1 Oncologia Medica, Casa di Cura Poliambulanza, Brescia; 2 Oncologia Medica, Ospedali Riuniti di Bergamo, Bergamo, Italy
* Correspondence to: Dr A. Zaniboni, Via Gabriele Rosa, 3, 25121, Brescia, Italy. Email: zanib{at}numerica.it
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Abstract |
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Key words: adjuvant therapy, Dukes' B stage II colon cancer
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Introduction |
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We therefore need to identify prognostic markers capable of establishing which stage II patients will suffer from recurrences and which could benefit from adjuvant treatment. It should be noted that practically all the negative prognostic factors that we will look at have never been confirmed on a prospective basis. Furthermore, even given the negative prognostic value of some of these factors, adjuvant treatment will not necessarily improve the prognosis of these patients.
We now look at the known data regarding the efficacy of adjuvant therapy and summarize the data regarding past and more recent prognostic factors.
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Adjuvant chemotherapy |
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The International Multi-center Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) investigators compared the effect of 6 months of chemotherapy with 5-FU and leucovorin (LV) versus surgery alone in 1016 patients with Dukes' B colon cancer treated in five different trials. The absolute risk reduction for treated patients was 3% for 5-year disease-free survival (DFS) and 2% for 5-year OS, which was not statistically significant. On the basis of these results, routine use of chemotherapy for stage II colon cancer was not recommended [5, 6
].
Conversely, the NSABP group performed a pooled analysis of outcome data from four of their trials (C-01 to C-04) with >1500 stage II patients. They compared outcomes for all patients treated on the superior treatment arms of the four trials examining different strategies and/or schedule with those patients treated in the inferior treatment arms, whether these included treatment or observation alone (Table 2). A mortality reduction of 30% was observed for adjuvant therapy. This benefit was also present in poor prognosis patients, such as T4 and obstructed/perforated patients [7, 8
].
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A more recently published systematic review on adjuvant therapy for stage II colon cancer analyzed survival data available for 4187 patients with stage II disease across 18 trials. The mortality RR was 0.87 (95% CI 0.75-1.01) for the treated patients [12].
The statistician point of view as to the difficulties and pitfalls of the analysis of adjuvant studies and the meta-analysis of stage II patients has been analyzed in depth elsewhere [13].
An indirect method of evaluating the usefulness of adjuvant therapy was made by Schrag et al. A group of 3725 patients with resected stage II colon cancer was studied evaluating the SEER-Medicare data (Table 3). Thirty-one per cent had received adjuvant therapy. At 5 years, 74% of the treated patients were alive compared with 72% of those not treated. No significant difference has come to light for the subgroup of patients with poor prognostic features (T4, obstructed/perforated) [14]. These data, even if they are not from a randomized trial, would indicate that generally only very few patients received adjuvant therapy and that a non-treated control group might be considered for future trials. At the 2003 ASCO Meeting, Gill et al [15
]. presented a pooled dataset of 3302 patients with stage II colon cancer from seven randomized trials comparing 5-FU/LV or levamisole versus surgery alone. The analysis was based on a Cox proportional hazards regression model. Despite a benefit in the DFS in favor of chemotherapy, no significant OS difference was detected among treated versus untreated patients [15
].
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Adjuvant immunotherapy |
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Recent data from three prospective, randomized and controlled clinical trials conducted in stage IIIII colon cancer using active specific immunotherapy (ASI) look promising [1618
]. A meta-analysis of the three studies all based on Oncovax (irradiated autologous tumor cells mixed with BCG) has recently been carried out [19
]. In stage II patients, Oncovax therapy produced an annual odds reduction of relapse of 34% (±18%; P=0.05). OS did not differ between the ASI group and control group. However, disease-specific survival was statistically better in stage II patients receiving four doses of vaccination. Toxicity was virtually absent.
Another immunotherapeutic approach is based on the use of Edrecolomab, a monoclonal antibody that binds to the tumor-associated CO17-1 A antigen [20]. Although preliminary results of a large-scale trial conducted in stage III patients do not seem to confirm the initial enthusiasm about this agent [21
], the results of a recently closed trial comparing Edrecolomab monotherapy versus surgery alone, conducted by CALGB, National Cancer Institute of Canada, US Colorectal Intergroup and EORTC (study 157-003), are awaited with keen interest.
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Quality of surgery and role of the hospital procedure volume |
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US data suggest that hospital procedure volume may also influence the prognosis of stage II patients (Figure 1). Using SEER-Medicare data, Schrag et al. showed that hospital volume was predictive of survival for patients with stage II disease [26]. These results, as well as another study [27
], show that in the USA colon cancer surgery is currently performed in many hospital with very low case volumes. Prospectively recorded data from a large clinical trial (INT 0089) indicate that patients whose colon cancer was resected at low-volume hospitals experienced a higher risk for long-term mortality, without detectable differences in colon cancer recurrences [28
].
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Cost-effectiveness analysis |
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The toxicity issue |
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Nevertheless, we must consider that treatment-related deaths are reported in 0.3% to 0.8% of patients treated with 5-FU/LV-based adjuvant treatments [10]. It is clear that even such a limited mortality rate is relevant if we consider that the potential benefit in terms of survival rate thanks to adjuvant therapy may be
2%, according to the IMPACT B2 analysis. Furthermore, it should be outlined that we do not know the long-term effect of toxicity and quality of life that new regimens, based on new drugs such as irinotecan and oxaliplatin, in the adjuvant treatment could have. Therefore, particular care should be shown, especially in the light of recent negative experiences in terms of toxic deaths with Tomudex [34
] and irinotecan in combination with weekly bolus 5-FU/LV [35
].
We should remember, finally, that there are no data related to the long-term effects of new drugs, for example in terms of the potential induction of secondary acute leukemia and myelodysplastic syndromes, a sad lesson already learned by the nitrosureas-based adjuvant trials of the past [36].
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Prognostic factors of potential interest for stage II patients |
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Obstructing or perforating tumors
Patients with obstructing or perforating node-negative cancers are known to have survival rates comparable to non-obstructed and non-perforated patients with stage III disease, as suggested by trial INT-0035 results [3]. The negative impact of obstruction on prognosis is also suggested by a recent observational study [43
], as well as by many historical observations [44
, 45
]. When the perforation is associated with bowel obstruction, recurrence rates are even higher, with as few as 19% of patients surviving at 5 years [46
].
Lymph node retrieval rate
The American Joint Committee on Cancer and TNM Committee of the International Union Against Cancer has stated that a minimum of 12 lymph nodes should be recovered from colon adenocarcinoma specimens in order to perform correct pathological staging. However, other authors claim that an even higher number ranging from 14 to 17 nodes should be obtained for optimal results [47, 48
]. An even more provocative report was recently published by Le Voyer et al., suggesting that the higher the number of analyzed nodes, the better the prognosis of stage II patients [49
]. The number of lymph nodes collected is dependent on the method of identifying nodes, i.e. a lower number with manual dissection and a higher number with fat-clearing techniques which are more time consuming and expensive [50
].
A recent Canadian survey showed that only 25% of the interviewed pathologists identified that a minimum of 12 nodes are necessary for accurate designation of node negativity, raising the question of a suboptimal education strategy [51].
Whatever the technique used, patients with stage II colon cancer with <12 retrieved nodes should probably be considered for adjuvant treatment even outside a clinical trial.
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The role of lymphatic mapping (LM) and sentinel lymphadenectomy (SL) |
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It should be outlined that isolated tumor cells in mesenteric nodes also seem to predict a worse prognosis in patients with stage II colon cancer, as recently suggested by Bukholm et al. [67]. Saha et al. have pioneered LM and SL in colon cancer. In their pilot study, they demonstrated a 99% rate of SN identification, a 96% rate of accuracy for the SN as an indicator of regional nodal status and a 17% rate of upstaging [68
]. In a subsequent multi-institutional study using cytokeratin immunohistochemical staining in combination with reverse transcription-PCR for processing SN, up to 53% of patients whose SN were negative by conventional staging techniques, were found to have micro-metastases [69
]. Many other studies were subsequently performed in an attempt to confirm Saha's results. A summary of these experiences is reported in Table 6 [70
76
]. In addition, the LM/SL were recently demonstrated to be feasible also during laparoscopic surgery [75
]. Overall, it could be said that this technique holds promise in identifying a subset of stage II patients who may benefit from adjuvant chemotherapy, even if its routine clinical use is still premature, as clearly outlined also by the conflicting results of the first confirmatory trail reported at the 2004 ASCO Meeting by the CALGB (77).
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Other pathological findings |
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In addition, considering mucinous tumors, we should add a further cautionary note. This characteristic is a feature of cancers with MSI, which occurs in younger patients and appears to be a marker of improved prognosis. Possibly, the negative effect of mucinous histology might be more significant in older patients. These observations, however, need to be confirmed by solid data derived from multivariate analysis.
Finally, further to the issue of the number of retrieved nodes already discussed, even the size of the lumphnodes seems to be of prognostic value in stage II patients (86).
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Miscellaneous possible prognostic markers |
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On the other hand, k-ras [92] mutations and thymidylate synthase expression [93
] seem to be of no potential value in identifying a subset of stage II colon cancer patients with worse prognosis. Furthermore, other factors, such as mutated p53 gene have not given any clear unequivocal results. In fact, a pooled analysis on the p53 overexpression or mutation as a prognostic factor in colorectal cancer conducted in 4416 patients failed to show any positive effect, as was the case for at least four out of seven studies specifically conducted in stage II patients [94
].
A detailed analysis of these theoretical prognostic markers is beyond the scope of this review. The interested reader is referred to reviews reported elsewhere [85, 95
98
].
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Chromosomal abnormalities |
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Jen et al [100]. retrospectively studied the influence of allelic loss of chromosome 18q on the prognosis of stage II colon cancer. At a median follow-up of 35 months, 83% of the patients without 18q allelic loss were alive, whereas only 58% of patients with 18q allelic loss were still alive [100
]. This observation has been confirmed by some studies [101
, 102
], but not by all [103
].
Gryfe et al. have more recently shown that high-frequency MSI in colorectal cancer predicts a favorable outcome even among patients with stage II disease [42]. However, other reports have produced discordant results [104
].
More recently, Zhou et al [105] have studied 180 node-negative colorectal cancer patients for imbalances of chromosomes 8p and 18q by a new sophisticated technique called digital single nucleotide polymorphism. Five-year DFS was 100% for patients with no allelic imbalances, whereas it was 58% for those patients with allelic imbalances of both chromosomes (P=0.0001) [105
]. However, it is not possible at the moment to foresee what the practical implications of these findings could be. Furthermore, there are no clinical adjuvant therapy studies at present that stratify patients according to these genetic parameters, with the exception of the planned E5202 trial (Figure 2).
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Conclusions |
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In everyday clinical practice, it is likely that stage II patients without T4 tumors, neither occluded nor perforated, with >12 examined lymph nodes (and probably with a negative SN), treated in hospitals that can guarantee a multi-disciplinary approach, have a very high surgical cure rate.
However, as for any clinical scenarios in which the evidence-based medicine is not of any particular help, the decision to treat a patient with stage II colon cancer outside a clinical trial must be taken after careful, detailed and frank talk with the patient, clarifying all the pros and cons the choice involves. To give such a patient the possibility to participate in a clinical trial still remains the best available choice.
Received for publication February 5, 2003. Revision received February 7, 2004. Accepted for publication February 10, 2004.
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