Version July 2025
INTRODUCTION —
For patients with metastatic (stage IV (table 1)) colorectal cancer (CRC), major advances in systemic therapy have expanded the therapeutic options and improved overall survival (OS). (See "General principles of systemic therapy for metastatic colorectal cancer".)
On the other hand, surgery provides a potentially curative option for selected patients with limited metastatic disease, especially if located in one organ system (such as the liver or lung), an isolated local recurrence, or limited intra-abdominal disease. With aggressive management integrating chemotherapy and surgery, long-term survival can be achieved in as many as 50 percent of cases. In selected patients, even resection of metastases in more than one organ has been successful in achieving long-term survival [1]. Aggressive surgical cytoreduction with intraperitoneal chemotherapy has been applied to patients with isolated peritoneal carcinomatosis, but the benefits of this approach remain controversial. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and 'CRS with or without HIPEC for peritoneal metastases' below and "Treatment of locally recurrent rectal adenocarcinoma".)
Surgical resection may also provide the best option for palliation of symptoms of obstruction and bleeding from the primary tumor in patients who are not candidates for a curative resection. (See "Surgical resection of primary colon cancer", section on 'Complicated disease'.)
This topic will review the management of the primary tumor (surgical and nonsurgical options) in patients who present with metastatic CRC, and surgical cytoreduction and intraperitoneal chemotherapy for isolated peritoneal carcinomatosis. General surgical principles in patients with primary colon cancer, management of patients with isolated, potentially resectable liver metastases, surgical management of lung metastases, and post-treatment surveillance are discussed in detail separately. (See "Surgical resection of primary colon cancer" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Post-treatment surveillance for colorectal cancer".)
OUTCOMES AFTER RESECTION OF ISOLATED METASTATIC DISEASE —
Surgery provides a potentially curative option for selected patients with limited metastatic disease. Long-term survival can be achieved with metastasectomy in as many as 50 percent of cases, and an aggressive surgical approach to both the primary and the metastatic sites is warranted in conjunction with systemic chemotherapy.
Limited hepatic and pulmonary metastatic disease — Management of potentially resectable hepatic metastases (including a discussion as to integration of systemic chemotherapy into the surgical paradigm) and resection of pulmonary metastases are discussed in detail separately. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Hepatic resection for colorectal cancer liver metastasis" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)
Isolated adrenal metastasis — Adrenal metastases are uncommon (14 percent in one autopsy series [2]); isolated adrenal metastases are even more rare. Aggressive surgical resection for isolated adrenal metastases is described in only a few case reports or observational series [3-8]. In an observational series of eight patients with apparently isolated adrenal metastasis from CRC (all of whom underwent adjuvant chemotherapy), one remained alive and disease-free 12 months after adrenalectomy, one was lost to follow-up, and six died of malignancy. The mean survival of the patients who died was 32 (range 12 to 60) months.
In contrast to the situation with isolated adrenal metastases, the development of adrenal metastases after liver resection for CRC liver metastases is associated with a poor prognosis, and adrenalectomy is probably not warranted [9].
Ovarian metastases — The incidence of ovarian metastases (synchronous or metachronous) in patients with CRC is 1 to 14 percent. They are more common in premenopausal as compared with postmenopausal women, and with colonic rather than rectal primaries [10]. While it is generally acknowledged that ovarian metastases (particularly if synchronous and bilateral) represent a poor prognostic factor, complete resection may improve survival [11-13].
Bulky ovarian metastases are often symptomatic and less responsive to systemic chemotherapy than are other sites of disease [13,14]. Resection is associated with fairly low morbidity, and in some cases, may improve quality of life and prolong survival, even in the setting of widespread extra-ovarian metastatic disease [15,16].
Retroperitoneal lymph nodes — An isolated retroperitoneal nodal recurrence occurs in less than 2 percent of patients following a curative-intent colon cancer resection [17-20]. Salvage surgery had previously been avoided due to the poor prognosis of this group of patients [21,22]. However, this concept has been challenged since these series were conducted prior to the use of contemporary chemotherapy regimens (eg, oxaliplatin, irinotecan, cetuximab, bevacizumab). Advances in chemotherapy and radiation therapy (RT) techniques have led to the use of surgery as potentially curative therapy for patients with apparently isolated paraaortic lymph node metastases (PALNMs) [18,23-25].
In this context, the role of resection was revisited in a systematic review of 18 retrospective, single-center case series of patients with apparently isolated PALNMs, published between 1998 and 2015; 5 series addressed management of synchronous PALNMs, 11 addressed patients with metachronous PALNMs, and 2 collectively addressed both populations [20]. A total of 370 patients were included; 145 had synchronous, and 225 had metachronous PALNMs. Compared with patients who did not undergo a paraaortic lymph node dissection, the median survival was longer in those who did (34 to 40 versus 3 to 14 months, respectively). For synchronous PALNMs, the five-year survival after metastasectomy ranged from 23 to 34 percent, while for metachronous PALNMs, it was 15 to 60 percent. There were no surgical mortalities, and the overall surgical morbidity rate ranged from 8 to 33 percent. The role of adjuvant or neoadjuvant chemotherapy was not addressed. Others report that predictors of improved survival outcomes for patients with synchronous PALNMs include well-differentiated histology, a complete (R0) resection, and low-volume disease (ie, fewer than two PALNMs); among those with metachronous disease, a longer disease-free interval has been associated with improved survival [17-19]. These results are difficult to interpret because these are retrospective studies with a limited number of patients. Patients with better performance and prognosis are more likely to undergo operation, and some of the studies in this review included patients with local recurrence in the retroperitoneum as well as patients with extra-retroperitoneal disease.
In our view, resection is a reasonable option for patients with isolated retroperitoneal nodal metastases who have not progressed after systemic chemotherapy and who have no extra-retroperitoneal metastatic disease, those whose retroperitoneal lymph node metastases are located below the left renal vein, and those with metachronous disease and long disease-free intervals.
As is the case in patients with resected CRC hepatic or pulmonary metastases, it is unclear if the addition of chemotherapy improves overall survival (OS). There are limited data addressing the benefit of chemotherapy after resection of isolated retroperitoneal nodal disease. In our view, management must be individualized and discussed in a multidisciplinary setting. (See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Benefit of postresection adjuvant therapy' and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Postoperative management'.)
MANAGEMENT OF THE PRIMARY TUMOR —
Initial management of the primary tumor site in patients who present with metastatic CRC is controversial, and there are no data from prospective randomized studies to guide treatment. In general, the choice and sequence of treatment of the primary tumor are guided by the presence or absence of symptoms from the primary tumor and whether or not the metastases are potentially resectable:
●For patients who present with synchronous metastatic disease and a symptomatic primary tumor (obstruction, bleeding, perforation), resection of the primary tumor is warranted. Even patients with incurable metastatic disease can benefit from surgical palliation for symptoms of obstruction and bleeding from the primary tumor. (See 'Symptomatic primary tumor' below.)
●For symptomatic patients who are not candidates for resection of the primary, proximal diversion or nonsurgical methods of palliation (endoluminal placement of a self-expanding metal stent or laser ablation for nonobstructing tumors) can be attempted. (See 'Nonsurgical palliative options' below.)
●For patients who are asymptomatic and who have potentially resectable metastatic disease, resection of the primary is also indicated as part of an aggressive management strategy aimed at cure. Issues related to the sequence and timing of resection of the primary and metastases in patients presenting with synchronous hepatic metastases are discussed separately. (See "Hepatic resection for colorectal cancer liver metastasis".)
●For patients with asymptomatic primary tumors and unresectable metastatic disease, we do not offer primary tumor resection. (See 'Unresectable metastatic disease' below.)
Surgical issues
Symptomatic primary tumor — For patients with a symptomatic primary tumor, the decision to proceed with surgery needs to be individualized depending on the presenting symptoms and signs as well as the extent of the metastatic disease. In general, patients with a perforated tumor need surgery, while for those with bleeding or obstruction, decisions regarding surgery are dependent on the clinical situation. (See "Surgical resection of primary colon cancer", section on 'Complicated disease'.)
Endoscopically deployed self-expanding metal stents (SEMS) may be used in the setting of obstruction, either as an independent solution or as a strategy to allow for bowel decompression to reduce the risk that operation leads to colostomy. (See 'Intraluminal stent placement' below.)
Initial systemic chemotherapy is an option for some patients, particularly those presenting with synchronous metastatic disease. Although the primary tumor may respond to contemporary systemic therapy regimens, this response may not be as robust in the primary site as it is in the liver metastases [26]. As a result, for patients with an in situ primary tumor (whether symptomatic or not) who are receiving chemotherapy, it is imperative to endoscopically evaluate the primary site periodically. (See "General principles of systemic therapy for metastatic colorectal cancer" and "Initial systemic therapy for metastatic colorectal cancer".)
If the patient is not a surgical candidate because of comorbidities, high operative risk(s), decreased life expectancy, or refuses surgery, nonsurgical options can be considered. (See 'Nonsurgical palliative options' below.)
Asymptomatic primary tumor — In practice, the decision to pursue surgical resection of an asymptomatic primary site is based on the resectability of metastatic disease.
Resectable metastatic disease — For most patients with resectable and potentially curable metastatic disease who are asymptomatic from the primary tumor, we suggest initial systemic chemotherapy rather than upfront resection to allow the natural history of disease progression to manifest. In the absence of widespread disease progression, re-evaluation and resection of both the primary tumor and metastases is reasonable if it is consistent with the patient's goals of care.
If the metastases are potentially resectable for cure, then an aggressive surgical approach is warranted for both the primary and metastatic sites with the aim of curing the patient. However, in our view, if there are five or more simultaneous, potentially resectable hepatic metastases (unless all are located in one lobe), extensive bilobar involvement, or if disease is borderline resectable due to location, initial chemotherapy followed by reassessment and delayed resection is probably a better strategy than upfront surgery. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Are there patients who might benefit from upfront chemotherapy?'.)
There are considerable differences in the approach to synchronous potentially resectable metastatic disease. Some reports indicate a poor prognosis in such patients, at least in part attributable to the failure to resect clinically occult micrometastatic liver disease [27,28].
One approach to address this concern is initial chemotherapy, which might also allow some patients with initially borderline resectable liver metastases to undergo successful hepatic resection. If there is widespread disease progression during chemotherapy, resection will likely provide no specific benefit. If, on the other hand, the disease has responded or is stable, resection of both the primary tumor and the metastatic disease could be attempted in either a single or separate operations. Survival rates after resection of colorectal carcinoma liver metastases are better in patients who experience an objective response to chemotherapy [29]. This needs to be balanced against the complexities introduced into liver resections in the event that upfront chemotherapy induces lobular sinusoidal distention ("blue liver") or steatohepatitis ("yellow liver"). This subject is discussed in detail separately. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Are there patients who might benefit from upfront chemotherapy?'.)
Another point of debate is whether the surgery should be carried out simultaneously or colorectal resection first followed by hepatectomy or hepatectomy first followed by resection of the primary tumor [26]. For most patients, simultaneous resection of the primary and metastatic disease is clearly preferable from the patient's perspective, and several surgical case series and meta-analyses have failed to confirm inferior survival or greater morbidity for patients who undergo a one-stage procedure compared with delayed (staged) hepatic resection, unless major hepatic resection (three or more segments) is needed [30-37]. Factors that influence a decision on single operation versus a staged approach include the anticipated complexity of the colectomy or proctectomy, the size of the future liver remnant, the likelihood of major blood loss or prolonged hepatic ischemic times, and patient comorbidities. Because of the incidence of synchronous second primary CRCs (approximately 3 to 5 percent), complete colonoscopy prior to surgical resection should be undertaken, if feasible. (See "Post-treatment surveillance for colorectal cancer", section on 'Diagnosing second cancers and polyps'.)
Unresectable metastatic disease — We recommend against primary tumor resection to patients with unresectable metastatic disease who are asymptomatic from their primary tumor. Most randomized trials have failed to demonstrate an overall survival (OS) advantage for the addition of primary tumor resection to systemic therapy in this population. In addition, the risk of surgical complications from a primary tumor resection generally outweighs the potential risks of leaving the primary tumor surgically intact. Surgical complications can also delay (or even preclude) necessary systemic therapy.
Data that support foregoing primary tumor resection in this population are as follows:
●Lack of OS benefit for primary tumor resection – Although observational studies initially suggested that primary tumor resection was associated with an OS advantage in this population [38-43], these outcomes may have been influenced by a selection bias toward surgery (which is typically offered to healthier patients). Subsequently, most randomized trials, but not all [44], have failed to demonstrate an OS benefit for the addition of primary tumor resection to systemic therapy in this population [45-49]. As examples:
•In a combined analysis of two multicenter randomized clinical trials (SYNCHRONOUS and CCRe-IV), 393 patients with synchronous unresectable metastatic CRC were randomly assigned to undergo either primary tumor resection or no primary tumor resection prior to initial chemotherapy [49]. Patients with tumor-related symptoms or diagnostic findings requiring primary surgery (eg, lower GI [gastrointestinal] bleeding requiring transfusion, bowel obstruction, tumor perforation, intractable pain) were ineligible for study enrollment. At a median follow-up of 37 months, upfront primary tumor resection failed to improve OS compared with immediate systemic therapy (median OS 17 versus 19 months, hazard ratio [HR] 0.94, 95% CI 0.74-1.21).
•In a separate randomized trial (Japan Clinical Oncology Group [JCOG] 1007), 165 patients with incurable metastatic CRC and no symptoms attributable to the primary tumor were randomly assigned to primary tumor resection plus oxaliplatin-based chemotherapy versus chemotherapy alone [46]. At a median follow-up of 22 months, the addition of primary tumor resection to chemotherapy failed to improve three-year OS (33 percent for both treatment arms). Furthermore, among the 81 patients treated with primary tumor resection, there were three deaths (4 percent) due to postoperative complications. Of note, study accrual was terminated early for futility after a preplanned interim analysis.
•In a phase III trial (CAIRO4) of 198 patients with synchronous unresectable metastatic CRC and few or no symptoms related to the primary tumor, the addition of primary tumor resection to fluoropyrimidine plus bevacizumab-based chemotherapy increased sixty-day mortality (3 versus 11 percent) [47]. At a median follow-up of 69 months, this approach also failed to improve OS (median 20 versus 18 months) [50].
●What are the risks of observing the primary tumor? – In patients with metastatic disease and an intact asymptomatic primary tumor who are managed (at least initially) without primary tumor resection, data suggest a relatively low risk of GI bleeding (approximately 3 percent) or bowel obstruction/perforation (between 7 to 14 percent) [45,51-55]. The risk of future bowel obstruction may also be lower with right-sided than left-sided primary tumors. However, even patients at high risk for subsequent complications due to tumor site or colonoscopic findings (ie, a nearly obstructing lesion or inability to advance an endoscope beyond the tumor) can be well controlled with systemic therapy [56].
As an example, in a phase II trial (National Surgical Adjuvant Breast and Bowel Project [NSABP] C-10), 86 patients with metastatic disease and an asymptomatic primary tumor who could safely be spared an initial resection were treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in combination with bevacizumab without resection of the primary tumor [55]. At a median follow-up of 21 months, the incidence of major morbidity was 16 percent. Surgery was eventually required for 10 patients (12 percent) due to either bowel obstruction, perforation, or pain. There were two patient deaths (one from bowel obstruction and one from bowel perforation). Median OS was 20 months and did not appear to be compromised by leaving the primary tumor intact.
●What are the risks of resecting the primary tumor? – On the other hand, primary tumor resection is associated with possible surgical morbidity and mortality in this population. For patients with metastatic CRC who undergo primary tumor resection, the risk of postoperative morbidity is between 20 to 30 percent, and the risk of perioperative mortality is between 1 to 6 percent [49,51,53,57,58].
Postoperative complications can also delay (or even preclude) necessary systemic therapy [47,49]. In a combined analysis of two randomized trials (SYNCHRONOUS and CCRe-IV), upfront primary tumor resection resulted in a high postoperative complication rate (23 percent) and was associated with a lower likelihood of receiving chemotherapy [49].
Methods for surgical palliation — The methods for surgical palliation for patients with symptomatic colon or rectal cancer with incurable metastatic disease are listed below and are discussed separately (see "Surgical resection of primary colon cancer", section on 'Metastatic disease'):
●Resection of cancer and primary anastomosis
●Diverting end colostomy with mucous fistula
●Bypass procedure
Nonsurgical palliative options
Intraluminal stent placement — Successful local palliation of an obstructing or nearly obstructing tumor may be achieved through endoscopic or radiographic placement of SEMS. Among the advantages of SEMS over palliative surgery are a faster recovery time (permitting earlier administration of chemotherapy) and a shorter hospital stay [59-61].
Potential complications include perforation and stent migration. As an example, in a retrospective series of 37 patients undergoing placement of a SEMS for an obstructing rectosigmoid cancer, three had early stent dislodgement [62]. At a median follow-up of seven months, 27 (78 percent) had successful restoration of luminal patency and resolution of obstructive symptoms; two patients required a second stent placement because of tumor growth either at the distal or proximal end, two had delayed perforations, and one had a late distal migration. Tumor ingrowth has only occasionally been reported; when it occurs, it can be successfully treated with laser ablation and the insertion of overlapping stents. (See "Enteral stents for the management of malignant colorectal obstruction".)
Accumulating data suggest a significantly increased risk of perforation in patients treated with the antiangiogenic agent bevacizumab. Thus, colonic stenting should not be performed in patients who are receiving bevacizumab. In addition, patients with low-lying rectal cancer may develop rectal pain and/or tenesmus secondary to the stent. These data are addressed in detail separately. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Bevacizumab' and "Enteral stents for the management of malignant colorectal obstruction", section on 'Perforation'.)
Local tumor ablation — If the tumor is not completely obstructing, electrofulguration or laser ablation (using an Nd:YAG or argon ion [argon plasma coagulation or APC] laser) can be attempted to maintain the patency of the lumen [63-70]. Laser ablation is effective in restoring luminal patency in 88 to 97 percent of patients with obstructive symptoms [68-70]. However, most patients require more than one treatment session, and the risk of perforation is significant, especially with repeated applications. Furthermore, the duration of palliation may be short.
Electrofulguration and/or laser ablation can also be attempted in patients with rectal bleeding. Radiation therapy (RT) directed at the primary rectal tumor is another alternative to control bleeding.
Rectal cancer and the role of pelvic radiation therapy — There are established treatment paradigms for rectal cancer in patients without metastatic disease. Total mesorectal excision improves rates of local control and recurrence-free survival compared with other surgical options. For patients with T3 or node-positive disease, the addition adjuvant radiation therapy (RT) and adjuvant chemotherapy improves outcomes over radical surgery alone. The combination of preoperative chemotherapy and RT in patients with locally advanced disease is association with fewer local recurrences and improved sphincter preservation rates, although a survival benefit compared with postoperative chemoradiotherapy has not been shown. (See "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy", section on 'Stage II to III disease after transabdominal surgery' and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Long-course chemoradiation'.)
There are no established guidelines for treatment of the rectal primary in patients with resectable, synchronous liver metastases, and in particular, the role of pelvic RT. However, the available data support the view that in such patients, the predominant pattern of disease recurrence is distant, not local, and that the addition of pelvic RT does not significantly reduce rates of local recurrence or improve disease-specific survival. Thus, while RT has a clear role in improving rates of sphincter preservation for low-lying tumors, and in patients for whom the likelihood of achieving a complete (R0) resection is in doubt based on local disease extent, the omission of RT may be reasonable in patients without these issues who have a simultaneous diagnosis of resectable liver metastases. This subject is addressed in detail separately. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Local treatment for patients with distant metastases'.)
CRS WITH OR WITHOUT HIPEC FOR PERITONEAL METASTASES
Overt peritoneal carcinomatosis — The optimal management of patients with peritoneal carcinomatosis without distant disease after a rigorous diagnostic workup is controversial. Although long-term survival can be achieved in a limited number of patients using multimodality approaches such as aggressive cytoreductive surgery (CRS) with or without heated (hyperthermic) intraperitoneal chemotherapy (HIPEC) [71], there remains insufficient evidence to conclude whether any survival advantage seen in these patients is due to treatment or to biologic features that allow these patients to undergo complete CRS. Furthermore, because the quality of the CRS is dependent on the skills and level of experience of the surgeon, favorable results (particularly with regard to treatment-related toxicity [72-74]) achieved by international experts may not be replicated in routine clinical practice. The independent contribution of HIPEC to the success of this approach has not been proven, and a major unresolved issue is whether results with CRS with or without HIPEC are better than what could be achieved using oxaliplatin- and/or irinotecan-based systemic chemotherapy, with or without biologic agents.
For all of these reasons, in our view CRS with or without HIPEC is not a standard treatment approach for all patients with metastatic CRC and peritoneal metastases. CRS may be appropriate for selected patients without extraperitoneal metastases who are deemed amenable to complete resection after multidisciplinary assessment. Shared decision-making with the patient should emphasize the potential impact on quality of life and the rate of adverse events associated with CRS.
Furthermore:
●Most patients should undergo an initial period of systemic chemotherapy to ensure that those who have early evidence of dissemination to extraperitoneal sites can be spared the toxicity of CRS [75,76]. Some consensus-based guidelines suggest that upfront surgery may be reasonable for certain patients with low-risk disease (disease-free interval >1 year, younger age, node-negative, predicted low peritoneal cancer index [PCI]) [75]. If upfront CRS is chosen, postoperative adjuvant chemotherapy appears to be safe [77], and is a reasonable approach, particularly for those with synchronous peritoneal metastases [78].
●Although limited, at least some data suggest that patients with BRAF mutations have a particularly poor outcome from CRS with or without HIPEC, and these patients should be evaluated for alternative approaches [79].
●Appropriate patient selection is critical to the success of this approach, if it is chosen. CRS should not be attempted if the preoperative assessment of the PCI predicts incomplete cytoreduction [80]. CRS should only be pursued in centers with demonstrated expertise, preferably in the context of a clinical trial. An international list of centers with expertise in treatment of peritoneal surface malignancies is available online [81].
Frequency of isolated peritoneal metastases — Distinct from lymphatic and hematogenous spread, colon cancers may give rise to transcoelomic spread within the peritoneal cavity, resulting in peritoneal carcinomatosis. Peritoneal carcinomatosis carries a uniquely poor prognosis compared with metastatic disease in the visceral organs [82,83]. Most oncologists view peritoneal carcinomatosis as a non-curative condition, to be palliated only with systemic chemotherapy. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Treatment goals'.)
However, in approximately 25 percent of cases, the peritoneal cavity appears to be the only site of metastatic disease after a detailed workup of the lungs and liver. This has led some to hypothesize that in some cases, peritoneal carcinomatosis may represent a first site of dissemination, and therefore, not necessarily indicative of generalized disease [84-86]. This appears to be rare overall. In a combined series of 2095 patients with metastatic CRC who were enrolled in two chemotherapy trials, 364 (17 percent) had peritoneal carcinomatosis, but only 44 (2.1 percent) had peritoneal carcinomatosis as the sole presentation of metastatic disease [82].
Randomized trials of CRS with or without HIPEC — To date, four randomized controlled trials have been conducted of surgical cytoreduction with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal dissemination of CRC, none of which provide definitive results [87-90]. Only two used combination chemotherapy as the control comparator arm:
●In the first Dutch trial, 105 patients with established peritoneal carcinomatosis of colorectal (n = 87) or appendiceal (n = 18) origin were randomly assigned to cytoreductive surgery (CRS) and HIPEC with mitomycin followed by systemic chemotherapy (fluorouracil [FU] and leucovorin), or systemic FU and leucovorin alone with palliative debulking surgery as needed [87]. Despite the high postoperative mortality rate (8 percent), the median disease-specific survival in the intraperitoneal treatment group was significantly longer (22 versus 13 months, hazard ratio [HR] 0.55, 95% CI 0.32-0.95). At the latest analysis, median follow-up of eight years, only nine of the original 105 patients were still alive, five were progression-free [91].
This trial has a number of flaws that limit interpretation. Patients were relatively unselected for enrollment. A chest radiograph was sufficient to rule out the presence of thoracic metastases, and there were no entry requirements for likelihood of complete surgical cytoreduction either by preoperative abdominal CT or intraoperative evaluation. Furthermore, the control arm used chemotherapy that is inferior by contemporary standards. The use of a systemic oxaliplatin or irinotecan-containing regimen with a biologic agent in the control arm could potentially have narrowed and even eliminated the survival difference between the groups, since median survival durations in contemporary reports are beyond 24 months. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Overview of the therapeutic approach'.)
●The second trial, which also randomly assigned patients following aggressive CRS to systemic therapy (FU-based) with or without HIPEC, only accrued 35 of the planned cohort of 90 patients (30 CRC, 5 appendiceal cancers) [88]. Although the two-year survival rate of patients undergoing intraperitoneal chemotherapy was 60 percent (much higher than would be expected among patients treated with systemic FU/leucovorin chemotherapy), the difference in survival between the experimental and control groups was not statistically significant.
●Two trials included systemic oxaliplatin-containing chemotherapy, but only one had a chemotherapy alone control arm:
•The first trial was terminated prematurely due to recruitment difficulties after enrolling only 48 patients [89]. Patients who were deemed resectable preoperatively were randomly assigned to surgery and intraperitoneal FU (550 mg/m2 daily for six consecutive days with courses repeated monthly) or to a systemic oxaliplatin and FU-containing regimen every other week; both treatments continued for six months. Two-year overall survival (OS) was significantly better in the surgery arm (54 versus 38 percent), and after five years, eight surgically treated patients remained alive compared with one medically treated patient. The limited size of this study limits the conclusions that can be drawn from the analysis.
•The second trial, the multicenter PRODIGE 7 trial, randomly assigned 265 patients with metastatic CRC, isolated peritoneal metastases and a PCI <25 to CRS followed by HIPEC or to CRS alone; 96 percent of the patients in both arms received systemic chemotherapy (per clinician choice) for six months prior to surgery, after surgery, or both [90]. Assessment of the PCI, a quantitative indicator of prognosis derived from the size and distribution of nodules on the peritoneal surface as assessed by preoperative imaging or diagnostic laparoscopy [80], is discussed separately. (See "Epithelial tumors of the appendix", section on 'Patient selection'.)
At a median follow-up of 64 months, HIPEC did not increase median OS (median 41.7 versus 41.2 months; five-year survival 39 versus 37 percent), relapse-free survival, or 30-day morbidity relative to CRS alone, but it nearly doubled the rate of severe (grade 3 to 5) 60-day postoperative morbidity (26 versus 15 percent). At five years, approximately 15 percent of patients in each arm were recurrence free. Notably, 91 percent of the patients in this trial were able to achieve complete macroscopic cytoreduction. In an unplanned subgroup analysis patients with a PCI <10 or >15 derived no benefit from HIPEC, whereas there was a suggestion of an OS benefit for those with a PCI between 11 and 15 with an HR of 0.44 (95% CI 0.21-0.9).
While data from the PRODIGE 7 trial provide the clearest indicator for a lack of benefit for HIPEC in patients undergoing CRS, the role of CRS combined with systemic chemotherapy as compared with systemic chemotherapy alone remains uncertain. Randomized trials are still needed to assess the benefit of CRS relative to systemic chemotherapy alone, preferably stratified according to PCI.
High-risk patients — CRS with or without HIPEC cannot be recommended for high-risk patients in the absent of overt disseminated peritoneal metastases.
A different question, whether second-look surgery plus HIPEC could benefit patients at high risk for peritoneal recurrence, was addressed in the PROPHYLOCHIP-PRODIGE 15 trial, in which 150 patients who had a primary CRC with synchronous but localized colorectal peritoneal metastases removed during tumor resection, resected ovarian metastases, or a perforated tumor were randomly assigned to surveillance or second-look surgery (with resection of all peritoneal implants if resectable) plus HIPEC following six months of systemic chemotherapy with no evidence of disease recurrence [92]. Although more than one-half of the patients undergoing second-look surgery (37 of 71) had macroscopic peritoneal metastases, at a median follow-up of 51 months, three-year disease-free survival, the primary outcome, was not significantly better with early aggressive therapy (44 versus 53 percent with surveillance alone), and 41 percent had grade 3 or 4 complications from the procedure.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Colon and rectal cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Treatment of metastatic colorectal cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●General principles
•Surgery provides a potentially curative option for selected patients who present with limited metastatic colorectal cancer (CRC). If the metastases are potentially resectable, especially if they are located in one organ system (such as the liver or lung), both the primary and the metastases should be managed aggressively. With integration of surgery and chemotherapy, long-term survival can be achieved in as many as 50 percent of cases. (See 'Introduction' above.)
•Even patients who are not candidates for a curative resection can benefit from surgical palliation for symptoms of obstruction and bleeding from the primary tumor. These patients must be managed by a multidisciplinary team.
●Management of potentially resectable, isolated metastatic disease
•Hepatic metastases – Specific recommendations for surgical management of potentially resectable hepatic metastases (including a discussion as to integration of systemic chemotherapy into the surgical paradigm) and resection of pulmonary metastases are provided separately. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)
•Retroperitoneal lymph nodes – For patients with metastatic disease involving retroperitoneal lymph nodes, attempted resection is reasonable in very highly selected patients if the primary is controlled and the staging evaluation shows no evidence of disease at other sites, although recurrence rates are high. (See 'Retroperitoneal lymph nodes' above.)
•Isolated adrenal metastasis – For the rare patient with a single adrenal metastasis, resection is a reasonable option if the primary is controlled and the staging evaluation shows no evidence of extra-adrenal disease involvement; however, this decision must be individualized. (See 'Isolated adrenal metastasis' above.)
•Ovarian metastases – Resection is also reasonable for patients with symptomatic bulky ovarian metastases, even in the presence of extra-ovarian metastatic disease. (See 'Ovarian metastases' above.)
●Management of the primary tumor – Initial management of the primary site in patients who present with metastatic disease should be guided by the presence or absence of symptoms from the primary tumor and whether or not the metastases are potentially resectable:
•Symptomatic primary tumor – For patients with synchronous metastatic disease and a symptomatic primary tumor, the decision to proceed with surgery needs to be individualized depending on the presenting symptoms and signs, as well as the extent of the metastatic disease. In general, patients with a perforated tumor need urgent surgery, while for those with bleeding or obstruction, decisions regarding surgery are dependent on the clinical situation. Initial systemic chemotherapy is an option for some patients. (See 'Symptomatic primary tumor' above and "Surgical resection of primary colon cancer", section on 'Complicated disease'.)
For symptomatic patients who are not candidates for resection of the primary tumor, other options to manage the primary tumor include surgical bypass, diverting colostomy and mucous fistula or loop colostomy, placement of an intraluminal self-expanding metal stent, or for nonobstructing tumors, laser ablation. (See 'Methods for surgical palliation' above and "Surgical resection of primary colon cancer", section on 'Metastatic disease'.)
•Asymptomatic primary tumor with resectable metastases – For most patients with resectable and potentially curable metastatic disease who are asymptomatic from the primary tumor, we suggest initial systemic chemotherapy rather than upfront resection (Grade 2C) to allow the natural history of disease progression to manifest. In the absence of widespread disease progression, reevaluation and resection of both the primary tumor and metastases is reasonable if it is consistent with the patient's goals of care. (See 'Asymptomatic primary tumor' above.)
•Asymptomatic primary tumor with unresectable metastases – For patients with unresectable metastatic disease who are asymptomatic from the primary tumor, we recommend against upfront primary tumor resection (Grade 1B). Primary tumor resection does not confer an overall survival (OS) advantage in most randomized trials, and the risk of surgical complications generally outweighs the potential risks of leaving the primary tumor surgically intact. Surgical complications can also delay (or even preclude) necessary systemic therapy. (See 'Unresectable metastatic disease' above.)
●Peritoneal carcinomatosis – The optimal management of patients with apparently isolated peritoneal carcinomatosis after a rigorous diagnostic workup is controversial. Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is not a standard treatment approach for all such patients. CRS may be appropriate for selected patients without extraperitoneal metastases who are deemed amenable to complete resection after multidisciplinary assessment. Shared decision-making should emphasize the potential impact on quality of life and the high rate of adverse events. If chosen, CRS should only be pursued in centers with demonstrated expertise. (See 'Overt peritoneal carcinomatosis' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Miguel A Rodriguez-Bigas, MD, who contributed to earlier versions of this topic review.
