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The key clinical question is whether delivery of up‐front full‐dose systemic chemotherapy and increased compliance improves disease‐specific outcomes. Long‐term survival data following TNT are lacking and predominantly limited to small case series. A systematic review of oncological outcomes following TNT, including seven prospective studies reporting five‐year survival data, found similar long‐term survival outcomes when compared with standard nCR. The overall weighted mean five‐year OS and DFS were 74.4 and 65.4% respectively. Comparative analysis of seven studies by Petrelli et al., however, demonstrated that patients who received TNT had better DFS (HR 0.75, 95% CI 0.52–1.07, p = 0.11) and OS (HR 0.73, 95% CI 0.59–0.9, p = 0.004) than those who received conventional nCRT only [29]. In a multi‐institutional phase II trial, better disease‐specific survival was observed with consolidation chemotherapy (two, four, or six cycles of modified FOLFOX) compared with conventional nCRT [32]. After a median follow‐up of 59 months, five‐year DFS was 81% following consolidation chemotherapy compared to 50% with nCRT (p = 0.0005). There were no significant differences in survival among the experimental arms. Notably, the primary endpoint of this trial was pCR and it was not adequately powered to show differences in survival. Similarly, a North American multicenter retrospective analysis of 110 patients with cT3/4 N0–2 disease treated with short‐course radiotherapy also observed improved DFS with consolidation FOLFOX [33]. DFS at three years was 85% compared with 68% among patients treated with standard nCRT and adjuvant chemotherapy (p = 0.032). A single‐arm Chinese study of 96 patients with cT3/4 or node‐positive disease treated with consolidation XELOX (capecitabine and oxaliplatin) also reported comparable five‐year DFS of 83% [34]. Interestingly, the Polish phase III randomized trial of 515 patients with cT4 or fixed cT3 reported no significant difference in DFS between those receiving short‐course radiotherapy with three cycles of consolidation FOLFOX4 compared to traditional CRT [35]. DFS at eight years was 43 vs. 41% respectively.

The most meaningful potential advantage of early full‐dose chemotherapy is targeting subclinical micrometastases and reducing distant disease failure. In a systematic review of ten prospective studies, the overall weighted mean distant recurrence rate was 20.6% (range 5–31%). Eight studies reported distant failure rates consistent with the standard treatment paradigm (19–31%). The remaining two studies reported significantly lower rates [36, 37]. This discrepancy may be related to the shorter length of follow‐up because of differences in clinical stage, compliance, and/or the use of adjuvant therapy. It will be interesting to see if the three‐year metastasis‐free survival benefit seen in RAPIDO and PRODIGE 23 is maintained with prolonged follow‐up.