© 2006 Foundation for Promotion of Cancer Research
Editorial |
Adjuvant Therapy in Rectal Cancer: What is the Truth?
Internal Medicine II, Osaka Medical College, Takatsuki, Osaka, Japan
For reprints and all correspondence: Hiroya Takiuchi, Internal Medicine II, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan. E-mail: in2028{at}poh.osaka-med.ac.jp
It's just like déjà vu. Japanese surgeons have often been dismissive of the value of adjuvant treatment for gastric cancer reported from Europe and America (1,2) because of differences in the degree of lymph node dissection between Japan and Europe/America (3). In contrast, Japanese surgeons may be surprised and delighted at the results of the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC) of postoperative adjuvant chemotherapy for rectal cancer published in this issue of the JJCO (4), the results of which have not been so exciting for European and American oncologists. Such differences have resulted from attitudes towards the basic surgical procedures and the strategy of postoperative adjuvant treatment for rectal cancer.
In Europe and America, adjuvant therapy for rectal cancer has included radiotherapy as a standard. In Japan, postoperative chemotherapy has been the primary treatment mainly because of excellent outcomes of surgery including autonomic nerve-preserving D3 dissection (lateral lymphadenectomy). The latest National Comprehensive Cancer Network (NCCN) guidelines prescribe preoperative concomitant radiotherapy and chemotherapy (FU ± LV or Capecitabine) and postoperative chemotherapy (FU ± LV or FOLFOX or Capecitabine) or, when preoperative chemoradiotherapy was not given, postoperative concomitant radiotherapy and chemotherapy (FU ± LV or FOLFOX or Capecitabine) (5). The use of chemotherapy has been based on the evidence of postoperative adjuvant chemotherapy in colon cancer, not rectal cancer. As for radiotherapy, local recurrence was reduced but the survival rate not increased in most reports.
In the USA, postoperative radiotherapy following surgery for rectal cancer has been used from the beginning for local control. A randomized controlled trial of MOF therapy and postoperative adjuvant radiotherapy using surgery alone as the control arm has been performed (NSABP R-01 study). The 5 year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the MOF therapy group. Local control was significantly better in the postoperative adjuvant radiotherapy group, but DFS and OS were not (6). Although these findings did not clarify the significance of postoperative adjuvant radiotherapy, the 1990 NCI Consensus Development Conference defined chemotherapy + postoperative adjuvant radiotherapy as a standard postoperative adjuvant therapy for stage II and III rectal cancer (7). The subsequent NSABP R-02 study concluded that postoperative adjuvant radiotherapy did not improve the prognosis of rectal cancer. This study used the MOF therapy group, which was effective compared with the surgery alone group in the NSABP R-01 study, as the control. It investigated MOF versus MOF + postoperative adjuvant radiotherapy, MOF versus 5-FU/LV, and 5-FU/LV versus 5-FU/LV + postoperative adjuvant radiotherapy. No significant differences were noted in DFS or OS between the groups treated with adjuvant chemotherapy alone and chemotherapy +adjuvant radiotherapy after surgery. Disease free survival was significantly higher in the 5-FU/LV group when compared with MOF, but there was no difference in OS (8). These findings had a great impact on postoperative adjuvant radiotherapy, and the American Society of Clinical Oncology (ASCO) initiated discussion on the role of postoperative adjuvant radiotherapy. A subsequent meta-analysis performed by the Colorectal Cancer Collaboration Group confirmed that postoperative adjuvant radiotherapy significantly reduced local recurrence, but showed no significant difference in OS (9). Since it was clarified that postoperative adjuvant radiotherapy did not improve the prognosis of rectal cancer, the emphasis turned to the role of preoperative adjuvant radiotherapy.
Various trials on the role of preperative adjuvant radiotherapy for rectal cancer have been reported, but a final conclusion is not yet reached. Two recent meta-analyses have shown that preoperative adjuvant radiotherapy reduces local recurrence rates by almost 50% and overall mortality by 2–10% (9, 10). Preoperative radiotherapy with higher biologically effective doses (of at least 30 Gy) have shown a larger reduction than either preoperative radiotherapy with lower doses or postoperative radiotherapy. However, the trials included in these meta-analyses all started before the broad introduction of total mesorectal excision (TME) surgery. The only randomized trial of TME with or without preoperative radiotherapy was that conducted by the Dutch Colorectal Cancer Group. After 2 years follow-up the estimated local recurrence rates were 2.4% with preoperative radiotherapy and 8.2% without preoperative radiotherapy. This relative reduction of local control recurrence was similar to that seen in the meta-analysis. However, the survival rate was not significantly different from that in the group treated with TME alone (11). This suggested that preoperative radiotherapy did not lead to improved survival when distant metastasis to the liver and lung were not prevented. Thus the role of postoperative adjuvant chemotherapy could be important for the improvement of the therapeutic results. Moreover, some reports have suggested limiting the application of preoperative short-term radiotherapy to cases with a high risk of local recurrence because it frequently causes delayed adverse reactions (12). Therefore, preoperative adjuvant radiotherapy for rectal cancer should also be carefully evaluated.
In this study (NSAS-CC), liver and lung metastasis were prevented and the survival rate significantly increased in the uracil–tegafur (UFT) treatment group, demonstrating the significance of UFT in preventing distant metastases. The incidence of grade 3 or higher adverse drug reactions was low, and compliance was good. Hence, 1 year treatment with UFT may be used as the standard postoperative adjuvant chemotherapy for stage III rectal cancer. However, this could only occur in Japan where lateral pelvic lymphadenectomy is the standard procedure. The Japan Clinical Oncology Group (JCOG) is currently conducting a phase III study in patients with resectable clinical stage II or III lower rectal cancer without apparent lateral pelvic lymph node metastasis. This will evaluate the effectiveness of mesorectal excision (ME), the international standard surgery, with autonomic nerve-preserving D3 lymphadenectomy (nerve-preserving D3 dissection), the Japanese standard (JCOG 0212). A common ground between Japanese and European/American surgeons may yet appear when the results of this study are reported. The data will show the importance of clinical trials, providing us with the truth, whether we like it or not. And then, we can start to discuss future trials to compare UFT treatment or other adjuvant therapies for patients with rectal cancer.
References
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5 National Comprehensive Cancer Network. Clinical Practice Guideline in oncology-version 4. 2005.
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8 Wormark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388–96.
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