Colorectal Carcinoma – Causes, Symptoms, Treatment

Carcinoembryonic antigen (CEA)

Measurement of CEA, a serum glycoprotein, is frequently used in the management and follow-up of patients with rectal cancer. A review of the use of this tumor marker for rectal cancer suggests the following:[43]

• Serum CEA testing is not a valuable screening tool for rectal cancer because of its low sensitivity and low specificity.
• Postoperative CEA testing is typically restricted to patients who are potential candidates for further intervention, as follows:
• Patients with stage II or III rectal cancer (every 2–3 months for at least 2 years after diagnosis).
• Patients with rectal cancer who would be candidates for resection of liver metastases.

In one Dutch retrospective study of total mesorectal excision for the treatment of rectal cancer, investigators found that the preoperative serum CEA level was normal in the majority of patients with rectal cancer, and yet, serum CEA levels rose by at least 50% in patients with recurrence. The authors concluded that serial, postoperative CEA testing cannot be discarded based on a normal preoperative serum CEA level in patients with rectal cancer.[52,53]

Lymph node status

The AJCC and a National Cancer Institute-sponsored panel suggested that at least 10 to 14 lymph nodes be examined in radical colon and rectum resections in patients who did not receive neoadjuvant therapy. In cases in which a tumor is resected for palliation or in patients who have received preoperative radiation therapy, fewer lymph nodes may be present.[10–12] This takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen.

Retrospective studies, such as Intergroup trial INT-0089 (NCT00201331), have demonstrated that the number of lymph nodes examined during colon and rectal surgery may be associated with patient outcome.[13–16] A new tumor-metastasis staging strategy for node-positive rectal cancer has been proposed.[17]

Preoperative chemoradiation therapy

Neoadjuvant therapy for rectal cancer, using preoperative chemoradiation therapy, is the preferred treatment option for patients with stages II and III disease. However, postoperative chemoradiation therapy for patients with stage II or III rectal cancer remains an acceptable option.[12]

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III), based on the results of several studies:

• German Rectal Cancer Study Group trial.[13]
• National Surgical Adjuvant Breast and Bowel Project R-03 trial NSABP R-03 (NCT00410579).[14][Level of evidence: 1iiA] (Refer to the Stages II and III Rectal Cancer section of this summary for more information.)

Multiple phase II and III studies examined the benefits of preoperative chemoradiation therapy, which include the following:[12]

• Tumor regression and downstaging of the tumor.
• Improved tumor resectability.
• Higher rate of local control.
• Improved toxicity profile of chemoradiation therapy.
• Higher rate of sphincter preservation.

Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[15–22] However, preoperative radiation therapy is associated with increased complications compared with surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[23–26]

(Refer to the Preoperative chemoradiation therapy section in the Stages II and III Rectal Cancer section of this summary for more information about these studies.)

Postoperative chemoradiation therapy

Preoperative chemoradiation therapy is the current standard of care for stages II and III rectal cancer. However, before 1990, the following studies noted an increase in both disease-free survival (DFS) and overall survival (OS) with the use of postoperative combined-modality therapy:

1. The Gastrointestinal Tumor Study Group trial (GITSG-7175).
2. The Mayo/North Central Cancer Treatment Group trial (NCCTG-794751).
3. The National Surgical Adjuvant Breast and Bowel Project trial (NSABP-R-01).

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems.

Fluorouracil (5-FU): The following studies examined optimal delivery methods for adjuvant 5-FU:

1. Intergroup protocol 86-47-51 trial (MAYO-864751).[27][Level of evidence: 1iiA]
2. Intergroup 0114 trial (INT-0114 [CLB-9081]).[25][Level of evidence: 1iiA]
3. Intergroup 0144.[28]

(Refer to the Stages II and III Rectal Cancer section of this summary for detailed information about these study results.)

Acceptable postoperative chemoradiation therapy for patients with stage II or III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation and four cycles of adjuvant maintenance chemotherapy with bolus 5-FU with or without modulation with leucovorin (LV).

Findings from the NSABP-R-01 trial compared surgery alone with surgery followed by chemotherapy or radiation therapy.[29] Subsequently, the NSABP-R-02 (NCT00410579) study, addressed whether adding postoperative radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[30][Level of evidence: 1iiA]

In the NSABP-R-02 study, the addition of radiation therapy significantly reduced local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02) but failed to demonstrate a significant survival benefit. Radiation therapy appeared to improve survival among patients younger than 60 years and among patients who underwent abdominoperineal resection.

While this trial has initiated discussion in the oncologic community about the proper role of postoperative radiation therapy, omission of radiation therapy seems premature because of the serious complications of locoregional recurrence.

Chemotherapy regimens

Table 8 describes the chemotherapy regimens used to treat rectal cancer.

Treatment toxicity

The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment.

Of greater concern is the potential for late morbidity after rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter.[31] Patients treated with radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than do patients who undergo surgical resection alone.[24,32–37]

An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction than do patients who undergo surgical resection alone.[38] A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with radiation therapy.[31]

Improved radiation therapy planning and techniques may minimize these acute and late treatment-related complications. These techniques include the following:[39–43]

• The use of high-energy radiation machines.
• The use of multiple pelvic radiation fields.
• Prone patient positioning.
• Customized patient molds (belly boards) to exclude as much small bowel as possible from the radiation fields and immobilize patients during treatment.
• Bladder distention during radiation therapy to exclude as much small bowel as possible from the radiation fields.
• Visualization of the small bowel through oral contrast during treatment planning so that when possible, the small bowel can be excluded from the radiation field.
• The use of 3-dimensional or other advanced radiation planning techniques.

In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy × five daily treatments) followed by surgery one week later, rather than the long-course chemoradiation approach used in the United States. One reason for this difference is the concern in the United States for heightened late effects when high radiation doses per fraction are given.

Polypectomy or surgery

Local excision or simple polypectomy may be indicated for stage 0 rectal cancer tumors.[1] Because of its localized nature at presentation, stage 0 rectal cancer has a high cure rate. For large lesions not amenable to local excision, full-thickness rectal resection by the transanal or transcoccygeal route may be performed.

Surgery with or without chemoradiation therapy

There are three potential options for surgical resection in stage I rectal cancer:

• Local excision. Local excision is restricted to tumors that are confined to the rectal wall and that do not, on rectal ultrasound or magnetic resonance imaging, involve the full thickness of the rectum (i.e., are not T3 tumors). The ideal candidate for local excision has a T1 tumor with well-to-moderate differentiation that occupies less than one-third of the circumference of the bowel wall. Local excision is associated with a higher risk of local and systemic failure and is applicable to only very select patients with T2 tumors. Local transanal or other resection [1,2] with or without perioperative external-beam radiation therapy (EBRT) plus fluorouracil (5-FU) may be indicated.
• Low-anterior resection. Wide surgical resection and anastomosis are options when an adequate low-anterior resection can be performed with sufficient distal rectum to allow a conventional anastomosis or coloanal anastomosis.
• Abdominoperineal resection. Wide surgical resection with abdominoperineal resection is used for lesions too distal to permit low-anterior resection.

Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement about 20% of the time. Patients may want to consider additional therapy, such as radiation therapy and chemotherapy, or wide surgical resection of the rectum.[3] Patients with poor histologic features or positive margins after local excision may consider low-anterior resection or abdominoperineal resection and postoperative treatment as dictated by full surgical staging.

For patients with T1 and T2 tumors, no randomized trials are available to compare local excision with or without postoperative chemoradiation therapy to wide surgical resection (low-anterior resection and abdominoperineal resection).

Evidence (surgery)

Surgery

Total mesorectal excision with either low anterior resection or abdominoperineal resection is usually performed for stages II and III rectal cancer before or after chemoradiation therapy.

Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with surgery and no additional therapy have a very low risk of local and systemic recurrence.[1]

Preoperative chemoradiation therapy

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.

Evidence (preoperative chemoradiation therapy)

The German Rectal Cancer Study Group (CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society]) randomly assigned 823 patients with ultrasound-staged T3 or T4 or lymph node-positive rectal cancer to either preoperative chemoradiation therapy or postoperative chemoradiation therapy (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional fluorouracil [5-FU] 1,000 mg/m² daily for 5 days during the first and fifth weeks of radiation therapy).[2][Level of evidence: 1iA] All patients underwent total mesorectal excision and received four additional cycles of 5-FU–based chemotherapy.

Postoperative chemoradiation therapy

Progress in the development of postoperative treatment regimens relates to the integration of systemic chemotherapy and radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stages II and III rectal cancer was established by a series of prospective, randomized clinical trials, including the following:[9–11]

• Gastrointestinal Tumor Study Group (GITSG-7175).
• Mayo/North Central Cancer Treatment Group (NCCTG-794751).
• National Surgical Adjuvant Breast and Bowel Project (NSABP-R-01).

These studies demonstrated an increase in DFS interval and OS when radiation therapy was combined with chemotherapy after surgical resection. After the publication in 1990 of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference recommended postoperative combined-modality treatment for patients with stages II and III rectal carcinomas.[12] Since that time, preoperative chemoradiation therapy has become the standard of care, although postoperative chemoradiation therapy is still an acceptable alternative. (Refer to the Preoperative chemoradiation therapy section of this summary for more information.)

Additional evidence (postoperative chemoradiation therapy):

• Intergroup protocol 86-47-51 (MAYO-864751) compared continuous-infusion 5-FU (225 mg/m²/day throughout the entire course of radiation therapy) with bolus 5-FU (500 mg/m²/day for 3 consecutive days during the first and fifth weeks of radiation therapy).[13][Level of evidence: 1iiA]

  • A 10% improvement in OS was demonstrated with the use of continuous-infusion 5-FU.

• A three-arm randomized trial, determined whether continuous-infusion 5-FU given throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous infusion 5-FU given only during pelvic radiation therapy. Median follow-up was 5.7 years.[14]

  1. Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m²/day) and after (450 mg/m²/day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m²/day) during radiation therapy.
  2. Arm 2 received continuous infusion 5-FU before (300 mg/m²/day for 42 days), after (300 mg/m²/day for 56 days), and during (225 mg/m²/day) radiation therapy.

  3. Arm 3 received bolus 5-FU/LV in two 5-day cycles before (5-FU, 425 mg/m²/day; LV, 20 mg/m²/day) and after (5-FU, 380 mg/m²/day; LV, 20 mg/m²/day) radiation therapy, and bolus 5-FU/LV (5-FU, 400 mg/m²/day; LV, 20 mg/m²/day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.

     • No DFS, OS, or locoregional failure difference was detected (across all arms: 3-year DFS, 67%–69%; 3-year OS, 81%–83%; locoregional failure, 4.6%–8%).
     • Lethal toxicity was less than 1%, with grades 3 to 4 hematologic toxicity in 55% of patients in arm 1 and in 49% of the patients in arm 3, versus in 4% of patients in the continuous-infusion arm.[14][Level of evidence: 1iiA]
• The final study results of Intergroup trial 0114 (INT-0114) showed no survival or local-control benefit with the addition of LV, levamisole, or both to 5-FU administered postoperatively for patients with stages II and III rectal cancers at a median follow-up of 7.4 years.[15][Level of evidence: 1iiA]
• A pooled analysis of 3,791 patients enrolled in clinical trials demonstrated that, for patients with T3, N0 disease, the 5-year OS rate with surgery plus chemotherapy (OS, 84%) compared favorably with the survival rates of patients treated with surgery plus radiation therapy and bolus chemotherapy (OS, 76%) or surgery plus radiation therapy and protracted-infusion chemotherapy (OS, 80%).[16]

Preoperative oxaliplatin with chemoradiation therapy

Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models.[17] Phase II studies that combined oxaliplatin with fluoropyrimidine-based chemoradiation therapy have reported pathologic complete response rates ranging from 14% to 30%.[18–22] Data from multiple studies have demonstrated a correlation between rates of pathologic complete response and endpoints including distant metastasis-free survival, DFS, and OS.[23–25]

There is no current role for off-trial use of concurrent oxaliplatin and radiation therapy in the treatment of patients with rectal cancer.

Evidence (preoperative oxaliplatin with chemoradiation therapy)

Postoperative oxaliplatin-containing regimens

On the basis of results of several studies, oxaliplatin as a radiation sensitizer does not appear to add any benefit in terms of primary tumor response, and it has been associated with increased acute treatment-related toxicity. The question of whether oxaliplatin should be added to adjuvant 5-FU/LV for postoperative management of stages II and III rectal cancer is an ongoing debate. There are no randomized phase III studies to support the use of oxaliplatin for the adjuvant treatment of rectal cancer. However, the addition of oxaliplatin to 5-FU/LV for the adjuvant treatment of colon cancer is now considered standard care.

Evidence (postoperative oxaliplatin)

It is unclear whether the results of these colon cancer trials can be applied to the management of patients with rectal cancer. There are no randomized phase III studies to support the routine practice of administering FOLFOX as adjuvant therapy to patients with rectal cancer.

Primary chemoradiation therapy followed by intensive surveillance for complete clinical responders

Since the advent of preoperative chemoradiation therapy in rectal cancer, the standard approach has been to recommend definitive surgical resection by either abdominoperineal resection or laparoscopic-assisted resection. In most series, after long-course chemoradiation therapy, 10% to 20% of patients will have a complete clinical response in which there is no sign of persistent cancer by imaging, rectal exam, or direct visualization during sigmoidoscopy. It was a long-held belief that most patients who did not undergo surgery for personal or medical reasons would experience a local and/or systemic recurrence. However, it became clear that patients with a pathologic complete response to preoperative chemoradiation therapy followed by definitive surgery had a better DFS than did patients who did not have a pathologic clinical response.[33]

Several single-institution studies have challenged this standard of care by demonstrating that most patients with complete clinical response will be cured of rectal cancer without surgery and that many patients who experience a local recurrence can be treated with surgical resection (abdominoperineal resection or laparoscopic-assisted resection) at the time of their recurrence.[34–37] These institutional series were hampered by their small size and inherent selection bias.

Evidence (primary chemoradiation therapy followed by intensive surveillance for complete clinical responders)

Surgery with or without chemotherapy or radiation therapy

For patients with locally recurrent, liver-only, or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.[1] Patients with limited pulmonary metastasis, and patients with both pulmonary and hepatic metastasis, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[2–5] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[6]

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone after an initial, attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival.[7,8]

The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation.[9,10] Intraoperative radiation therapy in patients who underwent previous external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity.[11]

First-line chemotherapy and targeted therapy

The following are active U.S. Food and Drug Administration (FDA)-approved drugs that are used alone and in combination with other drugs for patients with metastatic colorectal cancer:

• Fluorouracil (5-FU).
• Irinotecan.
• Oxaliplatin.
• Capecitabine.
• Bevacizumab.
• FOLFOXIRI (irinotecan, oxaliplatin, leucovorin [LV], and 5-FU).
• Cetuximab.
• Aflibercept.
• Ramucirumab.
• Panitumumab.
• Anti-epidermal growth factor receptor (EGFR) antibody versus anti-vascular endothelial growth factor (VEGF) antibody with first-line chemotherapy. .
• Regorafenib.
• TAS-102.
• Pembrolizumab.

Palliative therapy

Palliative radiation therapy,[11,56] chemotherapy,[13,58–63] and chemoradiation therapy [64,65] may be indicated. Palliative, endoscopically-placed stents may be used to relieve obstruction.[66]

Surgery

Hepatic metastasis may be considered to be resectable based on the following factors:[55,70–82]

• Limited number of lesions.
• Intrahepatic locations of lesions.
• Lack of major vascular involvement.
• Absent or limited extrahepatic disease.
• Sufficient functional hepatic reserve.

For patients with hepatic metastasis that is considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the North Central Cancer Treatment Group trial NCCTG-934653 (NCT00002575).[83–87][Level of evidence: 3iiiDiv] Improved surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of neoadjuvant chemotherapy.[88]

Neoadjuvant chemotherapy

Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.[88]

Local ablation

Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[89–95] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.

Adjuvant chemotherapy

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.

Evidence (adjuvant chemotherapy)

Additional studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone would provide results similar to hepatic intra-arterial therapy plus systemic treatment.