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Management of Rectal Cancer: Short- vs. Long-Course Preoperative Radiation
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 3, pp. 636–643, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2008.05.069
CRITICAL REVIEW
MANAGEMENT OF RECTAL CANCER: SHORT- VS. LONG-COURSE PREOPERATIVE RADIATION MOHAMMED MOHIUDDIN, M.D.,* JOHN MARKS, M.D.,y AND GERALD MARKS, M.D.y * Geisinger Cancer Institute, Wilkes Barre, PA; and y Main Line Health System, Lankenau Institute for Medical Research, Wynnewood, PA There is considerable debate on the optimum approach to neoadjuvant therapy in rectal cancer. This review of major published studies of short-course preoperative radiation and the more conventional approach of long-course neoadjuvant chemoradiation was undertaken in an effort to understand the potential advantages and disadvantages of each of these approaches. Studies were evaluated with regard to patient selection, clinical outcomes, and toxicities. Short-course preoperative radiation has shown a clear advantage over surgery alone in reducing local recurrence rates and improving survival of patients with rectal cancer. However, studies using short-course preoperative treatment have included a significant number of early (30%; Stage I/II) and more proximal cancers yet appear to have higher positive margin rates, higher abdominoperineal resection rates, and lower aggregate survival than patients treated with long-course neoadjuvant chemoradiation. Although long-course preoperative chemoradiation is associated with higher rates of reversible acute toxicity, there appears to be more significant and a higher rate of late gastrointestinal toxicity observed in short-course preoperative radiation studies. Patient convenience and lower cost of treatment, however, can be a significant advantage in using a short-course treatment schedule. Selective utilization of either of these approaches should be based on extent of disease and goals of treatment. Patients with distal cancers or more advanced disease (T3/T4) appear to have better outcomes with neoadjuvant chemoradiation, especially where downstaging of disease is critical for more complete surgical resection and sphincter preservation. Ó 2008 Elsevier Inc. Rectal cancer, Neoadjuvant, Chemoradiation.
rates, and low pelvic recurrence rates (6–8). The significant differences in these approaches, ‘‘short- vs. long-course pre operative radiation,’’ have led to some confusion as to the most optimum approach to preoperative radiation in the management of this disease. In a recent editorial in the Journal of Clinical Oncology, Kachnic et al. (9), discussed the role of neoadjuvant therapy for T3, N0 rectal cancers. It was suggested that because there is an 18% overstaging for these cancers in spite of endorectal ultrasound staging (10) and a 22% understaging (11), a compromise approach to treatment would be to use short-course (5 Gy 5) preoperative radiation as per the Swedish (5) and Dutch (12) experiences. Kachnic et al. (9) also made an argument that short-course treatment would allow patients with positive nodes to receive adjuvant chemotherapy. Because the standard of care in patients receiving preoperative chemoradiotherapy is to administer adjuvant chemotherapy postoperatively regardless of the pathologic findings, as evidenced by the clinical practice guidelines published by the National Comprehensive Cancer Network, this argument of Kachnic et al. (9)
INTRODUCTION Neoadjuvant therapy is widely accepted as the current standard of care in the treatment of advanced rectal cancer. However, there is considerable debate regarding the best approach to neoadjuvant therapy. Early studies with preoperative radiation, although showing a consistent reduction in local recurrence rates, had failed to show a survival advantage (1–4). The Swedish Rectal Cancer Trial (5) was the first randomized study to show that a ‘‘short course’’ of preoperative radiation (5 Gy 5) alone, without chemotherapy, followed by immediate surgery, resulted in a significant improvement in 5-year survival and a reduction in the local recurrence rate for all stages of cancer. The experience in the United States has largely focused on a more protracted or ‘‘long course’’ of preoperative radiation using conventional doses of 1.8–2 Gy per fraction over 5–6 weeks, for a total dose of 45 to 50.4 Gy. Several institutional studies have reported exceptionally good survival with this more conventional approach with considerable downstaging of tumor, improved resectability
Conflict of Interest: None. Received March 17, 2008, and in revised form May 5, 2008. Accepted for publication May 12, 2008.
Reprint requests to: Mohammed Mohiuddin, MD, Geisinger Cancer Institute, 1000 East Mountain Boulevard, Wilkes Barre, PA 18711. Tel: (570) 819-5859; Fax: (570) 819-5485; E-mail: [email protected] 636
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becomes irrelevant. The question remains as to whether the short-course treatment should be considered a compromise between no preoperative radiation and the long-course treatment or whether there are pros and cons to each treatment that need to be clearly understood and appropriately used. The purpose of this review is to get a clear understanding of each of these approaches to neoadjuvant radiation for rectal cancer.
METHODS AND MATERIALS Recent literature on preoperative radiation for rectal cancer was reviewed with a particular emphasis on published randomized studies between 1996 and 2007 (Table 1). A comparison was made of the two different approaches using short-course preoperative radiation and the more conventional long-course neoadjuvant chemoradiation with regard to patient selection, clinical outcomes, and toxicities in an effort to understand the potential advantages and disadvantages of each of these approaches to adjuvant therapy in the management of rectal cancers. Short-course preoperative radiation has been delivered in the Swedish (5) and Dutch (12) trials as five fractions of 5 Gy each. The 2-Gy biologic equivalent of 25 Gy in five fractions is 37.5 Gy10 (if a/b = 10 for early effects) and 66.67 Gy3 (if a/b = 3 for late effects). The higher biologic effect in late-responding tissue with the potential for serious late complications has been a major factor in the consideration of a more conventional approach to preoperative radiation at 1.8–2 Gy per fraction to total doses of 45–55 Gy in the United States. Lower doses per fraction have also allowed for the use of
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combined chemotherapy with the radiation in the neoadjuvant setting to further maximize both local and systemic effects of treatment.
RESULTS Much of the European experience is based on the shortcourse preoperative radiation (without chemotherapy) followed by immediate surgery. The data in these studies are based on large randomized trials in which the focus has been on survival and local recurrence rates. The American experience is largely based on data from institutional studies and Phase II trials using conventional radiation plus/minus chemotherapy followed by delayed surgery. Although survival and local recurrence have been important in these studies, considerable attention has been paid to tumor downstaging to allow improved resectability and opportunities for sphincter preservation for a more improved quality of life. There has been one study undertaken by the Polish Colorectal Study Group (13) that has randomized patients to shortcourse radiation, 5 Gy x 5, in 1 week followed by immediate total mesorectal excision (TME) vs. a protracted course of 50.4 Gy in 28 fractions of 1.8 Gy per fraction plus 5-FU followed by a 4- to 6-week interval before TME surgery. The end point of the study was to determine whether sphincter preservation rates could be increased using protracted radiation with the addition of chemotherapy. Results of the study indicate that there was no difference in survival between the short-course preoperative radiation group as compared with
Table 1. Recent randomized studies of neoadjuvant radiation for rectal cancer Randomized studies
Eligibility criteria (stage/level)
Arm 1 Preop RT (5 Gy 5) + immediate surgery Preop RT (5 Gy 5) + immediate surgery (TME) Preop RT (5 Gy 5) + immediate surgery
Swedish (5)
Resectable/0–16 cm
Dutch (12)
Mobile/0–16 cm
Polish (13)
T3T4, N+/0–15 cm
German (10)
T3/T4, N+/0–16 cm
EORTC 22921 (27)
T3/T4, N+/0–15 cm
FFCD 9203 (28)
T3/T4, N+/0–15 cm
Preop RT (45 Gy) + delayed surgery
National Surgical Adjuvant Breast and Bowel Project R04 (15) Radiation Therapy Oncology Group 0012 (29)
T3/T4, N+/0–12 cm
Preop RT (50 cGy) + Xeloda oxaliplatin + delayed surgery
T3/T4, N+/0–12 cm
Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery
Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery (TME) Preop RT (45 Gy) + delayed surgery
Arm 2 Surgery alone Surgery alone (TME) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery (TME) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery Preop chemo/RT (50.4 Gy + 5-FU oxaliplatin + delayed surgery) Preop chemo/RT (50.4 Gy + 5-FU oxaliplatin + delayed surgery) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery
Abbreviations: preop = preoperative; chemo = chemotherapy; RT = radiation therapy; TME = total mesorectal excision.
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the chemoradiation group. This was a small study of 316 patients and was not powered to detect differences in survival. There was also no difference in the primary end point, which was the rate of sphincter preservation between the two groups of patients with 39% of patients undergoing abdominoperineal resection (APR) after the short-course preoperative radiation as compared to 42% in the chemoradiation arm (p = 0.57) even though tumors in the chemoradiation arm were on average 1.9 cm smaller than the tumors in the short-course radiation arm (p < 0.001). A confounding factor in the Polish Rectal Trial (14) was also that 15% of patients did not receive the assigned treatment as per protocol in the chemoradiation arm. Considering that this was a relatively small study (156 patients in each arm), it raises the question as to how posttreatment tumor assessment impacted choice of surgical approach and how valid are the conclusions based on an intent-to-treat analysis. If we assume that there was significant downstaging after the preoperative chemoradiation arm (tumors were 1.9 cm smaller than in the ‘‘short course preop’’ arm), the lack of difference in the APR rates in this study conflicts with the data from the German Rectal Cancer Trial (10) in which patients with low rectal cancers (n = 188) had twice the rate of sphincter preservation (39%) after preoperative chemoradiation as compared with surgery alone (19%, p = 0.004). It is possible that the lack of improved sphincter preservation rates in the Polish study despite documented significant downstaging raises the question of whether the Polish surgeons, who are not accustomed to the downstaging that occurs with long-course chemoradiation, were unwilling to change the planned surgery, assuring that sphincter preservation could not be improved regardless of the intraoperative findings. Bujko et al. have argued that the German study (10) was not a valid demonstration of sphincter preservation with neoadjuvant therapy, because there was an imbalance in distal tumors between the two arms, and if one considers the entire cohort of patients (rather than the subset for whom surgeons thought an APR would be needed). the rate of sphincter preservation is actually the same in both arms of the study. Although it is true that the overall APR rate in the German trial (10) was 26% in the neoadjuvant chemoradiation arm compared with 23% in the postoperative radiation arm, this may be a function of tumor location rather than the effects of chemoradiation. In contrast, almost twice the number (42%) of patients in the chemoradiation arm of the Polish study underwent an APR. In addition, 14.6% of patients in the latter study had stomas not reversed or underwent subsequent stomas for an overall stoma rate of 51.6%. This high rate of persistent stomas in the Polish study (13) raises some serious questions and, because both studies identified patients who were planned to undergo an APR as a subset to assess the impact of neoadjuvant therapy, the analysis of equivalence by Bujko et al. does not appear valid. These studies, therefore, raise more questions than they answer. To appreciate the nuances and merits of each approach to preoperative radiation, a comparative understanding of the various treatment parameters and outcomes of these studies may be helpful.
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Stage of cancer Stage of cancer is often the most significant variable in outcome of treatment. The short-course preoperative radiation studies have generally included a greater proportion of early stage tumors. All patients entered in the Swedish (5) and Dutch studies (12) were considered to have mobile or resectable cancers at initial evaluation. In the Swedish trial, 553/ 583 (90.5%) patients randomized to this arm underwent surgery. Of these patient, 181 (33%) were found to have Stage I disease, whereas 195 (35%) had Stage II, and the rest Stage III disease. If no significant downstaging occurred in these patients as a result of the short duration to surgery, the pathologic extent of tumor should represent the initial stage of cancer. Similarly, in the Dutch Rectal Cancer Trial using short-course preoperative radiation, 276/828 (33.3%) patients had early-stage disease, Stage 0 or Stage I, whereas 252 (30.4%) had Stage II disease, and the remaining 36% of patients had Stage III disease. On the other hand, in the German study (10), the group undergoing surgery followed by postoperative radiation represents a comparable distribution to the neoadjuvant chemoradiation arm in which there was only 18% with Stage I disease (Table 2). The current National Surgical Adjuvant Breast and Bowel Project R-04 (15), Radiation Therapy Oncology Group (RTOG) (16), and other multicenter trials using long-course preoperative chemoradiation have excluded early cancers (T1 and T2) and included only the more advanced stages (i.e., ultrasoundstage T3/T4 or N+ cancers). Although it is never valid to compare results across different studies, when considering the various trials of short-course radiation to those using long-course chemoradiation, it is essential to keep in mind that the short-course trials included a much larger proportion of Stage I patients. If the treatment approaches are equivalent, as suggested by the Polish experience, then the outcomes should be worse in the long-course trials because of the inclusion of patients with more advanced disease. Tumor location Tumor location in the rectum is known to be an important prognostic factor in results of treatment (17, 18). The inclusion of patients with only distal tumors in the long-course preoperative chemoradiation studies may also bias the results unfavorably in comparing outcomes in the two groups. The funnel-shaped bony pelvis limits tumor access, visualization, and mobilization in resection of distal cancers. It is also important to understand that, although the current surgical buzz word is TME, the mesorectum, in the most distal segment of the rectum, is often incomplete and lateral Table 2. Distribution of patients by pathologic stage Trials Swedish (5) Dutch (12) German (10) (surgery + postoperative therapeutic arm)
Stage I Stage II Stage III 33% 33% 18%
35% 30% 29%
32% 36% 47%
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surgical margins are limited because of proximity of other organs and or bony structures. Distal tumors also have a higher incidence of lymph node metastasis (19) making the overall prognosis much worse, 15–20% less compared to proximal cancers of the rectum (20). Patients entered into the short-course radiation in the Swedish and Dutch rectal cancer studies included tumors located between 0 and 16 cm from the anal verge. The National Surgical Adjuvant Breast and Bowel Project (21), RTOG (16), and most institutional studies of chemoradiation include patients with tumors between 0 to 10 or 12 cm from the anal verge. The differences regarding tumor location may appear small in these studies, but can substantially influence overall outcomes unless proportionate numbers of patients at each level are appropriately stratified and compared individually. Tumor location will continue to be a confounding issue in future trials especially if sphincter preservation rates are critical determining factors in selection of appropriate adjuvant therapy.
Resectability and margin status The hallmark of successful treatment of rectal cancer is not only resection of the primary tumor with negative margins (R0), but en bloc resection of the rectum within the mesorectal envelope (i.e., the TME procedure). Several studies have now documented the significant negative impact of close or positive surgical margins on recurrence rates and survival of patients (22–26). Results from the short-course preoperative radiation studies have generally suggested a lower rate of ‘‘R0’’ resections than in the long-course neoadjuvant chemoradiation studies. Ninety percent of patients in the Swedish Rectal Cancer Trial (5) underwent surgical resection after short-course preoperative radiation and the rate of ‘‘R0’’ resections was only 77.8%. Similarly, in the Dutch Rectal Cancer Trial (12), only 1,351 of 1,759 patients were found to have tumor-free margins after surgical resection for a ‘‘R0’’ resection rate of 77%. This is surprisingly low considering that all patients in both these trials were considered to have ‘‘mobile’’ or ‘‘resectable’’ cancers, and in the case of the Dutch study, were operated on by surgeons trained to perform TME and, in fact, the majority of patients (64%) in this study had early cancers (Stage I or Stage II) and only 34% had Stage III disease. In the Polish randomized study (13), 16% of patients in the short-course preoperative radiation arm had either positive distal margins (12%) or positive radial margins (4%), whereas only 4% of the patients in the chemoradiation arm had positive distal margins (p = 0.017), indicating a significantly greater downstaging and ‘‘R0’’ resection rate with chemoradiation. Although it has been shown that less than an ‘‘R0’’ resection does lead to higher recurrence rates and poorer survival, it should be remembered that where surgery is performed immediately after completing radiation, it is possible that the cells visualized at the margins are no longer viable and would not have been seen had the surgery been done 4–6 weeks later, as is the standard after long-course neoadjuvant chemoradiation.
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Table 3. Rate of non-curative resection with positive margins Trial
5 5 Gy
Swedish (5) 23% Dutch (12) 23% Polish (13) 16% German (10) — EORTC (29) — French (28) Radiation Therapy — Oncology Group (29) Rodel et al. (48) Gambacorta et al. (32) Guillem et al.(45)
50.4 Gy + chemotherapy
4%
p value
0.017
13% 14% 5% 5% 6% 2%
In contrast to the short-course radiation studies, the data from several other European and American studies indicate that curative surgery as defined by ‘‘R0’’ resection rates is higher with long-course preoperative radiation (Table 3). In a European Organization for Research and Treatment of Cancer (EORTC) study using 45 Gy plus chemotherapy, 87% of the patients had an ‘‘R0’’ resection (27). In the German study (10) of ultrasound-staged T3/T4 or N+ patients, 88% of patients receiving preoperative 50.4 Gy of radiation with chemotherapy underwent ‘‘R0’’ resection. In a similar French study (28), 86% of patients underwent ‘‘R0’’ resection and in the RTOG 0012 trial (29) including ultrasound-staged T3/T4 cancers only, 95% of the patients underwent ‘‘R0’’ resection after a higher dose of 55 Gy preoperative radiation plus infusional 5-FU chemotherapy (Table 3). This would indicate that not only in mobile, resectable cancers but especially in marginally resectable or fixed cancers, preoperative chemoradiation is likely to consistently allow for ‘‘R0’’ resection and negative margins. Sphincter preservation Historically, sphincter preservation has not been a focus of many of the European trials irrespective of whether shortcourse or long-course radiation is used. Generally, the long-course preoperative studies have reported higher sphincter preservation rates than the short-course treatment. The APR rate in the Swedish trial (5) was 58% and in the Dutch trial 35% (12). Similarly, in patients undergoing chemoradiation, the French trial (28) had an APR rate of 46% and the EORTC trial (27) a 48% APR rate. In the Polish trial (13), as mentioned earlier, the APR rate was 42%, but the rate of persistent stomas was 51.6%. The American experience has largely shown a consistent drop in the abdominoperineal resection rate with the increasing use of long-course preoperative radiation, from a high of 40+% b 1985–1986 to less than 30% by the mid-1990s (30). This has continued to drop with evolution of new stapling techniques and advances in minimally invasive surgery in other countries as well (31). The US national average would suggest that the abdominoperineal resection rate in the United States remains less than
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Table 4. Abdominoperineal resection rates European trials Swedish (5) Dutch (total mesorectal excision) (12) French (28) EORTC (27) Institutional studies Rodel et al. (48) Valentini et al. (49)
58% 35% 46% 48% 23% 12.8%
20%. Several institutional studies have reported APR rates of 9–20% even for patients with distal cancers (32–37) (Table 4). Of particular importance is that assessment of surgical options for sphincter preservation be based on posttreatment residual size and location of cancer in the rectum and not the pretreatment stage of disease, which may have influenced the sphincter preservation rates in the Polish study. Toxicity Acute toxicity is known to be considerably higher when neoadjuvant chemoradiation is used as compared with similar doses of radiation alone. Late toxicity, however, may not be influenced by the addition of chemotherapy and appears to be less with more protracted course of radiation. Acute toxicity Based on the intent-to-treat analysis in the Polish randomized study (14), there appears greater Grade 3/4 toxicity with chemoradiation (18.2%) than with short-course radiation (3.2%) (p < 0.001). In the German study (36), Grade 3 gastrointestinal-related acute toxicity was approximately 12% in the preoperative chemoradiation arm. The addition of chemotherapy with any radiation treatment has been shown to increase acute toxicity significantly. In the EORTC study (27), Grade 2 toxicity was 29.7% with radiation alone (45 Gy in 5 weeks) as compared with 38.4% with chemoradiation. Grade 3 or higher toxicity was observed in 7.4% of patients with radiation alone and 13.9% (p < 0.001) of patients with chemoradiation. One result of the greater acute toxicity with chemoradiation is that substantial numbers of patients may not receive the full planned treatment or have interruptions to treatment that could negatively impact outcomes. In the Polish study (14), 98% of the patients receiving short-course radiation, completed prescribed treatment as compared with only 69.2% of patients receiving chemoradiation. Surgical toxicity There was some increase in the postsurgical toxicity after short-course radiation in the Dutch Rectal Cancer Trial that was not seen in the German study (10) chemoradiation. There was slightly more blood loss (median 1,000 vs. 900 mL; p < 0.001) with short-course preoperative radiation and in patients who had APR 26% had perineal complications as compared with 18% with surgery alone, p = 0.05.
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Late toxicity Based on the intent-to-treat analysis in the Polish randomized study, it was reported that there was very little difference between the late toxicity of short-course radiotherapy compared with the chemoradiation arm (38). Sixteen late complications were observed in 14 patients in the short-course arm compared with 13 complications in 10 patients in the chemoradiation arm. However, the relative risk of severe late toxicity in the short course compared with the chemoradiation group was reported as 1.43 (95% CI, 0.67–3.07). Longterm data from the Swedish study (39) would indicate that patients undergoing short-course preoperative radiation experience significant ongoing problems with bowel function compared with surgery alone. Incontinence rate reported from the Dutch trial (40) of 51% was significantly higher than the 37% with surgery alone (p = 0.002). The incidence of sexual problems was also higher after short-course preoperative radiation as compared to surgery alone, 31% compared to 21% with surgery alone (p = 0.03). What was even more concerning from the Swedish Rectal Cancer Trial (41) was that long-term follow-up beyond 5 years indicates a continuing pattern of late small bowel obstructions in patients receiving the short-course radiation compared with patients undergoing surgery alone. Although these reported high rates of toxicities may be a function of more longterm follow-up in the short-course preoperative radiation studies, there has not been the same level of late toxicities reported in the EORTC trial (27) or institutional studies with long-term follow-up after long-course preoperative radiation (42). In the EORTC study, fecal incontinence was only 9% and anastomotic stricture formation was 1.4% after chemoradiation. Local recurrence Although it is difficult to compare the local recurrence rate between the different studies and treatment techniques, both approaches appear to reduce the recurrence rate for various stages of cancer by 50%. The Swedish Rectal Cancer Trial (5), which predated the TME era, had a local recurrence rate of 40% for Stage III disease with surgery alone and 20% after short-course preoperative radiation and surgery. In contrast, the German Rectal Cancer Trial (10) using chemoradiation had a local recurrence rate of 21.5% with surgery (TME) and postoperative radiation compared with 11.2% (p < 0.001) with preoperative radiation for Stage III cancers. However, the data from the Dutch TME trial (43) indicates that the true benefit of the short course of radiation in terms of local recurrence occurred only in the subgroup of patients with mid-rectal tumors located 5–10 cm from the anal verge. There was no improvement in local recurrence rates for distal cancers between 0 and 5 cm or in the more proximal cancers between 10 and 15 cm (Table 5). This may be reflected in the fact that total mesorectal excision could only be performed on 65% of the patients with distal cancers between 0 and 5 cm, 85% of the patients with cancers between 5 and 10 cm, and 100% of the patients with cancers between 10 and 15 cm.
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Table 5. Dutch TME Rectal Cancer Trial: distance of tumor vs. local recurrence Distance from anal verge
0–5 cm
5–10 cm
10–15 cm
65% 85% 100% Curative resection (total mesorectal excision) 13% 15% 11% Local recurrence— surgery alone 15% (p = 0.122) 7% (p = 0.001) 7% (p = 0.578) Local recurrence— preoperative radiation therapy + surgery
The value of the short-course radiation approach, therefore, may be greatest where reasonable TME surgery can be performed with negative but somewhat limited circumferential margins as in the mid-rectum, but may not be sufficient in distal cancers where surgical margins of a necessity are limited. The radiation dose may not be adequate to obtain sufficient tumor regression to provide safe margins of resection where TME is most difficult or inadequate. In the proximal rectum, where surgical access is relatively easier and wide margins of resection are likely, shortcourse radiation may provide limited or no benefit. Data from long-course chemoradiation studies suggest that its greatest benefit may be in improving results in the most distal cancers where the mesorectum may be incomplete (34). Analysis of the German Rectal Cancer Trial (44) highlights the importance of adequate radiation dose for optimum results. Patients in this study who did not receive radiation had a 29.6% local recurrence rate, and those that received inadequate radiation (<43 Gy), a 21.2% local recurrence as compared to 6.6% in patients receiving adequate radiation (p = 0.0001) This also translated into a significant difference in disease free survival (55% with no radiation
Table 6. Neoadjuvant therapy for rectal cancer Study Swedish trial (5) Danish trial (12) Radiation Therapy Oncology Group trial (27) French trial (28) German trial (10) Radiation Therapy Oncology Group trial (29) Guillem et al. (45) Cocco et al. (46) Shivnani et al. (47)
Treatment
5-y survival
5 Gy 5 5 Gy 5 45 Gy + chemotherapy
54% 63% 65%
50 Gy + chemotherapy 50.4 Gy + chemotherapy 55 Gy + chemotherapy
67% 74% 76%
50.4 Gy +chemotherapy 50.4 Gy + chemotherapy 55 Gy + chemotherapy
76% 76% 81%
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therapy, 57% with inadequate radiation therapy, and 69% with adequate radiation therapy). It is therefore possible that the difference in treatment compliance of only 70% in the chemoradiation group to 98% in the short-course radiation group could have accounted for a lack of difference in the local recurrence and survival in the two arms of the Polish trial (14). Survival In spite of including a generally more favorable cohort of patients in the short-course preoperative radiation studies, the reported survival in the chemoradiation studies appears higher. The Swedish Rectal Cancer Study (5) reported a 5year survival of 54% in ‘‘resectable’’ rectal cancer, but it predates the era of TME surgery and modern imaging. The Dutch study (12) reported a 5-year survival of 63% with a short course of preoperative radiation and TME in ‘‘mobile’’ rectal cancers. These results were similar to survival reported in the EORTC study (27) and the French study (28) (65%) after long-course chemoradiation. However, the 5-year survival in the German Rectal Cancer Trial (10) with preoperative chemoradiation was reported as being 74% and in the RTOG 0012 study (28) was 76%. Several institutional experiences indicate a survival outcome that is even higher, ranging from 78% to 81% (Table 6). These current trends in survival improvements with long-course preoperative radiation especially for distal and advanced cancers have established new benchmarks that may be more difficult to achieve with short-course preoperative radiation approaches alone. Whether all of the benefit of the long-course chemoradiation is due to tumor downstaging and higher frequency of negative margins or due to the systemic effects of chemotherapy is not altogether clear, but from the postoperative adjuvant therapy experience (50), it is reasonable to expect that there is both a local and a systemic benefit with the addition of chemotherapy. It is this survival advantage with the increasing option for sphincter preservation that has led several of the ongoing national trials both in Europe and the United States opting for the use of more conventional dose–time fractionation of radiation with chemotherapy. The focus has shifted to intensifying the neoadjuvant regimen by using a multidrug approach with the addition of oxaliplatin, irinotecan, or molecular-targeted agents to the 5-FU regimen. As newer and more intensive neoadjuvant treatments evolve, both the efficacy and shortand long-term toxicity will need to be continuously and carefully evaluated as newer toxicities such as the long-term neuropathy of oxaliplatin-containing regimens may result in a compromised quality of life compared with preoperative radiation alone either as a short- or long-course treatment. CONCLUSION On the basis of this review, it is clear that neoadjuvant therapy should not be considered as a ‘‘one size fits all’’ approach. Short-course preoperative radiation may be a valuable treatment option for patient convenience, cost reduction, and in patients with a short life expectancy because of age or
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comorbidities and thus unlikely to experience late complications or those patients who are unable to participate in a more prolonged course because of other barriers such as transportation or compliance issues. In some early cancers (T2) located in the mid-rectum (5–10 cm), it may be effective in reduction of local recurrence, but it does not appear appropriate for T3 or more advanced cancers. Optimum multifield radiation techniques to limited treatment volumes (10 10
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cm or smaller to the true pelvis), must be used to minimize late toxicity. For all distal rectal cancers and all T3 or higher staged cancers in the mid- to proximal rectum, the conventional approaches with 1.8–2 Gy per fraction with careful attention to total dose, combined with multiagent chemotherapy may yield greater downstaging, improved ‘‘R0’’ resection rates, sphincter preservation, low recurrence rates, and most significantly provide substantial improvement in survival.
REFERENCES 1. Higgins CA, Humphrey EW, Dwight RW, et al. Preoperative radiation and surgery for cancer of the rectum: Veterans Administration Surgical Oncology Group trial 11. Cancer 1986;58:352. 2. Gerard A, Buyse M, Nordinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal carcinoma. Ann Surg 1988; 208:606–614. 3. Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 1996;348:1605–1610. 4. Stockholm Colorectal Cancer Study Group. Randomized study on preoperative radiotherapy in rectal carcinoma. Ann Surg Oncol 1996;3:423–430. 5. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997; 336:980–987. 6. Janjan NA, Crane CN, Feig BW, et al. Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2000;47:713–718. 7. Mohiuddin M, Marks C. High dose preoperative irradiation for cancer of the rectum, 1976–1988. Int J Radiat Oncol Biol Phys 1990;20:37–43. 8. Mendenhall WM, Bland KI, Copeland EM 3rd, et al. Does preoperative radiation therapy enhance the probability of local control and survival in high-risk distal rectal cancer? Ann Surg 1992;215:696–705. 9. Kachnic LA, Hong TS, Ryan DP. Rectal cancer at the crossroads: the dilemma of clinically staged T3, N0, M0 disease. J Clin Oncol 2008;26:350–351. 10. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 11. Guillem JG, Diaz-Gonzalez JA, Minsky BD, et al. cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 2008;26:368–373. 12. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–646. 13. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 2004;72:15–24. 14. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Longterm results of a randomized trial comparing preoperative shortcourse radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93: 1215–1223. 15. NSABP R-04. Phase III randomized study of preoperative chemoradiotherapy comprising radiation therapy and either capecitabine or fluorouracil with or without oxaliplatin in patients with resectable rectal cancer. Available at: http://www.nsabp.pitt. edu. Accessed November 1, 2005.
16. Mohiuddin M, Winter K, Mitchell E, et al. Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J Clin Oncol 2006;24:650–655. 17. Pilipshen SJ, Heilweil M, Quan SI-I, et al. Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer 1984;53:1354–1362. 18. Wolmark N, Wieand HS, Rockette HE, et al. The prognostic significance of tumor location and bowel obstruction in Dukes B and C colorectal cancer. Findings from the NSABP clinical trials. Ann Surg 1983;198:743–752. 19. Brodsky J, Richard GK, Cohen AM, et al. ‘‘Variables correlated with the risk of lymph node metastasis in early rectal cancer.’’ Cancer 1992;69:322–326. 20. Mohiuddin M, Marks C. Adjuvant radiation therapy for colon and rectal cancer. Semin Oncol 1991;18:411–420. 21. Roh MS, Colangelo L, Wieand S, et al. Response to preoperative multimodality therapy predicts survival in patients with carcinoma of the rectum (abstract). Proc Am Soc Clin Oncol 2004; 23:247a. 22. Baik SH, Kim NK, Lee YC, et al. Prognostic significance of circumferential resection margin following total mesorectal excision and adjuvant chemoradiotherapy in patients with rectal cancer. Ann Surg Oncol 2007;14:462–469. 23. Dent OF, Haboubi N, Chapuis PH, et al. Assessing the evidence for an association between circumferential tumour clearance and local recurrence after resection of rectal cancer. Colorectal Dis 2007;9:112–222. 24. Quirke P, Durdey P, Dixon MF, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumor spread and surgical excision. Lancet 1986;2:996. 25. Hall NR, Finan PJ, al-Jaberi T, et al. Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent. Predictor of survival but not local recurrence? Dis Colon Rectum 1998;41:979. 26. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707. 27. Collette L, Bosset JF, den Dulk D, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379–4386. 28. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 2006;24:4620–4625. 29. Mohiuddin M, Garcia M, Mitchell E, et al. Three year results of RTOG-0012 randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer [abstract]. Int J Radiat Oncol Biol Phys 2006;66:260.
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30. Jessup JM, Stewart AK, Menck HR. The National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985–1995. Cancer 1998;83:2408. 31. Tilney HS, Heriot AG, Purkayastha S, et al. A national perspective on the decline of abdomino-perineal resection for rectal cancer. Ann Surg 2008;247:77–84. 32. Gambacorta MA, Valentini V, Coco C, et al. Sphincter preservation in four consecutive phase II studies of preoperative chemoradiation: Analysis of 247 T3 rectal cancer patients. Tumori 2007;93:160–169. 33. Ota DM, Jacobs L, Kuvshinoff B. Rectal cancer: The sphinctersparing approach. Surg Clin North Am 2002;82:983–993. 34. Mohiuddin M, Regine W, Marks GJ, et al. High-dose preoperative radiation and the challenge of sphincter preservation surgery for cancers of the distal 2 cm of the rectum. Int J Radiat Oncol Biol Phys 1998;40:569–574. 35. Crane CH, Skibber JM, Feig BW, et al. Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer 2003;97:517–524. 36. Wallace MH, Glynne-Jones R. Saving the sphincter in rectal cancer: are we prepared to change practice? Colorectal Dis 2007;9:302–309. 37. Howard JH, Gonzalez Q, Arnoletti JP, et al. Prognostic factors and preoperative radiation therapy associated with sphincter preservation in patients with resectable rectal cancer. Am J Surg 2008;195:239–243. 38. Bujko K, Nowacki MP, Kepka L, et al. Postoperative complications in patients irradiated pre-operatively for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs chemoradiation. Colorectal Dis 2005;7:410–416. 39. Birgisson H, Pahlman L, Gunnarsson U, et al. Adverse effects of preoperative radiation therapy for rectal cancer: Long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 2005;23:8697. 40. Peeters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—a Dutch colorectal cancer group study. J Clin Oncol 2005;23:6199.
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41. Pollack J, Holm T, Cedermark B, et al. Late adverse effects of short-course preoperative radiotherapy in rectal cancer. Br J Surg 2006;93:1519–1525. 42. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355:1114–1123. 43. Peeters KC, Marijinen CA, Nagtegaal ID, et al. The TME trial after a median follow up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007;246:693–701. 44. Fietkau R, Rodel C, Hohenberger W, et al. Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: Results of study CAO/ARO/AIO-94. Int J Radiat Oncol Biol Phys 2007;67: 1008–1019. 45. Guillem JG, Chessin DB, Cohen AM, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 2005;241:829–836. 46. Coco C, Valentini V, Manno A, et al. Long-term results after neoadjuvant radiochemotherapy for locally advanced resectable extraperitoneal rectal cancer. Dis Colon Rectum 2006;49: 311–318. 47. Shivnani AT, Small W Jr., Stryker SJ, et al. Preoperative chemoradiation for rectal cancer: Results of multimodality management and analysis of prognostic factors. Am J Surg 2007;193: 389–393. 48. Rodel C, Liersch T, Hermann RM, et al. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 2007;25:110–117. 49. Valentini V, Coco C, Minsky BD, et al. Randomized, multicenter, phase IIb study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy versus cisplatin + 5-fluorouracil + radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:403–412. 50. O’Connell MJ, Martenson JA, Wieand HS, et al. Improved combined modality surgical adjuvant therapy for high-risk rectal cancer. N Engl J Med 1994;331:502–507.
doi:10.1016/j.ijrobp.2008.05.069
CRITICAL REVIEW
MANAGEMENT OF RECTAL CANCER: SHORT- VS. LONG-COURSE PREOPERATIVE RADIATION MOHAMMED MOHIUDDIN, M.D.,* JOHN MARKS, M.D.,y AND GERALD MARKS, M.D.y * Geisinger Cancer Institute, Wilkes Barre, PA; and y Main Line Health System, Lankenau Institute for Medical Research, Wynnewood, PA There is considerable debate on the optimum approach to neoadjuvant therapy in rectal cancer. This review of major published studies of short-course preoperative radiation and the more conventional approach of long-course neoadjuvant chemoradiation was undertaken in an effort to understand the potential advantages and disadvantages of each of these approaches. Studies were evaluated with regard to patient selection, clinical outcomes, and toxicities. Short-course preoperative radiation has shown a clear advantage over surgery alone in reducing local recurrence rates and improving survival of patients with rectal cancer. However, studies using short-course preoperative treatment have included a significant number of early (30%; Stage I/II) and more proximal cancers yet appear to have higher positive margin rates, higher abdominoperineal resection rates, and lower aggregate survival than patients treated with long-course neoadjuvant chemoradiation. Although long-course preoperative chemoradiation is associated with higher rates of reversible acute toxicity, there appears to be more significant and a higher rate of late gastrointestinal toxicity observed in short-course preoperative radiation studies. Patient convenience and lower cost of treatment, however, can be a significant advantage in using a short-course treatment schedule. Selective utilization of either of these approaches should be based on extent of disease and goals of treatment. Patients with distal cancers or more advanced disease (T3/T4) appear to have better outcomes with neoadjuvant chemoradiation, especially where downstaging of disease is critical for more complete surgical resection and sphincter preservation. Ó 2008 Elsevier Inc. Rectal cancer, Neoadjuvant, Chemoradiation.
rates, and low pelvic recurrence rates (6–8). The significant differences in these approaches, ‘‘short- vs. long-course pre operative radiation,’’ have led to some confusion as to the most optimum approach to preoperative radiation in the management of this disease. In a recent editorial in the Journal of Clinical Oncology, Kachnic et al. (9), discussed the role of neoadjuvant therapy for T3, N0 rectal cancers. It was suggested that because there is an 18% overstaging for these cancers in spite of endorectal ultrasound staging (10) and a 22% understaging (11), a compromise approach to treatment would be to use short-course (5 Gy 5) preoperative radiation as per the Swedish (5) and Dutch (12) experiences. Kachnic et al. (9) also made an argument that short-course treatment would allow patients with positive nodes to receive adjuvant chemotherapy. Because the standard of care in patients receiving preoperative chemoradiotherapy is to administer adjuvant chemotherapy postoperatively regardless of the pathologic findings, as evidenced by the clinical practice guidelines published by the National Comprehensive Cancer Network, this argument of Kachnic et al. (9)
INTRODUCTION Neoadjuvant therapy is widely accepted as the current standard of care in the treatment of advanced rectal cancer. However, there is considerable debate regarding the best approach to neoadjuvant therapy. Early studies with preoperative radiation, although showing a consistent reduction in local recurrence rates, had failed to show a survival advantage (1–4). The Swedish Rectal Cancer Trial (5) was the first randomized study to show that a ‘‘short course’’ of preoperative radiation (5 Gy 5) alone, without chemotherapy, followed by immediate surgery, resulted in a significant improvement in 5-year survival and a reduction in the local recurrence rate for all stages of cancer. The experience in the United States has largely focused on a more protracted or ‘‘long course’’ of preoperative radiation using conventional doses of 1.8–2 Gy per fraction over 5–6 weeks, for a total dose of 45 to 50.4 Gy. Several institutional studies have reported exceptionally good survival with this more conventional approach with considerable downstaging of tumor, improved resectability
Conflict of Interest: None. Received March 17, 2008, and in revised form May 5, 2008. Accepted for publication May 12, 2008.
Reprint requests to: Mohammed Mohiuddin, MD, Geisinger Cancer Institute, 1000 East Mountain Boulevard, Wilkes Barre, PA 18711. Tel: (570) 819-5859; Fax: (570) 819-5485; E-mail: [email protected] 636
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becomes irrelevant. The question remains as to whether the short-course treatment should be considered a compromise between no preoperative radiation and the long-course treatment or whether there are pros and cons to each treatment that need to be clearly understood and appropriately used. The purpose of this review is to get a clear understanding of each of these approaches to neoadjuvant radiation for rectal cancer.
METHODS AND MATERIALS Recent literature on preoperative radiation for rectal cancer was reviewed with a particular emphasis on published randomized studies between 1996 and 2007 (Table 1). A comparison was made of the two different approaches using short-course preoperative radiation and the more conventional long-course neoadjuvant chemoradiation with regard to patient selection, clinical outcomes, and toxicities in an effort to understand the potential advantages and disadvantages of each of these approaches to adjuvant therapy in the management of rectal cancers. Short-course preoperative radiation has been delivered in the Swedish (5) and Dutch (12) trials as five fractions of 5 Gy each. The 2-Gy biologic equivalent of 25 Gy in five fractions is 37.5 Gy10 (if a/b = 10 for early effects) and 66.67 Gy3 (if a/b = 3 for late effects). The higher biologic effect in late-responding tissue with the potential for serious late complications has been a major factor in the consideration of a more conventional approach to preoperative radiation at 1.8–2 Gy per fraction to total doses of 45–55 Gy in the United States. Lower doses per fraction have also allowed for the use of
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combined chemotherapy with the radiation in the neoadjuvant setting to further maximize both local and systemic effects of treatment.
RESULTS Much of the European experience is based on the shortcourse preoperative radiation (without chemotherapy) followed by immediate surgery. The data in these studies are based on large randomized trials in which the focus has been on survival and local recurrence rates. The American experience is largely based on data from institutional studies and Phase II trials using conventional radiation plus/minus chemotherapy followed by delayed surgery. Although survival and local recurrence have been important in these studies, considerable attention has been paid to tumor downstaging to allow improved resectability and opportunities for sphincter preservation for a more improved quality of life. There has been one study undertaken by the Polish Colorectal Study Group (13) that has randomized patients to shortcourse radiation, 5 Gy x 5, in 1 week followed by immediate total mesorectal excision (TME) vs. a protracted course of 50.4 Gy in 28 fractions of 1.8 Gy per fraction plus 5-FU followed by a 4- to 6-week interval before TME surgery. The end point of the study was to determine whether sphincter preservation rates could be increased using protracted radiation with the addition of chemotherapy. Results of the study indicate that there was no difference in survival between the short-course preoperative radiation group as compared with
Table 1. Recent randomized studies of neoadjuvant radiation for rectal cancer Randomized studies
Eligibility criteria (stage/level)
Arm 1 Preop RT (5 Gy 5) + immediate surgery Preop RT (5 Gy 5) + immediate surgery (TME) Preop RT (5 Gy 5) + immediate surgery
Swedish (5)
Resectable/0–16 cm
Dutch (12)
Mobile/0–16 cm
Polish (13)
T3T4, N+/0–15 cm
German (10)
T3/T4, N+/0–16 cm
EORTC 22921 (27)
T3/T4, N+/0–15 cm
FFCD 9203 (28)
T3/T4, N+/0–15 cm
Preop RT (45 Gy) + delayed surgery
National Surgical Adjuvant Breast and Bowel Project R04 (15) Radiation Therapy Oncology Group 0012 (29)
T3/T4, N+/0–12 cm
Preop RT (50 cGy) + Xeloda oxaliplatin + delayed surgery
T3/T4, N+/0–12 cm
Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery
Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery (TME) Preop RT (45 Gy) + delayed surgery
Arm 2 Surgery alone Surgery alone (TME) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery (TME) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery Preop chemo/RT (50.4 Gy + 5-FU oxaliplatin + delayed surgery) Preop chemo/RT (50.4 Gy + 5-FU oxaliplatin + delayed surgery) Preop chemo/RT (50.4 Gy +5-FU) + delayed surgery
Abbreviations: preop = preoperative; chemo = chemotherapy; RT = radiation therapy; TME = total mesorectal excision.
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the chemoradiation group. This was a small study of 316 patients and was not powered to detect differences in survival. There was also no difference in the primary end point, which was the rate of sphincter preservation between the two groups of patients with 39% of patients undergoing abdominoperineal resection (APR) after the short-course preoperative radiation as compared to 42% in the chemoradiation arm (p = 0.57) even though tumors in the chemoradiation arm were on average 1.9 cm smaller than the tumors in the short-course radiation arm (p < 0.001). A confounding factor in the Polish Rectal Trial (14) was also that 15% of patients did not receive the assigned treatment as per protocol in the chemoradiation arm. Considering that this was a relatively small study (156 patients in each arm), it raises the question as to how posttreatment tumor assessment impacted choice of surgical approach and how valid are the conclusions based on an intent-to-treat analysis. If we assume that there was significant downstaging after the preoperative chemoradiation arm (tumors were 1.9 cm smaller than in the ‘‘short course preop’’ arm), the lack of difference in the APR rates in this study conflicts with the data from the German Rectal Cancer Trial (10) in which patients with low rectal cancers (n = 188) had twice the rate of sphincter preservation (39%) after preoperative chemoradiation as compared with surgery alone (19%, p = 0.004). It is possible that the lack of improved sphincter preservation rates in the Polish study despite documented significant downstaging raises the question of whether the Polish surgeons, who are not accustomed to the downstaging that occurs with long-course chemoradiation, were unwilling to change the planned surgery, assuring that sphincter preservation could not be improved regardless of the intraoperative findings. Bujko et al. have argued that the German study (10) was not a valid demonstration of sphincter preservation with neoadjuvant therapy, because there was an imbalance in distal tumors between the two arms, and if one considers the entire cohort of patients (rather than the subset for whom surgeons thought an APR would be needed). the rate of sphincter preservation is actually the same in both arms of the study. Although it is true that the overall APR rate in the German trial (10) was 26% in the neoadjuvant chemoradiation arm compared with 23% in the postoperative radiation arm, this may be a function of tumor location rather than the effects of chemoradiation. In contrast, almost twice the number (42%) of patients in the chemoradiation arm of the Polish study underwent an APR. In addition, 14.6% of patients in the latter study had stomas not reversed or underwent subsequent stomas for an overall stoma rate of 51.6%. This high rate of persistent stomas in the Polish study (13) raises some serious questions and, because both studies identified patients who were planned to undergo an APR as a subset to assess the impact of neoadjuvant therapy, the analysis of equivalence by Bujko et al. does not appear valid. These studies, therefore, raise more questions than they answer. To appreciate the nuances and merits of each approach to preoperative radiation, a comparative understanding of the various treatment parameters and outcomes of these studies may be helpful.
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Stage of cancer Stage of cancer is often the most significant variable in outcome of treatment. The short-course preoperative radiation studies have generally included a greater proportion of early stage tumors. All patients entered in the Swedish (5) and Dutch studies (12) were considered to have mobile or resectable cancers at initial evaluation. In the Swedish trial, 553/ 583 (90.5%) patients randomized to this arm underwent surgery. Of these patient, 181 (33%) were found to have Stage I disease, whereas 195 (35%) had Stage II, and the rest Stage III disease. If no significant downstaging occurred in these patients as a result of the short duration to surgery, the pathologic extent of tumor should represent the initial stage of cancer. Similarly, in the Dutch Rectal Cancer Trial using short-course preoperative radiation, 276/828 (33.3%) patients had early-stage disease, Stage 0 or Stage I, whereas 252 (30.4%) had Stage II disease, and the remaining 36% of patients had Stage III disease. On the other hand, in the German study (10), the group undergoing surgery followed by postoperative radiation represents a comparable distribution to the neoadjuvant chemoradiation arm in which there was only 18% with Stage I disease (Table 2). The current National Surgical Adjuvant Breast and Bowel Project R-04 (15), Radiation Therapy Oncology Group (RTOG) (16), and other multicenter trials using long-course preoperative chemoradiation have excluded early cancers (T1 and T2) and included only the more advanced stages (i.e., ultrasoundstage T3/T4 or N+ cancers). Although it is never valid to compare results across different studies, when considering the various trials of short-course radiation to those using long-course chemoradiation, it is essential to keep in mind that the short-course trials included a much larger proportion of Stage I patients. If the treatment approaches are equivalent, as suggested by the Polish experience, then the outcomes should be worse in the long-course trials because of the inclusion of patients with more advanced disease. Tumor location Tumor location in the rectum is known to be an important prognostic factor in results of treatment (17, 18). The inclusion of patients with only distal tumors in the long-course preoperative chemoradiation studies may also bias the results unfavorably in comparing outcomes in the two groups. The funnel-shaped bony pelvis limits tumor access, visualization, and mobilization in resection of distal cancers. It is also important to understand that, although the current surgical buzz word is TME, the mesorectum, in the most distal segment of the rectum, is often incomplete and lateral Table 2. Distribution of patients by pathologic stage Trials Swedish (5) Dutch (12) German (10) (surgery + postoperative therapeutic arm)
Stage I Stage II Stage III 33% 33% 18%
35% 30% 29%
32% 36% 47%
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surgical margins are limited because of proximity of other organs and or bony structures. Distal tumors also have a higher incidence of lymph node metastasis (19) making the overall prognosis much worse, 15–20% less compared to proximal cancers of the rectum (20). Patients entered into the short-course radiation in the Swedish and Dutch rectal cancer studies included tumors located between 0 and 16 cm from the anal verge. The National Surgical Adjuvant Breast and Bowel Project (21), RTOG (16), and most institutional studies of chemoradiation include patients with tumors between 0 to 10 or 12 cm from the anal verge. The differences regarding tumor location may appear small in these studies, but can substantially influence overall outcomes unless proportionate numbers of patients at each level are appropriately stratified and compared individually. Tumor location will continue to be a confounding issue in future trials especially if sphincter preservation rates are critical determining factors in selection of appropriate adjuvant therapy.
Resectability and margin status The hallmark of successful treatment of rectal cancer is not only resection of the primary tumor with negative margins (R0), but en bloc resection of the rectum within the mesorectal envelope (i.e., the TME procedure). Several studies have now documented the significant negative impact of close or positive surgical margins on recurrence rates and survival of patients (22–26). Results from the short-course preoperative radiation studies have generally suggested a lower rate of ‘‘R0’’ resections than in the long-course neoadjuvant chemoradiation studies. Ninety percent of patients in the Swedish Rectal Cancer Trial (5) underwent surgical resection after short-course preoperative radiation and the rate of ‘‘R0’’ resections was only 77.8%. Similarly, in the Dutch Rectal Cancer Trial (12), only 1,351 of 1,759 patients were found to have tumor-free margins after surgical resection for a ‘‘R0’’ resection rate of 77%. This is surprisingly low considering that all patients in both these trials were considered to have ‘‘mobile’’ or ‘‘resectable’’ cancers, and in the case of the Dutch study, were operated on by surgeons trained to perform TME and, in fact, the majority of patients (64%) in this study had early cancers (Stage I or Stage II) and only 34% had Stage III disease. In the Polish randomized study (13), 16% of patients in the short-course preoperative radiation arm had either positive distal margins (12%) or positive radial margins (4%), whereas only 4% of the patients in the chemoradiation arm had positive distal margins (p = 0.017), indicating a significantly greater downstaging and ‘‘R0’’ resection rate with chemoradiation. Although it has been shown that less than an ‘‘R0’’ resection does lead to higher recurrence rates and poorer survival, it should be remembered that where surgery is performed immediately after completing radiation, it is possible that the cells visualized at the margins are no longer viable and would not have been seen had the surgery been done 4–6 weeks later, as is the standard after long-course neoadjuvant chemoradiation.
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Table 3. Rate of non-curative resection with positive margins Trial
5 5 Gy
Swedish (5) 23% Dutch (12) 23% Polish (13) 16% German (10) — EORTC (29) — French (28) Radiation Therapy — Oncology Group (29) Rodel et al. (48) Gambacorta et al. (32) Guillem et al.(45)
50.4 Gy + chemotherapy
4%
p value
0.017
13% 14% 5% 5% 6% 2%
In contrast to the short-course radiation studies, the data from several other European and American studies indicate that curative surgery as defined by ‘‘R0’’ resection rates is higher with long-course preoperative radiation (Table 3). In a European Organization for Research and Treatment of Cancer (EORTC) study using 45 Gy plus chemotherapy, 87% of the patients had an ‘‘R0’’ resection (27). In the German study (10) of ultrasound-staged T3/T4 or N+ patients, 88% of patients receiving preoperative 50.4 Gy of radiation with chemotherapy underwent ‘‘R0’’ resection. In a similar French study (28), 86% of patients underwent ‘‘R0’’ resection and in the RTOG 0012 trial (29) including ultrasound-staged T3/T4 cancers only, 95% of the patients underwent ‘‘R0’’ resection after a higher dose of 55 Gy preoperative radiation plus infusional 5-FU chemotherapy (Table 3). This would indicate that not only in mobile, resectable cancers but especially in marginally resectable or fixed cancers, preoperative chemoradiation is likely to consistently allow for ‘‘R0’’ resection and negative margins. Sphincter preservation Historically, sphincter preservation has not been a focus of many of the European trials irrespective of whether shortcourse or long-course radiation is used. Generally, the long-course preoperative studies have reported higher sphincter preservation rates than the short-course treatment. The APR rate in the Swedish trial (5) was 58% and in the Dutch trial 35% (12). Similarly, in patients undergoing chemoradiation, the French trial (28) had an APR rate of 46% and the EORTC trial (27) a 48% APR rate. In the Polish trial (13), as mentioned earlier, the APR rate was 42%, but the rate of persistent stomas was 51.6%. The American experience has largely shown a consistent drop in the abdominoperineal resection rate with the increasing use of long-course preoperative radiation, from a high of 40+% b 1985–1986 to less than 30% by the mid-1990s (30). This has continued to drop with evolution of new stapling techniques and advances in minimally invasive surgery in other countries as well (31). The US national average would suggest that the abdominoperineal resection rate in the United States remains less than
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Table 4. Abdominoperineal resection rates European trials Swedish (5) Dutch (total mesorectal excision) (12) French (28) EORTC (27) Institutional studies Rodel et al. (48) Valentini et al. (49)
58% 35% 46% 48% 23% 12.8%
20%. Several institutional studies have reported APR rates of 9–20% even for patients with distal cancers (32–37) (Table 4). Of particular importance is that assessment of surgical options for sphincter preservation be based on posttreatment residual size and location of cancer in the rectum and not the pretreatment stage of disease, which may have influenced the sphincter preservation rates in the Polish study. Toxicity Acute toxicity is known to be considerably higher when neoadjuvant chemoradiation is used as compared with similar doses of radiation alone. Late toxicity, however, may not be influenced by the addition of chemotherapy and appears to be less with more protracted course of radiation. Acute toxicity Based on the intent-to-treat analysis in the Polish randomized study (14), there appears greater Grade 3/4 toxicity with chemoradiation (18.2%) than with short-course radiation (3.2%) (p < 0.001). In the German study (36), Grade 3 gastrointestinal-related acute toxicity was approximately 12% in the preoperative chemoradiation arm. The addition of chemotherapy with any radiation treatment has been shown to increase acute toxicity significantly. In the EORTC study (27), Grade 2 toxicity was 29.7% with radiation alone (45 Gy in 5 weeks) as compared with 38.4% with chemoradiation. Grade 3 or higher toxicity was observed in 7.4% of patients with radiation alone and 13.9% (p < 0.001) of patients with chemoradiation. One result of the greater acute toxicity with chemoradiation is that substantial numbers of patients may not receive the full planned treatment or have interruptions to treatment that could negatively impact outcomes. In the Polish study (14), 98% of the patients receiving short-course radiation, completed prescribed treatment as compared with only 69.2% of patients receiving chemoradiation. Surgical toxicity There was some increase in the postsurgical toxicity after short-course radiation in the Dutch Rectal Cancer Trial that was not seen in the German study (10) chemoradiation. There was slightly more blood loss (median 1,000 vs. 900 mL; p < 0.001) with short-course preoperative radiation and in patients who had APR 26% had perineal complications as compared with 18% with surgery alone, p = 0.05.
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Late toxicity Based on the intent-to-treat analysis in the Polish randomized study, it was reported that there was very little difference between the late toxicity of short-course radiotherapy compared with the chemoradiation arm (38). Sixteen late complications were observed in 14 patients in the short-course arm compared with 13 complications in 10 patients in the chemoradiation arm. However, the relative risk of severe late toxicity in the short course compared with the chemoradiation group was reported as 1.43 (95% CI, 0.67–3.07). Longterm data from the Swedish study (39) would indicate that patients undergoing short-course preoperative radiation experience significant ongoing problems with bowel function compared with surgery alone. Incontinence rate reported from the Dutch trial (40) of 51% was significantly higher than the 37% with surgery alone (p = 0.002). The incidence of sexual problems was also higher after short-course preoperative radiation as compared to surgery alone, 31% compared to 21% with surgery alone (p = 0.03). What was even more concerning from the Swedish Rectal Cancer Trial (41) was that long-term follow-up beyond 5 years indicates a continuing pattern of late small bowel obstructions in patients receiving the short-course radiation compared with patients undergoing surgery alone. Although these reported high rates of toxicities may be a function of more longterm follow-up in the short-course preoperative radiation studies, there has not been the same level of late toxicities reported in the EORTC trial (27) or institutional studies with long-term follow-up after long-course preoperative radiation (42). In the EORTC study, fecal incontinence was only 9% and anastomotic stricture formation was 1.4% after chemoradiation. Local recurrence Although it is difficult to compare the local recurrence rate between the different studies and treatment techniques, both approaches appear to reduce the recurrence rate for various stages of cancer by 50%. The Swedish Rectal Cancer Trial (5), which predated the TME era, had a local recurrence rate of 40% for Stage III disease with surgery alone and 20% after short-course preoperative radiation and surgery. In contrast, the German Rectal Cancer Trial (10) using chemoradiation had a local recurrence rate of 21.5% with surgery (TME) and postoperative radiation compared with 11.2% (p < 0.001) with preoperative radiation for Stage III cancers. However, the data from the Dutch TME trial (43) indicates that the true benefit of the short course of radiation in terms of local recurrence occurred only in the subgroup of patients with mid-rectal tumors located 5–10 cm from the anal verge. There was no improvement in local recurrence rates for distal cancers between 0 and 5 cm or in the more proximal cancers between 10 and 15 cm (Table 5). This may be reflected in the fact that total mesorectal excision could only be performed on 65% of the patients with distal cancers between 0 and 5 cm, 85% of the patients with cancers between 5 and 10 cm, and 100% of the patients with cancers between 10 and 15 cm.
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Table 5. Dutch TME Rectal Cancer Trial: distance of tumor vs. local recurrence Distance from anal verge
0–5 cm
5–10 cm
10–15 cm
65% 85% 100% Curative resection (total mesorectal excision) 13% 15% 11% Local recurrence— surgery alone 15% (p = 0.122) 7% (p = 0.001) 7% (p = 0.578) Local recurrence— preoperative radiation therapy + surgery
The value of the short-course radiation approach, therefore, may be greatest where reasonable TME surgery can be performed with negative but somewhat limited circumferential margins as in the mid-rectum, but may not be sufficient in distal cancers where surgical margins of a necessity are limited. The radiation dose may not be adequate to obtain sufficient tumor regression to provide safe margins of resection where TME is most difficult or inadequate. In the proximal rectum, where surgical access is relatively easier and wide margins of resection are likely, shortcourse radiation may provide limited or no benefit. Data from long-course chemoradiation studies suggest that its greatest benefit may be in improving results in the most distal cancers where the mesorectum may be incomplete (34). Analysis of the German Rectal Cancer Trial (44) highlights the importance of adequate radiation dose for optimum results. Patients in this study who did not receive radiation had a 29.6% local recurrence rate, and those that received inadequate radiation (<43 Gy), a 21.2% local recurrence as compared to 6.6% in patients receiving adequate radiation (p = 0.0001) This also translated into a significant difference in disease free survival (55% with no radiation
Table 6. Neoadjuvant therapy for rectal cancer Study Swedish trial (5) Danish trial (12) Radiation Therapy Oncology Group trial (27) French trial (28) German trial (10) Radiation Therapy Oncology Group trial (29) Guillem et al. (45) Cocco et al. (46) Shivnani et al. (47)
Treatment
5-y survival
5 Gy 5 5 Gy 5 45 Gy + chemotherapy
54% 63% 65%
50 Gy + chemotherapy 50.4 Gy + chemotherapy 55 Gy + chemotherapy
67% 74% 76%
50.4 Gy +chemotherapy 50.4 Gy + chemotherapy 55 Gy + chemotherapy
76% 76% 81%
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therapy, 57% with inadequate radiation therapy, and 69% with adequate radiation therapy). It is therefore possible that the difference in treatment compliance of only 70% in the chemoradiation group to 98% in the short-course radiation group could have accounted for a lack of difference in the local recurrence and survival in the two arms of the Polish trial (14). Survival In spite of including a generally more favorable cohort of patients in the short-course preoperative radiation studies, the reported survival in the chemoradiation studies appears higher. The Swedish Rectal Cancer Study (5) reported a 5year survival of 54% in ‘‘resectable’’ rectal cancer, but it predates the era of TME surgery and modern imaging. The Dutch study (12) reported a 5-year survival of 63% with a short course of preoperative radiation and TME in ‘‘mobile’’ rectal cancers. These results were similar to survival reported in the EORTC study (27) and the French study (28) (65%) after long-course chemoradiation. However, the 5-year survival in the German Rectal Cancer Trial (10) with preoperative chemoradiation was reported as being 74% and in the RTOG 0012 study (28) was 76%. Several institutional experiences indicate a survival outcome that is even higher, ranging from 78% to 81% (Table 6). These current trends in survival improvements with long-course preoperative radiation especially for distal and advanced cancers have established new benchmarks that may be more difficult to achieve with short-course preoperative radiation approaches alone. Whether all of the benefit of the long-course chemoradiation is due to tumor downstaging and higher frequency of negative margins or due to the systemic effects of chemotherapy is not altogether clear, but from the postoperative adjuvant therapy experience (50), it is reasonable to expect that there is both a local and a systemic benefit with the addition of chemotherapy. It is this survival advantage with the increasing option for sphincter preservation that has led several of the ongoing national trials both in Europe and the United States opting for the use of more conventional dose–time fractionation of radiation with chemotherapy. The focus has shifted to intensifying the neoadjuvant regimen by using a multidrug approach with the addition of oxaliplatin, irinotecan, or molecular-targeted agents to the 5-FU regimen. As newer and more intensive neoadjuvant treatments evolve, both the efficacy and shortand long-term toxicity will need to be continuously and carefully evaluated as newer toxicities such as the long-term neuropathy of oxaliplatin-containing regimens may result in a compromised quality of life compared with preoperative radiation alone either as a short- or long-course treatment. CONCLUSION On the basis of this review, it is clear that neoadjuvant therapy should not be considered as a ‘‘one size fits all’’ approach. Short-course preoperative radiation may be a valuable treatment option for patient convenience, cost reduction, and in patients with a short life expectancy because of age or
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comorbidities and thus unlikely to experience late complications or those patients who are unable to participate in a more prolonged course because of other barriers such as transportation or compliance issues. In some early cancers (T2) located in the mid-rectum (5–10 cm), it may be effective in reduction of local recurrence, but it does not appear appropriate for T3 or more advanced cancers. Optimum multifield radiation techniques to limited treatment volumes (10 10
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cm or smaller to the true pelvis), must be used to minimize late toxicity. For all distal rectal cancers and all T3 or higher staged cancers in the mid- to proximal rectum, the conventional approaches with 1.8–2 Gy per fraction with careful attention to total dose, combined with multiagent chemotherapy may yield greater downstaging, improved ‘‘R0’’ resection rates, sphincter preservation, low recurrence rates, and most significantly provide substantial improvement in survival.
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