Fluorouracil and leucovorin given for six months should form the control arm of randomised studies testing new drugs. In stage II colon cancer, because the risk of recurrence is lower, any absolute benefit of chemotherapy is likely to be less than stage III disease. The statistical power to detect what might be a clinically significant effect in survival for stage II disease is in general too small for the

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      Citation Excerpt :

      Surgery, radiotherapy or chemotherapy are the current treatment options of colon cancer patients [1–3]. However, above managements only showed limited value in improving overall survival (OS) of affected patients, especially for those with advanced or metastatic diseases [4,5]. Many different anti-colon cancer drugs are being utilized clinically, yet associated-side effects and drug resistance are two major drawbacks [4,5].

    • Increased adjuvant treatment and improved survival in elderly stage III colon cancer patients in the Netherlands

      2012, Annals of Oncology
      Citation Excerpt :

      Since the mid-1980s, improvement in colon cancer survival has been achieved among patients with lymph node-positive disease, in particular due to advances in adjuvant treatment [3, 4] and improved staging techniques which could have resulted in stage migration [5, 6]. The role of adjuvant treatment with 5-fluorouracil (5-FU)-based chemotherapy in younger stage III colon cancer patients is well established [7], and in more recent years, 5-FU has often been combined with oxaliplatin [8]. For selected elderly patients with stage III colon cancer on 5-FU-based chemotherapy, a survival benefit was reported [9, 10].

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