C u r ren t C o n t ro v e r s i e s i n Neoadjuvant Chemoradiation of Rectal Cancer P. Terry Phang,
MD, MSc, FRCSC
a,
*, Xiaodong Wang,
MD
b
KEYWORDS Rectal cancer Neo-adjuvant chemoradiation Short course Long course Complete pathologic response KEY POINTS Total mesorectal excision with preoperative radiation and chemotherapy provide the lowest local recurrence rates for rectal cancer. Timing of surgery after preoperative chemoradiation is being increased to optimize tumor downstaging. Permissive observation of complete clinical response is investigational at present. Preoperative and postoperative radiation provides improved local cancer control for superficial cancers removed by local excision. Good prognostic tumor characteristics are being investigated with the aim of selecting patients for whom preoperative radiation may be avoided.
BACKGROUND
In the history of rectal cancer surgery, outcomes have previously been less favorable than for colon cancer, with local recurrence rates on the order of 25% versus 5% and 5-year survival rates on the order of 30% versus 50%. To improve on rectal cancer surgery outcomes, postoperative (adjuvant) combination radiation and chemotherapy regimens were recommended, based on trials conducted by the US North Central Cancer Treatment Group (NCCTG),1 the Gastrointestinal Tumor Study Group (GITSG),2 and the National Surgical Adjuvant Breast and Bowel Project (NSABP).3 However, outcomes of rectal cancer remained less favorable despite this standard adjuvant treatment.4 A remarkable improvement in outcomes of rectal cancer was reported by Heald and Ryall5 using the technique of total mesorectal excision (TME). The report on Heald’s surgical results without adjuvant treatments by MacFarlane and colleagues6 showed a
Department of Surgery, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada; b Gastrointestinal Surgery Centre, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China * Corresponding author. E-mail address: [email protected] Surg Oncol Clin N Am 23 (2014) 79–92 http://dx.doi.org/10.1016/j.soc.2013.09.008 surgonc.theclinics.com 1055-3207/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
80
Phang & Wang
local recurrence outcomes to be superior to non-TME surgery with adjuvant treatments, 7% versus 19%. The second remarkable improvement in outcomes of rectal cancer was preoperative (neoadjuvant) radiation, introduced in the Swedish rectal cancer trials.7 Local recurrence and survival were improved in a randomized trial using short-course preoperative radiation versus surgery alone. However, surgery in this study was not based on TME technique. Outcomes with short-course preoperative radiation plus non-TME surgery remained suboptimal, stressing the importance of TME surgery as the main standard treatment of rectal cancer. The first randomized trial using TME was reported by Dutch investigators,8 who demonstrated that TME surgery could be learned and adopted by general surgeons, with good results. Norway has also adopted TME surgery on a national basis, with national local recurrence rates of 8%.9 Furthermore, the main finding of the Dutch trial was that the combination of short-course preoperative radiation plus TME had the lowest local recurrence rate.10 This large multicenter study provided new outcomes standards for rectal cancer that approach outcomes for colon cancer.11 The protocol of preoperative short-course radiation and TME surgery has also been used for populations in Sweden, Denmark, and British Columbia in Canada.10–12 Preoperative radiation was demonstrated to be superior to postoperative radiation in a German randomized trial,13 which also used TME as the standard surgery technique. Preoperative radiation reduced local recurrence by half compared with postoperative radiation (6% vs 13%). Moreover, the downstaging effect of preoperative radiation resulted in increased sphincter-preserving resection with less permanent colostomies in patients preoperatively judged to require abdominoperineal resection (39% vs 19%). This sphincter-preserving effect from downstaging by preoperative long-course chemoradiation was also seen in a Korean trial.14 The NSABP also conducted a trial of preoperative versus postoperative chemoradiation. Though unable to complete its full study because of incomplete recruitment, the NSABP did report trends toward improved disease-free survival with preoperative treatments, 64% versus 52% at 7 years.15 On this basis, preoperative radiation combined with chemotherapy has been adopted as the standard protocol for rectal cancer management by the National Institutes of Health (NIH) and the National Comprehensive Cancer Network (NCCN) in the United States and Canada. CONTROVERSIES: OUTLINE
The evolution of the management of rectal cancer provides a background for controversies over preoperative radiation in current management. Controversies to be discussed here include: The protocol of preoperative radiation (short vs long course): efficacy and toxicity Whether chemotherapy is used in combination with radiation, and which chemotherapy drugs are used The optimum timing of surgery after radiation to achieve maximum downstaging Whether radiation is used for all rectal cancers or on a selected basis only The preferred radiation protocol for treating superficial rectal cancer being considered for local excision Whether endocavitary radiation can be used as an effective treatment Table 1 lists randomized trials for each of the topics.
Rectal Cancer Radiation Controversies
THE PROTOCOL OF PREOPERATIVE RADIATION: EFFICACY AND TOXICITY
Two randomized trials have compared short-course and long-course preoperative chemoradiation. In the Polish trial,16 there was no difference in local recurrence or survival between short-course and long-course preoperative chemoradiation. Of note, there was a trend toward lower local recurrence with short-course preoperative radiation. In addition, although downstaging after long-course preoperative chemoradiation should facilitate sphincter-preserving resection, there was no difference in rates of abdominoperineal resection between short-course and long-course preoperative radiation groups. A second randomized trial that compared short-course with longcourse preoperative chemoradiation has been reported from the Trans-Tasman group.17 Again, there was no difference in local recurrence or survival between groups. The investigators suggested that long-course preoperative chemoradiation may have nonsignificant benefit for local recurrence of distal rectal cancers less than 5 cm from the anus. Toxicity of short-course preoperative radiation is predicted to be lower than for longcourse preoperative chemoradiation, owing to its lower radiobiological equivalent effect. Although larger fraction size used in short-course radiation is associated with higher risk for late toxicity, no difference in late toxicity was reported in the 2 trials that compared short-course and long-course preoperative radiation.17,18 Of note, the Swedish rectal cancer study using short-course preoperative radiation did report increased toxicity with femoral fractures, thromboembolism, small-bowel obstruction, and postoperative mortality.19,20 The increased toxicity in the initial Swedish trials was accounted for by use of extended radiation fields up to L1, use of 2 rather than 4 portals, and absence of blocking. With the use of small radiation fields, 4 portals, and blocking in the Polish study, toxicity was less for short-course preoperative radiation in the acute phase, and equivalent in the late phase relative to long-course preoperative chemoradiation.16 The German trial showed that toxicity was reduced with chemoradiation given preoperatively versus postoperatively, 27% versus 40% in the early stage and 14% versus 24% in the late stage.13 The reduced toxicity resulted in more patients completing the full dose of chemoradiation in the preoperative group, which in part may account for the improved outcomes seen with preoperative treatments. In the Polish trial, 98% of patients completed the prescribed short-course radiation treatment, compared with 69% of patients completing the prescribed long-course treatments.17 Intensity-modulated arc therapy has been used to minimize small-bowel radiation toxicity. Radiation is delivered in 3 to 6 arcs for a 180 cGy fraction while lowering total small-bowel dose from 17.0 Gy to 12.4 Gy and, hence, small-bowel toxicity.21–24 However, a phase II study reported in abstract form found no difference in gastrointestinal toxicity, 51% versus 58%, on comparing intensity-modulated with conventional preoperative chemoradiation, and showed a pathologic complete response of 15%.25 Pelvic radiation has adverse effects on the bowel, bladder, and sexual function. Impairments occur more with postoperative than with preoperative radiation.13 However, there was no difference in bowel impairment between preoperative short-course versus long-course radiation with respect to incontinence (72% vs 65%) or stool frequency (4 vs 5).17 Bladder incontinence occurs in about 40%, and sexual dysfunction in about 30% of irradiated patients who undergo rectal cancer surgery.26,27 WHETHER CHEMOTHERAPY IS USED IN COMBINATION WITH RADIATION AND WHICH CHEMOTHERAPY DRUGS ARE USED
The rationale for using a combination of chemotherapy and radiation is based on adjuvant studies by the NCCTG, GITSG, and NSABP between 1980 and 1990.1–4 After
81
82
FollowUp (mo)
Topic
Study
Groups
The protocol of preoperative radiation-efficacy and toxicity
Swedish Rectal Cancer Trial,7 1997 Kapiteijn et al,8 2001
Preoperative radiotherapy 1 surgery vs Surgery Preoperative radiotherapy 1 TME vs TME Preoperative chemoradiation vs postoperative chemoradiation Preoperative chemoradiation vs postoperative chemoradiation Short-course preoperative radiotherapy vs Long-course chemoradiation Short-course preoperative chemoradiation vs Long-course preoperative chemoradiation
75
Preoperative radiotherapy 1 chemotherapy vs Preoperative radiotherapy Preoperative radiotherapy vs Preoperative chemoradiation vs Preoperative radiotherapy 1 postoperative chemoradiation vs Preoperative chemoradiation 1 postoperative chemoradiation
Sauer et al,13 2004 Roh et al,15 2009 Bujko et al,16 2006
Ngan et al,17 2012
Whether chemotherapy is used in combination with radiation and which chemotherapy drugs are used
Gerard et al,30 2006
Bosset et al,31 2006
Hofheinz et al,33 2012
Postoperative radiotherapy 1 capecitabine vs 1 fluorouracil
Local Recurrence
Survival
11% vs 27%, P
MD, MSc, FRCSC
a,
*, Xiaodong Wang,
MD
b
KEYWORDS Rectal cancer Neo-adjuvant chemoradiation Short course Long course Complete pathologic response KEY POINTS Total mesorectal excision with preoperative radiation and chemotherapy provide the lowest local recurrence rates for rectal cancer. Timing of surgery after preoperative chemoradiation is being increased to optimize tumor downstaging. Permissive observation of complete clinical response is investigational at present. Preoperative and postoperative radiation provides improved local cancer control for superficial cancers removed by local excision. Good prognostic tumor characteristics are being investigated with the aim of selecting patients for whom preoperative radiation may be avoided.
BACKGROUND
In the history of rectal cancer surgery, outcomes have previously been less favorable than for colon cancer, with local recurrence rates on the order of 25% versus 5% and 5-year survival rates on the order of 30% versus 50%. To improve on rectal cancer surgery outcomes, postoperative (adjuvant) combination radiation and chemotherapy regimens were recommended, based on trials conducted by the US North Central Cancer Treatment Group (NCCTG),1 the Gastrointestinal Tumor Study Group (GITSG),2 and the National Surgical Adjuvant Breast and Bowel Project (NSABP).3 However, outcomes of rectal cancer remained less favorable despite this standard adjuvant treatment.4 A remarkable improvement in outcomes of rectal cancer was reported by Heald and Ryall5 using the technique of total mesorectal excision (TME). The report on Heald’s surgical results without adjuvant treatments by MacFarlane and colleagues6 showed a
Department of Surgery, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada; b Gastrointestinal Surgery Centre, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China * Corresponding author. E-mail address: [email protected] Surg Oncol Clin N Am 23 (2014) 79–92 http://dx.doi.org/10.1016/j.soc.2013.09.008 surgonc.theclinics.com 1055-3207/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
80
Phang & Wang
local recurrence outcomes to be superior to non-TME surgery with adjuvant treatments, 7% versus 19%. The second remarkable improvement in outcomes of rectal cancer was preoperative (neoadjuvant) radiation, introduced in the Swedish rectal cancer trials.7 Local recurrence and survival were improved in a randomized trial using short-course preoperative radiation versus surgery alone. However, surgery in this study was not based on TME technique. Outcomes with short-course preoperative radiation plus non-TME surgery remained suboptimal, stressing the importance of TME surgery as the main standard treatment of rectal cancer. The first randomized trial using TME was reported by Dutch investigators,8 who demonstrated that TME surgery could be learned and adopted by general surgeons, with good results. Norway has also adopted TME surgery on a national basis, with national local recurrence rates of 8%.9 Furthermore, the main finding of the Dutch trial was that the combination of short-course preoperative radiation plus TME had the lowest local recurrence rate.10 This large multicenter study provided new outcomes standards for rectal cancer that approach outcomes for colon cancer.11 The protocol of preoperative short-course radiation and TME surgery has also been used for populations in Sweden, Denmark, and British Columbia in Canada.10–12 Preoperative radiation was demonstrated to be superior to postoperative radiation in a German randomized trial,13 which also used TME as the standard surgery technique. Preoperative radiation reduced local recurrence by half compared with postoperative radiation (6% vs 13%). Moreover, the downstaging effect of preoperative radiation resulted in increased sphincter-preserving resection with less permanent colostomies in patients preoperatively judged to require abdominoperineal resection (39% vs 19%). This sphincter-preserving effect from downstaging by preoperative long-course chemoradiation was also seen in a Korean trial.14 The NSABP also conducted a trial of preoperative versus postoperative chemoradiation. Though unable to complete its full study because of incomplete recruitment, the NSABP did report trends toward improved disease-free survival with preoperative treatments, 64% versus 52% at 7 years.15 On this basis, preoperative radiation combined with chemotherapy has been adopted as the standard protocol for rectal cancer management by the National Institutes of Health (NIH) and the National Comprehensive Cancer Network (NCCN) in the United States and Canada. CONTROVERSIES: OUTLINE
The evolution of the management of rectal cancer provides a background for controversies over preoperative radiation in current management. Controversies to be discussed here include: The protocol of preoperative radiation (short vs long course): efficacy and toxicity Whether chemotherapy is used in combination with radiation, and which chemotherapy drugs are used The optimum timing of surgery after radiation to achieve maximum downstaging Whether radiation is used for all rectal cancers or on a selected basis only The preferred radiation protocol for treating superficial rectal cancer being considered for local excision Whether endocavitary radiation can be used as an effective treatment Table 1 lists randomized trials for each of the topics.
Rectal Cancer Radiation Controversies
THE PROTOCOL OF PREOPERATIVE RADIATION: EFFICACY AND TOXICITY
Two randomized trials have compared short-course and long-course preoperative chemoradiation. In the Polish trial,16 there was no difference in local recurrence or survival between short-course and long-course preoperative chemoradiation. Of note, there was a trend toward lower local recurrence with short-course preoperative radiation. In addition, although downstaging after long-course preoperative chemoradiation should facilitate sphincter-preserving resection, there was no difference in rates of abdominoperineal resection between short-course and long-course preoperative radiation groups. A second randomized trial that compared short-course with longcourse preoperative chemoradiation has been reported from the Trans-Tasman group.17 Again, there was no difference in local recurrence or survival between groups. The investigators suggested that long-course preoperative chemoradiation may have nonsignificant benefit for local recurrence of distal rectal cancers less than 5 cm from the anus. Toxicity of short-course preoperative radiation is predicted to be lower than for longcourse preoperative chemoradiation, owing to its lower radiobiological equivalent effect. Although larger fraction size used in short-course radiation is associated with higher risk for late toxicity, no difference in late toxicity was reported in the 2 trials that compared short-course and long-course preoperative radiation.17,18 Of note, the Swedish rectal cancer study using short-course preoperative radiation did report increased toxicity with femoral fractures, thromboembolism, small-bowel obstruction, and postoperative mortality.19,20 The increased toxicity in the initial Swedish trials was accounted for by use of extended radiation fields up to L1, use of 2 rather than 4 portals, and absence of blocking. With the use of small radiation fields, 4 portals, and blocking in the Polish study, toxicity was less for short-course preoperative radiation in the acute phase, and equivalent in the late phase relative to long-course preoperative chemoradiation.16 The German trial showed that toxicity was reduced with chemoradiation given preoperatively versus postoperatively, 27% versus 40% in the early stage and 14% versus 24% in the late stage.13 The reduced toxicity resulted in more patients completing the full dose of chemoradiation in the preoperative group, which in part may account for the improved outcomes seen with preoperative treatments. In the Polish trial, 98% of patients completed the prescribed short-course radiation treatment, compared with 69% of patients completing the prescribed long-course treatments.17 Intensity-modulated arc therapy has been used to minimize small-bowel radiation toxicity. Radiation is delivered in 3 to 6 arcs for a 180 cGy fraction while lowering total small-bowel dose from 17.0 Gy to 12.4 Gy and, hence, small-bowel toxicity.21–24 However, a phase II study reported in abstract form found no difference in gastrointestinal toxicity, 51% versus 58%, on comparing intensity-modulated with conventional preoperative chemoradiation, and showed a pathologic complete response of 15%.25 Pelvic radiation has adverse effects on the bowel, bladder, and sexual function. Impairments occur more with postoperative than with preoperative radiation.13 However, there was no difference in bowel impairment between preoperative short-course versus long-course radiation with respect to incontinence (72% vs 65%) or stool frequency (4 vs 5).17 Bladder incontinence occurs in about 40%, and sexual dysfunction in about 30% of irradiated patients who undergo rectal cancer surgery.26,27 WHETHER CHEMOTHERAPY IS USED IN COMBINATION WITH RADIATION AND WHICH CHEMOTHERAPY DRUGS ARE USED
The rationale for using a combination of chemotherapy and radiation is based on adjuvant studies by the NCCTG, GITSG, and NSABP between 1980 and 1990.1–4 After
81
82
FollowUp (mo)
Topic
Study
Groups
The protocol of preoperative radiation-efficacy and toxicity
Swedish Rectal Cancer Trial,7 1997 Kapiteijn et al,8 2001
Preoperative radiotherapy 1 surgery vs Surgery Preoperative radiotherapy 1 TME vs TME Preoperative chemoradiation vs postoperative chemoradiation Preoperative chemoradiation vs postoperative chemoradiation Short-course preoperative radiotherapy vs Long-course chemoradiation Short-course preoperative chemoradiation vs Long-course preoperative chemoradiation
75
Preoperative radiotherapy 1 chemotherapy vs Preoperative radiotherapy Preoperative radiotherapy vs Preoperative chemoradiation vs Preoperative radiotherapy 1 postoperative chemoradiation vs Preoperative chemoradiation 1 postoperative chemoradiation
Sauer et al,13 2004 Roh et al,15 2009 Bujko et al,16 2006
Ngan et al,17 2012
Whether chemotherapy is used in combination with radiation and which chemotherapy drugs are used
Gerard et al,30 2006
Bosset et al,31 2006
Hofheinz et al,33 2012
Postoperative radiotherapy 1 capecitabine vs 1 fluorouracil
Local Recurrence
Survival
11% vs 27%, P
