Can Pelvic Radiotherapy Be Omitted in Select Patients With Rectal Cancer?

Can Pelvic Radiotherapy Be Omitted in Select Patients With Rectal Cancer? Lily L. Lai,a Clifton D. Fuller,b,d Lisa A. Kachnic,c and Charles R. Thomas, Jrd Randomized prospective trials have shown the benefits of adjuvant radiotherapy in decreasing local recurrence rates in stage II and stage III rectal cancer. However, some patients with stage II lesions have relatively low risks of local recurrence when treated with modern surgery alone. This article will discuss important prognostic, diagnostic, and therapeutic factors including depth of tumor invasion, tumor location, improvements in staging with endorectal ultrasound and magnetic resonance imaging, enhanced surgical technique with total mesorectal excision, circumferential tumor margin, and lymph node dissection that may help to better define a subset of stage II rectal cancer patients in which pelvic radiation may be safely omitted. Semin Oncol 33(suppl 11):S70-S74 © 2006 Elsevier Inc. All rights reserved.

O

f the new cases of colorectal cancer (CRC) that will be diagnosed in the United States in 2006, one third of those cases are rectal in origin. With the advent of novel cytotoxic and targeted systemic treatments, the overall survival of patients with CRC is an estimated 60% at 5 years. While the biology, development, and progression of colon and rectal cancer are similar, the anatomic considerations between the intraperitoneal colon and the extraperitoneal rectum account for different patterns of failure between the two diseases. The pelvic enclosure of the rectum is a physical challenge in the resection of the cancer. In addition, the lack of serosa, as well as the close and fixed proximity of structures in the pelvis, predispose rectal cancer to local recurrences. Consequently, emphasis in the adjuvant treatment for rectal cancer has centered on locoregional control, in comparison to the focus on preventing distant recurrence, when treating extra-pelvic colon cancer. In rectal cancer, rates of locoregional relapse (LRR) are, in large part, a function of tumor depth of invasion (T stage) and spread of cancer to lymph nodes (N stage). Because of the less than 5% risk of LRR for T1 lesions (or Dukes’ A) after definitive surgical resection, adjuvant radiation and chemoradia-

aDivision

of Surgery, City of Hope National Medical Center, Duarte, CA. of Radiation Oncology, University of Texas HSC, San Antonio,

bDepartment

TX. cDepartment

of Radiation Oncology, Boston Medical Center, Boston, MA. of Radiation Medicine, Oregon Health & Science University, Portland, OR. Address reprint requests to Charles R. Thomas, Jr, MD, Department of Radiation Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, MC L337, Portland, OR. E-mail: thomasch@ ohsu.edu dDepartment

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0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2006.10.019

tion are not routinely offered in this subgroup of patients.1 Without adjuvant therapy, surgery alone in lesions with mural wall invasion (T3, T4, or Dukes’ B) and or lymph node involvement (Dukes’ C) results in LRR rates of approximately 50%.2 The use of radiation as adjuvant therapy in this patient population to reduce the risk of local recurrence was formally tested in a number of randomized, prospective trials in the United States and in Europe, completed in the 1980s. In almost all instances, either with or without chemotherapy, and either pre- or post-operative, the addition of radiation significantly reduced LRR to 8% to 14% and did not affect overall survival (Table 1). Based on these findings, adjuvant chemoradiation with systemic chemotherapy is currently recommended for patients diagnosed with stage II–III rectal cancer. While the use of radiation and chemoradiation is successful in reducing the LRR rates for patients with stage II and III disease, it is associated with significant morbidity and costs. Treatment-related death rates are higher (range, 2% to 8%) in patients treated with adjuvant radiation and chemoradiation than with surgery alone (⬍1% to 2%),3 as are acute effects including radiation enteritis, ileus, diarrhea, bowel obstruction, wound healing problems, and hematologic toxicities.4-6 Approximately 60% to 81% of all patients on multimodality treatment will have at least a grade 3 toxicity during therapy.7 In addition, functional anorectal outcome such as the number of bowel movements per day, fecal continence, and sexual function have been shown to be worse in patients receiving radiation.8-11 Prospective trial data indicate that LRR risk for stage II or Dukes’ B patients not treated with radiotherapy ranges from

27

<.001 .02

<.01 .036

.02

S71 Table 2 Stage II (Dukes’ B) Local Regional Recurrence (LRR) Rates in Prospective Adjuvant Radiation Trials

8

N/A N/A

13.5

Study Odense5 Uppsala35

LRR (%) Surgery Alone

LRR (%) ⴙ Radiation (%)

B B

16

B II

37 22

16 Preop: 9.7 Postop: 20 16 6

Stage

13 11 27 Pre Post 5-FU None 5-FU/semustine Vincristine (MOF) or 5-FU/LV 25 Gy/5 Gy 5040 Gy/ 1.8 Gy 156 93

53 84 849 204 Stockholm I3,4 NCCTG36

1,168 694

23 Pre Post Pre Post None None None 5-FU Sequential 5-FU/ semustine 25.5 Gy/5 Gy 60 Gy/1.8 Gy 25 Gy/5 Gy 50 Gy/1.8 Gy 72 471 Uppsala35

Swedish RCT17,37 NSABP R0238

12 21 11 25

21 16 15 16 18 30 25 Post Pre Post None None None

None None 5-FU/semustine/ vincristine (MOF) None None None None 494 341 555 Odense5 EORTC33 NSABP R0134

24 60 60

227

80

40-50 Gy/ 180-200 cGy 50 Gy/2 Gy 34.5 Gy/2.3 Gy 50 Gy/1.8 Gy

5-FU/semustine

5-FU

Post

24

20

Stockholm I3 Swedish Rectal Cancer Trial17

GITSG32

Pre/Post Chemotherapy Radiation Follow-Up (mos) No. of Patients Study

NS .003 .06

.009 11

LRR (%) ⴙChemotherapy LRR (%) ⴙRadiotherapy

LRR (%) ⴙRadiotherapy and Chemotherapy LRR (%) Surgery Alone Concurrent Chemotherapy and Radiation

Table 1 Local Failure in Phase III Trials of Resection and Adjuvant Chemoradiation in T3 and/or N1–2 Rectal Cancer

P Value

Omitting Pelvic Radiotherapy for CRC?

16% to 37% (Table 2). Pre- or post-operative radiation significantly decreased recurrence rates in most of the trials in stage II (Dukes’ B) patients. In one trial, there was no difference in recurrence rates between the surgery alone versus the surgery and radiation groups.6 These data argue for multimodality treatment for all patients with stage II rectal cancer. However, these older trials were conducted and completed in an era of limited imaging modalities for accurate staging and less than optimal surgical resection techniques. More contemporary rectal trials suggest there may be groups of patients who have favorable disease and may not require adjuvant chemoradiation. In the Intergroup 0114 study, pathologic stage II and III rectal cancer patients were randomized to one of four different postoperative chemoradiation regimens with 5-fluorouracil, leucovorin, and/or levamisole. There was no significant difference in survival outcome between the treatment groups. The study noted locoregional recurrence rates at 5 years of 7% for the low-risk group (T1-2 N⫹ or T3NO) versus 18% for the high-risk group (T3N⫹ or T4). These authors suggest that in certain low-risk lesions, adjuvant chemoradiation to the pelvis may not be required.12 Recent analysis of the phase III North-American rectal cancer trials showed independent prognostic significance of each TN category of resected rectal cancer and supports the value of substaging beyond the standard stage II and III categories.13 In these analyses, three risk groups of patients were defined: intermediate (T1-2N1, T3N0), moderately high (T1-2N2, T3N1, T4N0), and high (T3N2, T4N1, T4N2). Stage II patients with a single high-risk factor (such as T3N0) had better disease-free survival and local control than patients with other categories of stage II disease. Surgery and chemotherapy, without radiation, for these patients resulted in a 5-year overall survival rate of approximately 85%. Therefore, the use of trimodality therapy (surgery plus radiation and chemotherapy) for all T3N0 stage II patients may be excessive in consideration of the associated treatment-related morbidities. Important prognostic, diagnostic, and therapeutic factors including depth of tumor invasion into the perirectal fat, tumor location, localized staging with endorectal ultrasound and magnetic resonance imaging (MRI), surgical technique with total mesorectal excision (TME), circumferential tumor margin, and lymph node dissection may help to define a subset of T3N0 patients in which pelvic radiation may be safely omitted.

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Minimal Depth of Tumor Invasion into the Perirectal Fat The need for radiation for T3 lesions has been evaluated in retrospective data sets. Willett et al14 analyzed the prognostic factors predictive of local recurrence in T3N0 rectal cancer patients who had undergone classic, non-TME, low anterior resection, and had not received adjuvant radiotherapy or chemotherapy. The population studied had an overall 10year local recurrence rate of 20%. On multivariate analysis, depth of invasion into the perirectal fat was predictive of local recurrence. Local recurrence rate was 7% in patients who had a T3 lesion with less than 2 mm of perirectal fat invasion, which was lower by a factor of three or more as compared with lesions with more than 2 mm of invasion into the perirectal fat. In addition to depth of invasion into the perirectal fat, differentiation and vascular invasion were predictive of overall disease outcome.14

Tumor Location in the Upper Rectum Location of the rectal cancer also affects the likelihood of local recurrence. The Cleveland Clinic (Cleveland, OH) evaluated 891 patients treated with curative intent from 1980 to 1990. The rectal cancers were stratified as upper rectal if located within 10 to 15 cm from the anal verge and low rectal if located less than 10 cm from the anal verge. Local recurrence rates at 5 years were 7.5% in the upper rectal group compared with 21.5% in the lower rectal group (P ⬍ .01). Multivariate analysis confirmed that the location of cancer predicted clinical outcome.15 Other studies have confirmed that upper rectal cancers have lower locoregional recurrence rates.16-18

Improved Localized Staging With Endorectal Ultrasound and Magnetic Resonance Imaging If local recurrence rates of T3 rectal cancers in the upper rectum with minimal, less than 2 mm invasion of the perirectal fat, are less than 7%, then perhaps radiation to this selected group of T3 cancers may be safely omitted. However, critical to this assessment and treatment plan is the ability to accurately image the lesion, stage the primary tumor and the nodes, and determine the level of tumor invasion. To this end, the development and use of endorectal ultrasound and MRI in accurately staging rectal cancer may support selective use of radiation. Endorectal ultrasound has been compared with computerized tomographic scanning and shown to have greater sensitivity and specificity in staging rectal cancer. Accuracy in determining depth of tumor invasion is greater than 90% and involvement of lymph nodes with cancer is approximately 80%.19-22 Limitations noted with the use of endorectal ultrasound, as is the case with all ultrasound diagnostic modali-

Lai et al ties, are user reproducibility and the steep learning curve. This variability decreases with user experience.20 MRI technology also continues to evolve with increasing ability to stage rectal cancers. T2-weighted images generated with the aid of a specific surface coil can reveal the critical relationship of the primary tumor to the mesorectal fascia and other structures of the pelvic floor. To further clarify the role of MRI as a pre-treatment staging adjunct, the Magnetic Resonance Imaging and Rectal Cancer European Equivalence Study (MERCURY) was undertaken to show the equivalence of MRI and histopathologic assessments of extramural depth of tumor spread within the mesorectum. Secondary study endpoints were to assess predicted circumferential resection margin (CRM) positivity rate using preoperative MRI; develop a surgical assessment technique for excision of low rectal cancer based on pelvimetry and assessment of the mesorectal size and tumor height; evaluate the reproducibility of high-resolution pelvic phased-array body-coil MRI in multiple facilities and assess inter-/intra-observer variation in reporting; and evaluate overall utility of MRI in the staging of tumors encroaching the anal canal. Full results of the MERCURY study have yet to be reported. However, preliminary results reported at the 2005 American Society of Colon and Rectal Surgeons meeting noted an 82% agreement (266/325; 95% confidence interval [CI], 77%85%) between MRI and histopathologic assessment of CRM status when MRI defined CRM involvement as a tumor with ⱕ 1 mm extension into the mesorectal fascia. Increasing the cut-off to 2 mm worsened accuracy to 61% (200/325; 95% CI, 56%-67%). The finding that MRI accurately predicts CRM status if a cut-off of 1 mm is used indicates that it can be an effective tool for the pre-operative identification of patients at risk of incomplete resection following TME surgery. Analysis of agreement among 295 patients showed mean depths of tumor invasion beyond the bowel wall of 2.77 mm with high spatial resolution MRI and 2.81 mm with histopathology (difference, ⫺0.046 mm; 95% CI, 0.487-0.395), respectively, indicating equivalence of the approaches in assessing depth of extramural invasion. The findings from MERCURY suggest that MRI may play an increasingly accurate role in the identification of patients who may not require combined-modality adjuvant therapy.23

Improved Surgical Technique With Total Mesorectal Excision The high risk of pelvic relapse after radical surgical resection alone for stage II and III rectal cancer mandated the addition of radiotherapy, as confirmed in prospective trials. As such, radiation was considered “salvage” for inadequate surgery. Before the description of TME by Heald and Ryall in England,24 and popularization of the technique by Enker et al25 in the United States about two decades ago, most colorectal surgeons practiced and taught blunt dissection of the rectum. After the sigmoid mesentery was mobilized and sigmoidal vessels were ligated, mobilization of the rectum was completed using blunt dissection with hands extended into the

Omitting Pelvic Radiotherapy for CRC?

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Table 3 Local Recurrence Rates (LRR) by Positive or Negative Circumferential Resection Margin Status Study

TME

No. of Patients

Median Follow-Up (mos)

Margins

LRR (%)

al39

No

52

23

Adam et al40

No

190

60

Hall et al41

Yes

152

41

Garcia-Granero et al30

Yes

225

43 (range, 14–132)

Positive Negative Positive Negative Positive Negative Positive Negative

85 3 78 10 15 10 28 3.3

Quirke et

Abbreviation: TME, total mesorectal excision.

pelvis. Much of the dissection was performed blindly and by palpation only. Because of the anatomy and lymphatic drainage peculiar to the rectum, this approach resulted in high rates of positive margin resection as well as leaving unresected, potentially involved lymph nodes. The initial description of the TME operation is well described by Heald and Ryall24 as a procedure that “requires painstaking downward development of the avascular plane between visceral structures (rectum and mesorectum) and somatic structures (autonomic nerve plexuses; sympathetic above and parasympathetic below). Sharp scissor dissection under direct vision is used throughout and conventional manual extraction is avoided in the belief that tearing into fragile tumor planes may compromise clearance of the cancer.” The dissection is carried to the end of the mesorectum, the fibrofatty tissue containing the lymphatics and lymph nodes draining the rectum and invested by the visceral fascia, at about the level of the levator muscles. The rectum and mesorectum are transected at this level and the proximal colon is anastomosed to the residual rectal cuff. This approach consists of complete resection of the rectum and mesorectum and permits separation of the visceral structures and the somatic structures including identification and preservation of the hypogastric nerves. Hypogastric injury results in genitourinary dysfunction. The use of TME has markedly reduced the rate of urinary retention, retrograde ejaculation and erectile dysfunction in patients who undergo definitive surgical resection.26 Multiple surgical series in Europe and the United States have documented institutional experiences with implementing TME resections for surgical treatment of rectal cancer. In all cases, the rate of local recurrence has decreased to less than 10% with surgery alone.24,25,27-29

Impact of TME on Circumferential Margin and Lymph Node Resection Histologic factors confirm the “belief” stated above; that is, keeping the “fragile tumor planes” intact reduces positive margin resections and ensures removal of perirectal lymph nodes, both critical factors in the determination of local relapse. To identify the circumferential margin, the pathologist evaluates the outer circumference of the rectal and mesorec-

tal specimen. This is often completed by inking the outer surfaces and bread-loafing the entire specimen, especially through the tumor. The extension of local invasion of the tumor through the rectal wall and perirectal fat (mesorectum) is described. Importantly, any involvement of the circumferential margin is recorded. Table 3 is a summary of studies evaluating the effect of positive circumferential, or radial, margins on local disease recurrence. Local recurrence rates are ⱕ10% when the circumferential margin is negative, while positive margins result in local recurrence rates up to 85%. In the recent study by Garcia-Granero et al30 using TME without adjuvant therapy in 225 consecutive patients, local recurrence occurred in 28% of patients with positive margins, and 3.3% of those with negative margins. Most local recurrences occurred within 24 months, at which time the actuarial recurrence rate was 5.2%. On multivariate analysis, independent risk factors for local recurrence were CRM involvement (P ⫽ .005; hazard ratio ⫽ 10) and tumor perforation (P ⫽ .025; hazard ratio ⫽ 9.9).30 In addition, the intact resection of the mesorectum ensures that all perirectal lymph nodes are removed. Studies have documented that local recurrence rates inversely correlate with the number of lymph nodes resected. For example, in a study reported by Pocard et al,31 resection of 0 to 4, 5 to 9, and more than 10 nodes was associated with recurrence rates of 0%, 8%, and 0%, respectively, among 37 patients with T1 or T2 disease, and 50%, 43%, and 10%, respectively, among 44 patients with T3 or T4 disease.31

Conclusion For carefully selected patients with upper T3N0 lesions (TNM stage IIA), it may be appropriate to omit pelvic radiation if careful pathology evaluation suggests a low risk of local recurrence (minimal perirectal fat invasion, negative circumferential margins, adequate node dissection) after a confirmed TME by an experienced surgeon.

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