The management of rectal cancer in patients with metastatic disease at presentation is highly variable. There are no phase III trials addressing therapeutic approaches, and the optimal sequencing of chemotherapy, radiation therapy, and surgery remains unresolved. Although chemoradiation is standard for patients with stage II/III rectal cancer, its role in the metastatic setting is controversial. Omitting chemoradiation may not be appropriate in all stage IV patients, particularly those with symptomatic primary tumors. Moreover, outcomes in this setting are vastly different, as some treatments carry the potential for cure in selected patients, while others are purely palliative. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (Modified Delphi) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.
Summary of Literature Review
According to the American Cancer Society, 40,000 new cases of rectal cancer were diagnosed in the United States in 2014. Approximately 15% of these patients had metastatic disease at presentation. The management of metastatic colorectal cancer (mCRC) has evolved over the past several decades with the introduction of improved surgical techniques, radiologic and pathologic staging, and regimens for systemic and radiation therapy (RT). As a result, the overall survival of patients with mCRC has improved significantly in recent years. Furthermore, a small but important group of these patients potentially may be cured of their disease through multimodality management. However, for the majority of patients with mCRC, the aim of therapy is to prolong survival and palliate symptoms.
Management of patients with newly diagnosed metastatic rectal cancer (mRC) may be complex, and treatment decisions benefit from multidisciplinary input. Management must be individualized based on the overall medical condition of the patient, the extent and distribution of metastatic disease, and the patient’s wishes.
Management of the Primary Tumor
The optimal management of the primary tumor in patients with metastatic disease is controversial; however, the paradigm is changing with the substantial improvements in systemic therapy and the expected duration of survival. Given the potential for cure after resection of all locoregional and distant disease, the approach to the primary tumor is determined by the resectability of the metastatic lesions as well as the severity of symptoms from the primary rectal mass.
Resectable Metastatic Disease
After resection of the primary tumor and distant metastases, patients with mCRC may experience long-term survival, and a small subset may be cured. Therefore, aggressive surgical management is warranted.
Patients with low-volume, stage T1-T2N0 metastatic disease, or high rectal primary tumors may be treated ideally with upfront resection of the primary tumor and metastases or with preoperative chemotherapy alone followed by a synchronous or staged resection of the primary tumor and metastases. On the other hand, patients with T3-4, regional node-positive or low-lying primary tumors should be considered for preoperative combined-modality therapy (CMT) with 5-fluorouracil (5-FU) and pelvic RT to reduce the risk of pelvic recurrence. Although limited data exist to support this approach in mRC, the improved local control and decreased toxicity with preoperative vs postoperative CMT may be extrapolated from the data on patients with locally advanced rectal cancer. In the United States, long-course chemoradiation (50.4 Gy in 28 fractions) is the standard preoperative management of rectal cancer; however, short-course RT (25 Gy in 5 fractions) may be considered in the setting of mRC to reduce the delay before surgery and initiation of full-dose systemic therapy. Any patient with an obstructing tumor should undergo surgical diversion prior to initiating CMT, regardless of the fractionation schedule used. A less preferable option for these patients would be endoscopic placement of a rectal stent.
Patients who have undergone upfront complete resection of both the primary tumor and all known metastatic disease can be considered candidates for the postoperative management routinely provided in stage II or III rectal cancer, which may include adjuvant chemotherapy with or without chemoradiation based on the stage and location of the primary tumor. Postoperative CMT should be strongly considered for any patient with T4 disease who did not receive preoperative pelvic RT.
Unresectable Metastatic Disease
The primary management of unresectable metastatic disease is chemotherapy. In the majority of cases, initiation of chemotherapy should not be postponed in favor of local therapy, given the high response rates and infrequency of rapid progression through first-line regimens. One important exception is patients with bowel obstructions, which require immediate diversion.
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. For example, patients with a low burden of metastatic disease, a bulky rectal tumor, and a high likelihood of long-term survival may benefit from treatment of the primary tumor to prevent symptoms from progressive or recurrent pelvic disease. Since preoperative CMT followed by resection may be the most effective approach for controlling the rectal primary, these patients may be appropriately treated with this regimen. Alternatively, chemotherapy may be provided upfront, and patients who achieve a favorable response may be treated subsequently with consolidative CMT and surgery to provide local control. On the other hand, patients with high-volume metastases and a small, asymptomatic rectal tumor are likely to die of their systemic disease before the primary tumor causes significant symptoms. In such patients, systemic chemotherapy is usually most appropriate, with local pelvic therapy reserved for palliation, if needed.
Management of Liver Metastases
The liver is the most frequent and often the only site of metastasis in CRC. Complete surgical resection of liver metastases can improve survival to an impressive 40% at 5 years and 25% at 10 years post treatment. Therefore, patients who are candidates for surgery, have resectable liver metastases, and have minimal or resectable extrahepatic disease should be directed to operative treatment. Such patients may undergo either a staged or synchronous resection of the metastases and primary rectal tumor.[8-11] There is no consensus regarding the best sequence; rather, institutional philosophy tends to guide management.
The classic approach is surgical removal of the primary tumor, which is considered to be the nidus of metastatic disease, followed by chemotherapy and a second surgery to remove the liver metastases at a later date. If patients progress while on chemotherapy between the two surgeries, the second surgery may not be performed. This approach may be most appropriate for patients who are symptomatic from their primary tumor. Evidence to support this classic approach suggests that the primary tumor affects the liver to promote angiogenesis and metastasis. A synchronous resection of primary tumor and liver metastases obviates the need for two separate operations, but the more arduous surgery may not be suitable for patients with a poor performance status. A more contemporary approach, commonly referred to as “liver-first,” is initial excision of the liver metastases, which demonstrates the genetic mutations and capacity to metastasize, then later resection of the local tumor. Frequently, the primary rectal disease is locally advanced, warranting neoadjuvant CMT; in select patients with a complete clinical response, close observation may delay or abrogate the need for rectal surgery.[13,14] In addition to resection of the primary tumor and liver metastases, systemic chemotherapy improves disease-free and progression-free survival.[15-17] Administration of chemotherapy before or after hepatectomy results in equivalent disease-free and overall survival.
Unfortunately, 70% to 80% of patients with CRC liver metastases are not candidates for resection at initial presentation. Upfront management of patients with unresectable metastases is chemotherapy. Primarily unresectable liver metastases may become resectable after responding to chemotherapy.[19-21] Portal vein embolization or hepatic arterial infusion with floxuridine/dexamethasone may increase the rates of conversion to resectability and thus improve long-term survival.[22,23] For tumors that remain unresectable, nonsurgical liver-directed therapies have yielded promising results and may be considered. For example, high-dose stereotactic body RT is well tolerated and provides local control rates of ≥ 77% at 1 year.[24-26] Radiofrequency ablation (RFA) yields excellent local control of small (< 3 cm) CRC liver metastases.[27-29] Radioembolization, using
yttrium-90 microspheres in combination with systemic therapy, results in a greater reduction in hepatic metastases than treatment with systemic therapy alone.[30,31] The addition of chemoembolization or cryotherapy to chemotherapy may also improve outcomes and is the topic of ongoing study[32-34] (see Variant 1 and Variant 2).
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