ACR Appropriateness Criteria^®: Rectal Cancer—Metastatic Disease at Presentation

Abstract

In 2009, an estimated 40,870 new cases of rectal cancer will be diagnosed in the USA. After decades of treating metastatic colorectal cancer (CRC) with 5-fluorouracil alone, newer agents have resulted in significant improvements in disease-free and overall survival rates. These improvements stem from combinations of newer cytotoxic agents and targeted therapies. Based on performance status and burden of disease, metastatic CRC patients are generally treated with either a curative or palliative intent. Curative paradigm patients often have low burden liver or lung metastases which are technically resectable. Patients with resectable colorectal liver metastases and no evidence of any extrahepatic metastases have impressive 5-year survival rates of 30%−70% following resection. Unfortunately, only 20%−30% of patients with colorectal liver metastases are candidates for resection at initial presentation. Patients with unresectable liver or lung metastasis are candidates for local therapies including radioablation, chemoembolization, radioembolization, and stereotactic radiation therapy. In select patients with metastatic CRC, neoadjuvant or adjuvant pelvic chemoradiation (CRT) is indicated to prevent local recurrence. Patients who have resectable metastatic disease with symptomatic, obstructive, Stage T3–4 and N1, or low-lying (≤5 cm) primary tumors should be considered for neoadjuvant CRT. This review summarizes the current literature on metastatic CRC and presents 4 simulated patient variants.

Summary of Literature Review

In 2010, an estimated 40,870 new cases of rectal cancer will be diagnosed in the USA (23,580 men and 17,290 women).¹ After decades of treating metastatic colorectal cancer (CRC) with 5-fluorouracil (5-FU) alone, newer agents have resulted in significant improvements in disease-free and overall survival rates. These improvements stem from combinations of newer cytotoxic agents (irinotecan and oxaliplatin) and targeted therapies (cetuximab, panitumumab, and bevacizumab). Based on performance status and the burden of disease (resectable liver-only or lung-only vs widely systemic disease), metastatic CRC patients are generally treated with either a curative or palliative intent.

Management of patients with newly diagnosed metastatic rectal cancer may be complicated, and treatment decisions will benefit from multidisciplinary inputs in most cases. Treatment decisions must be individualized based on the overall medical condition of the patient, the extent and distribution of extrapelvic metastatic disease, and the patient’s wishes.

Management of Patients with Colorectal Liver Metastases

Patients with resectable colorectal liver metastases and no evidence of any extrahepatic metastases have impressive 5-year survival rates of 30%−70% following resection. Unfortunately, only 20%−30% of patients with colorectal liver metastases are candidates for resection at initial presentation.² Management should be based on whether the patient has resectable disease and is an appropriate candidate for antitumor treatment, or whether debilitation has progressed to the degree that supportive care is more appropriate. In general, patients with minimal comorbidities and a Karnofsky performance status (KPS) >80% should be managed aggressively.

Management of the Primary in Patients with Resectable Metastatic Disease

The optimal management of this patient population is controversial; however, the paradigm is changing with the substantial improvements that have occurred over the last decade with chemotherapy. Patients who have resectable metastatic disease with symptomatic, obstructive, Stage T3–4 and N1, or low-lying (≤5 cm) primary tumors should be treated with preoperative combined-modality therapy (5-FU and radiation therapy [RT]). In these cases, resection of both the rectal primary tumor and metastases is often performed after combined-modality therapy and before systemic postoperative chemotherapy. Although there are limited data to support this regimen in patients with metastatic CRC, 1 could extrapolate the improved local control and decreased toxicity with preoperative versus postoperative chemoradiation reported by Sauer et al.³ Patients with resectable metastatic disease and low-volume, early-stage (T1-T2, N0) or high rectal primary tumors (>5 cm) may be ideally treated with upfront surgery or preoperative chemotherapy alone. Patients who have undergone complete resection of both the primary rectal cancer and all known metastatic disease can reasonably be considered candidates for standard postoperative management consistent with that given to patients with Stage II or III rectal cancer (Table 1).

TABLE 1.

Variant 1: Initial treatment for a 52-year-old male without a significant past medical history and an asymptomatic nonobstructing uT3N0 primary rectal tumor 8 cm from the anal verge and a solitary resectable 4 cm metastasis in the right lobe of the liver. KPS 90

Treatment	Rating*	Comments
Initial resection of rectal primary and liver lesion (either concurrent or sequential)	8
Initial systemic 5-FU-based chemotherapy (FOLFOX/FOLFIRI ± bevacizumab)	5
Initial preoperative pelvic RT + concurrent 5-FU-based chemotherapy	3
Resection of the liver lesion only	2
Best supportive care	1

^*Rating scale: 1–3, usually not appropriate; 4–6, may be appropriate; 7–9, usually appropriate.

Unresectable Liver Metastases

The primary management of unresectable metastatic disease is systemic chemotherapy. Some uncontrolled trials have investigated liver-directed therapies such as transarterial embolization (TACE), radioembolization, stereotactic body radiation therapy, chemoradiation, radiofrequency ablation, and cryotherapy in the palliative or, in rare cases, neoadjuvant setting in CRC. Randomized studies with long-term follow-up are needed to determine the efficacy of these modalities.^4–11

Management of the Primary in Patients with Unresectable Metastatic Disease

The primary management of unresectable metastatic disease is systemic chemotherapy. Given the high response rates and low rates of overt rapid progression through current first-line regimens, this approach should be strongly considered in all cases except in those patients who are obstructed or are extremely close to obstruction. As with all scenarios, however, care plans must be individualized to the particular needs of the patient, based on the pattern and pace of metastatic disease, degree of symptoms, risk of imminent obstruction, and comorbidities. Since preoperative chemoradiotherapy followed by resection is the most effective modality for controlling the rectal primary, patients who are judged to have a reasonable chance of surviving long enough to develop symptoms from progressive or recurrent pelvic disease may be appropriately palliated with 5-FU based chemoradiation. Alternatively, systemic combination chemotherapy may be used first, with consideration of consolidative radiation and concurrent chemotherapy for more definitive local control in those patients who respond to therapy. In patients with bulky metastatic cancer, demise from metastatic cancer is more likely to occur before pelvic symptoms become a problem. In such patients, systemic chemotherapy is usually most appropriate, with local pelvic therapy best reserved following systemic chemotherapy for treating symptomatic complications as needed.

Cytotoxic and Targeted Therapies

5-FU has been the basis of standard chemotherapy for treating CRC for the last 5 decades. Overall, prolonged infusion schedules appear to be more effective and less toxic, and bolus regimens should rarely be used at this time. Capecitabine, an oral fluoropyrimidine, has been shown to have superior response rates and lower incidence of adverse events, but no significant differences in survival when compared with the Mayo Clinic schedule of bolus 5-FU/leucovorin (LV).¹² This oral agent has a dose-limiting toxicity of hand-foot syndrome, which appears to be more common in the US population than in Europe, where most of the studies were done. In addition, capecitabine requires a highly motivated and reliable patient who will take oral medication correctly, will not miss or duplicate doses, and will hold medications at appropriate levels of toxicity.

Combining 5-FU/LV or capecitabine with newer agents, including irinotecan and oxaliplatin, has resulted in improved outcomes. Irinotecan, a topoisomerase I inhibitor, can be used independently in 5-FU-resistant advanced CRC, or can be combined with 5-FU/LV as first-line therapy in patients with metastatic disease.¹³ Oxaliplatin is a third-generation platinum compound that has been shown to be a superior regimen to bolus 5-FU-irinotecan regimens.¹⁴ When faced with treating a patient with advanced CRC in the first-line setting, there are multiple options, and comparative trials have indicated that both FOLFOX (oxaliplatin-based) and FOLFIRI (irinotecan-based) are acceptable first-line regimens.¹⁵

New “targeted” therapies such as cetuximab (Erbitux^™), panitumumab (Vectibix^™), and bevacizumab (Avastin^™) have increased the options available for treating metastatic disease. Cetuximab and panitumumab are monoclonal antibodies directed against the epidermal growth factor receptor (EGFR). Cetuximab received FDA approval for treatment of irinotecan-resistant disease. A 22% response rate was seen in patients treated with cetuximab/irinotecan, and an 11% response rate with cetuximab as a single agent.¹⁶ Panitumumab was FDA-approved after demonstrating improved progression-free survival versus best supportive care in patients with chemotherapy-refractory disease.¹⁷ The discovery that patients with KRAS-mutated tumors do not derive benefit from EGFR-targeted therapies has ushered an era of “personalized” therapy in CRC. For instance, in the large CO¹⁷ study of cetuximab versus best supportive care in chemotherapy-resistant advanced CRC, patients harboring a KRAS mutation had a response rate of 1% and median overall survival time (mOS) of 4.5 months. Subjects who had KRAS wild-type tumors had a response rate of 13% and mOS of 9.5 months.¹⁸ In a retrospective meta-analysis of the CRYSTAL and OPUS studies, the addition of cetuximab to chemotherapy resulted in a significant improvement in progression-free and overall survival times in patients with KRAS wild-type tumors.¹⁹ Conversely, in a Phase III study (COIN) comparing cetuximab in combination with capecitabine or intravenous 5-FU and oxaliplatin versus chemotherapy alone in first-line metastatic CRC, the former did not meet its primary endpoint of overall survival in KRAS wild-type patients (17 months vs 17.9 months; HR 1.04; 95% CI 0.90–1.20; P = 0.68).²⁰

Two recent studies OPUS²¹ and PRIME,²² evaluated cetuximab or panitumumab respectively with FOLFOX (first line) and demonstrated a PFS benefit with the addition of the EGFR inhibitor to standard chemotherapy. However, metastatic CRC patients with KRAS mutations were found to have significantly shorter overall survival times when compared with patients receiving FOLFOX alone. These studies collectively suggest that EGFR inhibitors should be considered in treating KRAS wild-type tumors, but should not be offered in KRAS mutant patients.

Bevacizumab is directed against the vascular endothelial growth factor (VEGF). In a randomized Phase III trial, adding bevacizumab 5mg/kg to bolus 5-FU/LV/irinotecan in patients with advanced CRC improved overall survival time by 4.5 months.²³ However, in a larger Phase III trial of oxaliplatin-based first-line chemotherapy, the addition of bevacizumab resulted in a modest but significant improvement in progression-free survival time, but no improvement in response rate and no significant impact on overall survival time.²⁴ In addition, whereas there were promising initial results with “double biologic” strategies of combining bevacizumab and EGFR-targeting monoclonal antibodies, large randomized trials have shown that patients are harmed. Both the PACCE (panitumumab) and CAIRO2 (cetuximab) trials showed shorter survival times and greater toxicity in the arms with double biologics.^25,26

Bevacizumab has a half-life of 20 days. The safe interval between administration of bevacizumab and an operation has not been determined. The common practice of waiting 6–8 weeks (2–3 half-lives) between bevacizumab and an elective operation is consistent with an approval study in which the longest interval between bevacizumab and wound dehiscence was 56 days. A large study that included unplanned operations had a mean of 20 days between bevacizumab and any wound-healing complication. A small study of planned hepatectomy after bevacizumab, with a mean interval of 6.9 weeks, found no increase in wound-healing complications when compared with matched controls. Delaying a planned operation 6–8 weeks after bevacizumab is today’s reasonable consensus practice^27–29 (Tables 2 and 3).

TABLE 2.

Variant 2: Initial treatment of a 60-year-old female without a significant past medical history, and an asymptomatic nonobstructing uT3N0 rectal cancer, bilobar hepatic metastases (50% liver replacement), and bilateral pulmonary metastases. KPS 90

Treatment	Rating*	Comments
Systemic 5-FU-based chemotherapy (FOLFOX/FOLFIRI ± bevacizumab)	9	Consider anti-EGFR agents with FOLFOX/FOLFIRI in wild-type KRAS tumors
Best supportive care	2
Surgical debulking of metastatic disease	1
Resection of rectal primary	1
Liver directed therapies (transarterial embolization, radiation, RFA)	1
Preoperative pelvic RT + concurrent 5-FU-based chemotherapy	1

^*Rating scale: 1–3, usually not appropriate; 4–6, may be appropriate; 7–9, usually appropriate.

TABLE 3.

Variant 3: Initial treatment of a 60-year-old female without significant past medical history, with uT3N0 rectal cancer, bilobar hepatic metastases (50% liver replacement), and bilateral pulmonary metastases. Rectal lesion causing pain and early symptoms of obstruction. KPS 80

Treatment	Rating*	Comments
Initial preoperative pelvic RT + concurrent 5-FU based chemotherapy	7
Initial systemic 5-FU-based chemotherapy (FOLFOX/FOLFIRI)	6	Consider anti-EGFR agents with FOLFOX/FOLFIRI in wild-type KRAS tumors
Initial palliative stent or loop colostomy to relieve obstruction	5
Initial systemic 5-FU-based chemotherapy (FOLFOX/FOLFIRI + bevacizumab)	4
Initial resection of rectal primary	3
Initial pelvic RT alone	2
Initial surgical debulking of metastatic disease	1
Initial liver directed therapies (transarterial embolization, radiation, RFA)	1
Best supportive care	1

^*Rating scale: 1–3, usually not appropriate; 4–6, may be appropriate; 7–9, usually appropriate.

Supportive Care

Patients with widespread unresectable metastatic rectal cancer, poor performance status, and multiple comorbidities are often best managed with supportive, comfort-oriented intent. Local therapies including radiofrequency ablation (RFA), transarterial chemoembolizations (TACE), and RT can also be considered for palliation of symptoms (Table 4).

TABLE 4.

Variant 4: Initial treatment of a 74-year-old female with history of coronary artery disease, severe emphysema, diabetes, now with an asymptomatic nonobstructing uT3N0 rectal primary cancer with extensive hepatic metastases and abdominal carcinomatosis. Poor oral intake. KPS 50

Treatment	Rating*	Comments
Best supportive care	8
Systemic biological or chemotherapy	2
Resection of rectal primary	1
Preoperative pelvic RT + concurrent 5-FU-based chemotherapy	1
Resection of metastatic disease	1

^*Rating scale: 1–3, usually not appropriate; 4–6, may be appropriate; 7–9, usually appropriate.