Effectiveness of Standard Treatment for Stage 4 Colorectal Cancer: Traditional Management with Surgery, Radiation, and Chemotherapy

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States comprising 7.9% of all new cancer diagnoses and 8.6% of all cancer deaths. The combined 5-year relative survival rate for all stages is 65.1% but in its most aggressive form, stage 4 CRC has a 5-year relative survival rate of just 15.1%. For most with stage 4 CRC, treatment is palliative not curative, with the goal to prolong overall survival and maintain an acceptable quality of life.

The identification of unique cancer genomic and biologic markers allows patient-specific treatment options. Treatment of stage 4 CRC consists of systemic therapy with chemotherapeutic agents, surgical resection if feasible, potentially including resection of metastasis, palliative radiation in select settings, and targeted therapy toward growth factors. Despite advances in surgical and medical management, metastatic CRC remains a challenging clinical problem associated with poor prognosis and low overall survival.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. ¹ In 2022, it is estimated there will be 151,030 new CRC cases diagnosed comprising 7.9% of all new cancer diagnoses, with 52,580 projected deaths (8.6% of all cancer deaths). ² When all stages are combined, the 5-year relative survival rate is 65.1%. At initial diagnosis, up to 20% of patients already have synchronous distant metastatic CRC, with another 40% diagnosed after recurrence of locally treated disease. ^{2 3} The 5-year relative survival rate of stage 4 CRC is significantly lower at 15.1%. ¹ Patients with metastatic disease who do not pursue further treatment have a 9-month survival while patients who receive only chemotherapy have increased median survival to 30 months. ^{4 5} This review highlights the effectiveness and limitations of treatment options for patients with stage 4 CRC.

Evaluation

Patients with metastatic CRC who present emergently with peritonitis, perforation, massive bleeding, or large bowel obstruction require surgery or other interventional procedures. In cases of perforation, resection, if possible, is indicated. For large bowel obstruction, diversion, resection, or stenting are options. For patients who have minimal or tolerable symptoms, the decision to resect the primary tumor is less straightforward. For any patient who does not present with an emergent surgical indication, a full staging evaluation, including computed tomography (CT) chest/abdomen/pelvis with contrast, magnetic resonance imaging (MRI) pelvis for rectal cancer, and carcinoembryonic antigen (CEA) level, should be performed.

Lynch syndrome screening should be performed by evaluating either mismatch repair deficiency through immunohistochemistry or microsatellite instability-high through polymerase chain reaction. ⁶ Molecular assessment of the tumor biology includes testing for KRAS, NRAS, and BRAF either individually or as part of a tissue or blood-based next-generation sequencing panel. ⁶

Treatment Goals

The treatment of metastatic CRC requires effective coordination of care between multiple medical and surgical subspecialists. Multidisciplinary cancer conferences influence treatment regimens and improve patient care, survival outcomes, continuity, and cost-effectiveness. ^{7 8 9 10} For most patients with stage 4 CRC, treatment is palliative not curative, with the goal to prolong overall survival and maintain an acceptable quality of life.

The selection of specific treatment regimens depends on the patient's unique disease burden, with special attention to distinguishing between surgically resectable and unresectable lesions. In those with resectable primary and metastatic lesions, treatment has the potential to be curative in some patients with liver and/or lung-isolated metastatic disease, local recurrence, or limited intra-abdominal disease. In those with surgically unresectable lesions, chemotherapy has the potential to downstage disease, making previously unresectable tumors appropriate for resection. In this strategy, a treatment regimen is selected based on tumor response rate and potential to decrease disease burden, not the overall survival benefit of a particular therapy. Ultimately, in unresectable stage 4 CRC, the goal is to delay disease progression. This is a discrete data point to consider as objective tumor response has not been shown to predict the magnitude of progression-free survival or overall survival benefit. ¹¹ Instead, lack of disease progression has been associated with better symptom control, health-related quality of life, and overall survival. ¹²

Systemic Therapy

The mainstay of treatment in metastatic CRC is systemic therapy, with recent trials demonstrating improved survival when using treatment regimens based on patient-specific molecular genetics and biologic tumor features. ¹³ Common chemotherapy options, based on oxaliplatin or irinotecan, include the following: 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX); 5-FU, leucovorin, and irinotecan (FOLFIRI); capecitabine and oxaliplatin (CAPOX); and capecitabine and irinotecan (CAPIRI). These traditional combinations increase median survival an additional 17 to 23 months. ^{14 15 16} Through the use of genomic profiling, tailored treatment regimens have been developed based on specific sequence variations and tumor biology. Identification of molecular subtypes is essential prior to the implementation of any chemotherapy regimen.

First-line therapy, for patients who are clinically able to tolerate chemotherapy, consists of FOLFOX or FOLFIRI, either alone or in combination with other agents, depending on the patient's molecular profile. Approximately 50% of patients have KRAS/NRAS/BRAF wild-type tumors, and in this population anti-epidermal growth factor receptor (EGFR) therapy with cetuximab and panitumumab plus standard chemotherapy extends median survival by an additional 30 months. ^{17 18} In BRAF V600E sequence variations (affecting ∼5–10%) combination therapy with BRAF and EGFR inhibitors increases overall survival to 9.3 months. ^{19 20} When genomic profiling identifies the 5% of metastatic CRC patients with microsatellite instability or mismatch repair deficiencies, immune checkpoint inhibitors for PD-1/PD-L1 can be considered. ²¹ Treatment with pembrolizumab, nivolumab, or a combination with nivolumab and ipilimumab have been evaluated in early phase trials with one trial demonstrating a 12-month survival rate of 73%. ^{22 23}

Patients are evaluated every 2 to 3 months with CT chest/abdomen/pelvis. Treatment failures, either in the form of poor tumor response, or inability to control metastatic progression, generally prompts transition to another chemotherapeutic agent or treatment regimen, until all treatment options are exhausted.

Surgical Treatment

CRC Liver Metastasis

In resectable liver metastasis, a simultaneous resection of the primary tumor with limited hepatectomy, achieves similar outcomes to staged procedures in select patients. ^{24 25 26} However, in patients requiring either complex rectal surgery or major hepatectomy with three or more segments, simultaneous surgery has higher morbidity and mortality. ²⁷ Delayed hepatic resection of metastatic CRC does not affect survival. ²⁸ For patients with resectable liver metastases, the order of surgery and chemotherapy remains unsettled. Chemotherapy regimens are varied and center around a patient's previous regimen, response, and toxicity. ⁶

Indications for surgery for hepatic metastases were established in 2012 by the Americas Hepato-Pancreato-Biliary Association. ²⁹ Resection is determined by the ability to obtain clear margins, the dimension of the future liver remnant, resectability of extrahepatic disease, intact arterial and portal inflow, venous outflow, and biliary drainage. ²⁹ A patient's performance status and molecular profile play a role in determining resectability and the order of treatment. Five-year survival after surgery ranges from 36 to 47.3%. ³⁰ Patients with unresectable CRC hepatic metastases are eligible for techniques targeted at decreasing the hepatic disease burden including radiofrequency ablation, cryosurgery, and selective hepatic artery chemoembolization.

CRC Lung Metastasis

Lung metastases, as the only site of metastatic spread, are uncommon, occurring in 6.9% of patients. ³¹ Pulmonary metastases are present at diagnosis in 11% of patients and another 5.8% develop lung metastases during follow-up. ³² Rectal cancer patients have a higher tendency to develop pulmonary metastases than patients with colon cancer and the lower the tumor, the higher the risk. ³³ Criteria for consideration of resection of pulmonary CRC metastases include completely resectable lesions, an acceptable cardiopulmonary reserve, and the absence of extrapulmonary disease (ideal) or at least controllable disease. ³⁴ The Society of Thoracic Surgeons consensus group additionally recommends three or fewer metastatic lesions or lymph nodes. ³⁵ In one large international registry study of cancer patients that was not exclusive to CRC but often extrapolated to metastatic CRC disease, complete resection of lung metastases was associated with a median survival of 36 versus 13 months. ³⁶ In patients undergoing pulmonary metastases resection, 5-year survival rates were generally higher for patients who reached a disease-free interval of greater than 36 months (45% vs. 33% for those with a disease-free interval of less than 1 year). In a multicenter cohort study of 522 patients who underwent pulmonary resection for colorectal metastases, the median survival was 54.9 months and the 5-year disease-specific survival was 46.1%. ³⁷ In CRC pulmonary metastases, lymph node involvement and elevated CEA levels are negative prognostic factors for resection. ^{38 39} Similar to liver metastasis, nonsurgical options to treat pulmonary metastatic disease burden include stereotactic radiotherapy, radiofrequency ablation, and cryoablation.

Peritoneal Carcinomatosis

In stage 4 CRC disease, the NCCN guidelines recommend systemic therapy in nonobstructing disease, reserving surgical intervention (resection/diverting ostomy/bypass/stenting) to those with imminent or frank obstruction. ⁶ There remains continued interest in hyperthermic intraperitoneal chemotherapy (HIPEC) for synchronous abdominal/peritoneal metastases based on one randomized controlled trial. The Dutch colorectal peritoneal carcinomatosis trial randomized 105 patients to receive 5-FU and leucovorin with or without surgical resection and HIPEC. Patients who received HIPEC had a median disease-specific survival of 22.2 months versus 12.6 months for patients who received only chemotherapy. ⁴⁰ Data on HIPEC, however, continues to be mixed with the PRODIGE 7 randomized control trial finding short duration (30 minutes) HIPEC with oxaliplatin did not improve relapse-free or overall survival in CRC with peritoneal carcinomatosis compared to cytoreductive surgery alone. ⁴¹ There appears to be specific tumor biology that impacts HIPEC efficacy. BRAF mutations are associated with an especially poor prognosis (0% 2-year survival) in those undergoing CRC surgery and HIPEC, while there is no difference in outcomes as they relate to HIPEC in wild-type versus sequence variant KRAS. ⁴² If considered, complete cytoreductive surgery and intraperitoneal chemotherapy should be performed at a highly specialized center with specific expertise in this treatment.

Radiation

Patients with metastatic rectal cancer require a multidisciplinary approach to address resectability of the primary and metastatic lesions, assess molecular profiles, and evaluate their overall clinical condition before embarking on an individualized treatment plan. The NCCN guidelines for metastatic rectal cancer recommend systemic chemotherapy only. ⁴³ For patients with bleeding or obstipation, radiation (60 Gy) can be given for palliation. ⁴⁴

Conclusion

Diagnostic evaluation and the selection of tailored therapeutic options for Stage 4 CRC require a multidisciplinary approach that aligns with patient-specific goals of care. Molecular profiling allows targeted therapy with some improvement in overall survival and the avoidance of particular toxicities. Despite several advances in surgical management, genomic and pathologic profiling, and the development of increasingly targeted therapeutic options, metastatic CRC remains a challenging clinical problem.