Generally, patients with a large tumour and several metastatic sites with an ECOG performance status of 2 or greater have a lower chance of response to chemotherapy. For many of these patients the attendance or supportive care is the recommended treat ment choice. On the other hand, patients who are in a good general condition with a small tumour, not previously exposed to chemotherapy, have response rates of approximately 50% when treated with CPT-11 and oxaliplatin. The cases in between the two conditions described are more difficult to manage and the approach must be individualised. If the patient is elderly, his general condition is not very good or he does not seek particular medical attention, it is reasonable to wait a month or two, check the rate of disease progression and withhold treatment until later in the course .
More debatable is the issue of treatment of the non-symptomatic patient. As the end-point of treatment is palliation, should we wait until symptoms develop (so that there is something to palliate) or should treatment be instituted right away? Several phase III studies concluded that patients who are treated at diagnosis of metastatic disease with conventional FU-based regimens live significantly longer (by 3-6 months) than patients in whom chemotherapy is delayed until symptoms develop; even if the overall response rate to standard chemotherapeutic regimens is low in unse-lected patients with advanced colorectal cancer, the subjective benefit is substantial .
At this time, there is a role for combination chemotherapy as a first-line treatment in fit patients. Standard systemic chemotherapy for advanced col-orectal cancer is the use of combination therapy with oxaliplatin or CPT-11. Only in some cases can FU-LV be considered the best choice. In general there is agreement that bolus FU alone is ineffective and that biochemical modulation is needed for bolus FU activity whereas it is not for protracted infusional FU. Biochemical modulation is also required when using intermittent high-dose infusional FU.
In fit patients chemotherapy is also indicated for second- and in some cases thirdline therapy. Treatment of patients who progress after first-line chemotherapy is guided by which treatment was used for first-line treatment. Patients who were treated with a FOLFOX-based regimen should be treated with a CPT-11-based regimen and patients who already received a CPT-11-based regimen should be treated with a FOLFOX-based regimen.
The GERCOR Group achieved 26-month median overall survival with the sequential use of continuous infusional FU-LV, oxaliplatin and CPT11 combinations in metastatic patients.
The analysis of large phase III trials using FU, CPT11 and oxaliplatin revealed that the higher proportion of patients was treated with all three drugs, the longer overall survival was achieved; the use of combination protocols as first-line chemotherapy was associated with a significant improvement in median survival of 3.5 months (p=0.0083) .
The anti-VEGF bevacizumab increases the efficacy of first-line CPT-11 therapy, while the addition of cetuximab restores CPT-11 sensitivity in second-line treatment.
Regarding the duration of chemotherapy for these patients, as long as there are no other factors that contraindicate treatment, chemotherapy should be recommended for approximately 2 months and then their outcome must be evaluated. If the treatment is fairly well tolerated and there is at least a stabilisation of the disease, chemotherapy should be continued until progression or toxicity. Usually in clinical practice chemotherapy is stopped after a maximum of 6 months. A recent trial has compared effectiveness of continuous and intermittent chemotherapy in patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy: they were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression) or continuous chemotherapy until progression. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival . Another strategy may be the so-called "stop and go therapy". In the OPTIMOX study reintroduction of oxaliplatin was feasible and achieved a response or stabilisation in 73% of patients. These results support the concept that intensified, repeated short courses of FOLFOX are efficacious and less toxic .
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