Chiaojung Jillian Tsai • Christopher H. Crane • Prajnan Das
Rectal Cancer – Highlights
Key Recent Clinical Studies
Samuelian et al. (IJROBP 2012) reported significantly less grade 2 toxicity in patients treated with IMRT compared to those receiving conventional radiotherapy. (PMID 21477938)
Garofalo et al. (IJROBP 2011) reported preliminary results of RTOG 0822, a phase II study of concurrent chemotherapy with IMRT, and demonstrated feasibility of rectal IMRT and adequate tumor coverage based on the pathologic complete response rate. (ASTRO abstract)
New IMRT Treatment Options
FIGURE 16-3. Treatment plan of a patient with T4N1 rectal cancer with biopsy-proven inguinal nodal involvement. IMRT was used to treat the gross endorectal tumor and involved inguinal node with a dose of 50 Gy in 25 fractions. Surrounding lymph node regions including the mesorectal, internal iliac, external iliac, presacral, and bilateral inguinal regions were treated with a dose of 45 Gy in 25 fractions.
(Left panel from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:115.)
• The rectum is located anterior to the lower sacrum, and extends from the rectosigmoid junction at the level of the third sacral vertebrae to the puborectalis ring. It is approximately 12 to 15 cm long, and is divided into three parts based on the distance from the anal verge.
• The upper third of the rectum is deep in the pelvis and is covered with peritoneum anteriorly and bilaterally. The middle third of the rectum is covered by the peritoneum anteriorly, and the lower third of the rectum is subperitoneal without peritoneal covering.
2. NATURAL HISTORY
2.1. Lymphatic Drainage
• Rectal cancer drains to perirectal, presacral, obturator, and internal iliac nodes. The upper half of the rectum drains to the perirectal and inferior mesenteric nodes.1,2
3. DIAGNOSIS AND STAGING SYSTEM
3.1. Signs and Symptoms
• The majority of patients present with rectal bleeding, hematochezia, mucous in the stool, change of bowel habit, and signs of rectal obstruction such as decreased stool caliber, diarrhea, constipation, incomplete emptying of the stool, and tenesmus.
• In patients with posterior extension of the disease, urinary symptoms and perineal pain can occur. Tumor invasion of sciatic notch can cause sciatic pain.2
3.2. Physical Examination
• In addition to complete history including family history of colorectal cancers and personal history of polyps, thorough digital examination of the rectum to evaluate the size, mobility, location, diameter of rectal lumen, and any ulceration of the tumor is warranted.
• Assessment of sphinter tone and function is also important for selecting candidates for sphincter preservation.
• For female patients, gynecologic exam is helpful to rule out other sites of disease origins.
• Sigmoidoscopy and proctoscopy provide direct visualization, allow biopsy of the lesion, and help evaluate the extent of obstruction and disease distance from anal verge. Colonoscopy should be done to look for synchronous lesions in the large bowel.2
• The main imaging tools for rectal cancer are endorectal ultrasound (EUS), computed tomography (CT) of the chest, abdomen, and pelvis, and magnetic resonance imaging (MRI) of the pelvis.
• Either EUS or MRI can be used to determine the T and N classification. CT can be used to evaluate nodal involvement and metastatic disease.
• The American Joint Committee on Cancer issued new staging guidelines in 2010.3 Changes include new subdivisions in stages II and III as well as the splitting of T4 into T4a and T4b lesions. Readers are strongly urged to consult the new manual for these and other changes.
4. PROGNOSTIC FACTORS
• Stage: Clinical and pathologic T and N categories are important prognostic factors.4 Tumors that are further away from anal verge are more favorable compared to more distal tumors.
• Treatment-related and Surgical Factors: Favorable response to neoadjuvant chemoradiation is associated with longer disease-free survival.5 The circumferential resection margin or radial margin is significantly associated with rates of local recurrence and overall survival. The number of lymph nodes examined is associated with disease-free survival among node-negative patients.
5. GENERAL MANAGEMENT
• For early-stage rectal cancer (T1-2, N0), surgery alone is usually recommended. For patients with resectable tumors invading beyond the bowel wall (T3-T4), and/or nodal involvement, combined modality therapy including preoperative chemoradiation therapy with infusional 5-FU (5-fluorouracil) or capecitabine followed by total mesorectal excision and adjuvant chemotherapy is recommended.
• Treatment needs to be individualized for patients with metastatic disease. Depending on the clinical situation, these patients may need any or all of the following: chemotherapy, surgery for the primary, surgery for the metastasis, and radiation therapy.
5.1. Surgical Management
• Common sphincter-preserving operations are local excision and low anterior resection. Abdominoprineal resection is a nonsphincter-sparing procedure typically reserved for distal tumors close to the anal verge.1
• Local excision, usually through a transanal approach, can be considered for selected T1N0 rectal cancers.
• Total mesorectal excision is now accepted as a standard of care for rectal cancer. Complete removal of the mesorectal fat and lymph nodes enhances local control.
5.2. Combined Modality Treatment
• Preoperative chemoradiation therapy combined with total mesorectal excision followed by postoperative chemotherapy is recommended for T3-T4 tumors or those with positive lymph nodes.
• Postoperative irradiation can be used for those with clinical T1-2 N0 disease but later found to have more advanced pathologic stage after surgery.
5.3. Radiation Therapy
• Preoperative chemoradiation therapy has the advantage of downsizing the tumor and making sphinter preservation more feasible, especially for distally located lesions. Preoperative chemoradiation also offers better local control, toxicity, and sphincter preservation compared with postoperative chemoradiation therapy.6 The common preoperative radiation dose is 45 Gy to the pelvis plus a boost of 5.4 Gy to the tumor, involved nodes, and adjacent pelvic and presacral regions.
• A shorter course of preoperative radiation therapy consisting of 25 Gy in 5 daily fractions has also been shown to improve local control and survival compared to surgery alone.7,8
• Postoperative radiation therapy typically uses a dose of 50.4 to 54 Gy (45 Gy to the pelvis plus a 4.5 to 9 Gy boost to the tumor bed).
• The commonly used agent for concurrent chemoradiation therapy is bolus or infusional 5-FU. Capecitabine, an oral prodrug that is metabolized to 5-FU, has been shown to be equivalent to 5-FU and is now accepted as an appropriate choice for concurrent chemotherapy.9
• For patients with stage II–III rectal cancer, adjuvant chemotherapy with a 5-FU-based regimen is recommended. Additional chemotherapy with oxaliplatin has been shown to improve disease-free survival and overall survival in colon cancer patients.10
6. INTENSITY-MODULATED RADIATION THERAPY IN RECTAL CANCER
6.1. Special Indications
• Intensity-modulated radiation therapy (IMRT) could potentially reduce radiation dose and toxicity to small bowel and other normal structures. This may be especially important in selected patients who have a large volume of small bowel near the target volume.
• IMRT could potentially be used for dose escalation and for boosting selected nodal regions (e.g., inguinal nodes or internal iliac nodes) in selected patients.
6.2. Target Volume Determination
• Gross tumor volume (GTV) for rectal carcinoma is the volume seen on CT, MRI, and/or endoscopy. The GTV should include any involved nodes.
• The mesorectal, presacral, and internal iliac regions should be always included as part of the elective nodal target.
º The external iliac regions should be included for T4 tumors with invasion of anterior structures.
º Consideration should be given to including the inguinals for ultra low rectal cancers.
6.3. Target Volume Delineation
• RTOG has published consensus guidelines and an atlas for contouring the elective clinical target volume (CTV) for rectal cancer.11 For rectal cancers, the nodal volume should always include the mesorectal, presacral, and internal iliac regions. The external iliac region should be included in the nodal volume for T4 rectal cancers with invasion of anterior structures, such as the bladder, prostate, cervix, and vagina. The inguinal region may be included in the nodal volume for selected ultra low rectal cancers. The boost volume should include the primary rectal tumor, involved nodes, and adjacent pelvic and presacral regions.
• Figure 16-1 shows GTV and CTV target delineation for a patient with T3N2 rectal cancer with suspicious internal iliac and para-aortic nodes. IMRT was used to include the para-aortic area in the treatment field.
• Figure 16-2 shows the treatment plan for a patient with T3N1 rectal cancer with biopsy-proven inguinal nodal involvement. IMRT was used to treat the inguinal nodes to 63 Gy.
• Figure 16-3 shows the treatment plan for a patient with T4N1 rectal cancer with biopsy-proven inguinal nodal involvement. IMRT was used to treat the inguinal nodes to 50 Gy.
• Figure 16-4 shows the target delineation for a patient with T4N1 rectal cancer treated with neoadjuvant chemoradiation. IMRT was used to deliver a dose of 54 Gy in 30 fractions with a simultaneous integrated boost to 60 Gy to the interface of the tumor with the pelvic sidewall.
6.4. Intensity-Modulated Radiation Therapy Results
• Ballonoff et al.12 conducted a phase II single-institution trial of eight patients with stage II and III rectal cancer treated with preoperative IMRT with accelerated simultaneous integrated boost (55 Gy in 2.2-Gy fractions to the rectal tumor and 45 Gy in 1.8-Gy fractions) to the regional lymphatics and concurrent capecitabine followed by total mesorectal excision. The study showed a complete pathologic response rate in three of eight patients. One of the patients had grade 4 diarrhea but no other patient had grade 3 or higher toxicity.
FIGURE 16-1. Gross tumor volume (GTV) and clinical target volume (CTV) delineation in a patient with T3N2 rectal adenocarcinoma with positive internal iliac and para-aortic nodes. GTV, red color wash; CTV50Gy, blue color wash; CTV45Gy, green color wash; bladder, yellow color wash. (A) Rectal GTV and CTV50Gy covering the presacral and internal iliac nodal stations as well as the posterior bladder. (B) CTV45Gy covering the para-aortic nodal region.
FIGURE 16-2. Treatment plan of a patient with T3N1 rectal cancer with biopsy-proven inguinal nodal involvement. The involved inguinal nodes as well as suspicious bilateral inguinal nodes were treated with a dose of 63 Gy in 28 fractions. The rectal tumor and enlarged perirectal and superior hemorrhoidal nodes were treated with 50.4 Gy in 28 fractions. The elective nodal regions (the mesorectal, presacral, internal/external iliac, and bilateral inguinal areas) were treated with a dose of 47 Gy in 28 fractions. GTV inguinal nodes, red color wash; CTV63Gy, blue color wash; GTV rectum, light blue color wash; CTV50.4Gy, green color wash; CTV47Gy, orange color wash.
FIGURE 16-3. Treatment plan of a patient with T4N1 rectal cancer with biopsy-proven inguinal nodal involvement. IMRT was used to treat the gross endorectal tumor and involved inguinal node with a dose of 50 Gy in 25 fractions. The surrounding lymph node regions including the mesorectal, internal iliac, external iliac, presacral and bilateral inguinal regions were treated with a dose of 45 Gy in 25 fractions. GTV rectum and node, red color wash; CTV50Gy, blue color wash; CTV45Gy, green color wash.
• A prospective trial conducted by De Ridder and colleagues13 included 24 T3/T4 rectal cancer patients, who were treated with preoperative IMRT to 46 Gy in 23 fractions using helical tomotherapy, with a simultaneous integrated boost of 55.2 Gy to the tumor in patients with a narrow circumferential resection margin. The metabolic response rate was 45% in the no-boost group as compared with 77% in the boost group. Only one grade 3 or higher toxicity (enteritis) was reported.
• Aristu and colleagues14 reported a phase I/II trial of preoperative hypofractionated IMRT with concurrent oxaliplatin and capecitabine in 20 patients. The radiation dose was increased from 37.5 to 42.5 Gy and then to 47.5 Gy maximum, all in 2.5-Gy fractions. Pathologic complete response was achieved in four (20%) patients; however, grade 3 diarrhea occurred in two (10%) patients and grade 2–3 proctitis occurred in eight (40%) patients.
• Samuelian et al.15 conducted a retrospective study to compare 31 patients treated with IMRT and 61 patients treated with conventional three-field radiotherapy. The rate of grade 2 or higher acute gastrointestinal toxicity was 32% among patients treated with IMRT and 62% among patients treated with conventional radiotherapy (P = 0.006). The rate of grade 3 acute toxicity was 3% in patients who received IMRT and 10% in patients who received conventional radiotherapy.
FIGURE 16-4. GTV and CTV delineation in a patient with T4N1 rectal adenocarcinoma with tumor involvement of the right pelvic sidewall and the sacrum. IMRT was used to treat the region of fixation to the sacrum and right pelvic side wall with a dose of 60 Gy in 30 fractions. The remainder of the rectal tumor and enlarged lymph nodes were treated with a dose of 54 Gy in 30 fractions. The other pelvic nodal regions including the mesorectum, presacral, and internal iliac areas were treated to a dose of 50 Gy in 30 fractions. GTV60Gy, orange color wash; GTV54Gy, red color wash; CTV54Gy, blue color wash; CTV50Gy, green color wash; bladder, yellow color wash.
• RTOG Trial: The Radiation Therapy Oncology Group (RTOG) has completed a phase II trial (RTOG 0822 of preoperative IMRT with concurrent capecitabine and oxaliplatin for cT3-T4, N0-N2 nonmetastatic adenocarcinoma of the low-mid rectum.16 Patients were treated with pelvic IMRT to 45 Gy in 25 fractions, followed by a three-dimensional (3D) conformal boost to deliver an additional 5.4 Gy in 3 fractions. Their toxicities were compared with a group of historic controls from RTOG 0247 in which the patients were treated with 3D radiation therapy and the same regimen of preoperative chemotherapy. A total of 35 out of 68 patients in the RTOG 0822 group developed ≥grade 2 preoperative gastrointestinal toxicity (25% grade 2, 22% grade 3, and 1% grade 4), whereas the rate of ≥grade 2 gastrointestinal toxicity in RTOG 0247 was 58% (30/52; P = 0.31). The pathologic complete response rate was 15% (10/68). Patterns of failure and survival analyses are being performed. The study demonstrated feasibility of rectal IMRT and adequate tumor coverage based on the pathologic complete response rate. However, the gastrointestinal toxicities were not significantly reduced when compared with RTOG 0247.
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5. Liersch T, Langer C, Ghadimi BM, et al. Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol 2006;24(25):4062–4068.
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7. 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 Oncol2005;23(25):6199–6206.
8. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997;336(14):980–987.
9. Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol ASCO Meeting Abstracts 2011; 29(15 Suppl):3503.
10. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27(19):3109–3116.
11. Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74(3): 824–830.
12. Ballonoff A, Kavanagh B, McCarter M, et al. Preoperative capecitabine and accelerated intensity-modulated radiotherapy in locally advanced rectal cancer: a phase II trial. Am J Clin Oncol 2008;31(3):264–270.
13. De Ridder M, Tournel K, Van Nieuwenhove Y, et al. Phase II study of preoperative helical tomotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2008;70(3):728–734.
14. Aristu JJ, Arbea L, Rodriguez J, et al. Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2008;71(3):748–755.
15. Samuelian JM, Callister MD, Ashman JB, Young-Fadok TM, Borad MJ, Gunderson LL. Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2012;82(5):1981–1987.
16. Garofalo M, Moughan J, Hong T, et al. RTOG 0822: A phase H study of preoperative (PREOP) chemoradiotherapy (CRT) utilizing IMRT in combination with capecitabine (C) and oxaliplatin (O) for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys2011;81(2):S3–S4.