Version May 2024
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. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Systemic therapy versus supportive care' and "Systemic therapy for metastatic colorectal cancer: General principles".)
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 stage IV 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 elsewhere. (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 after colorectal cancer treatment".)
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 elsewhere. (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 metastases — 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 small series [3-8]. In the largest 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. These series were largely collected over a time period when new chemotherapy regimens were evolving (eg, oxaliplatin, irinotecan, cetuximab, bevacizumab). In more recent years, advances in chemotherapy and radiation therapy techniques have led to their use 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 small number of patients, 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 the observed survival statistics. There are no data addressing the benefit of chemotherapy after resection of isolated retroperitoneal nodal disease. Consensus-based guidelines for management of resectable metachronous metastases from the National Comprehensive Cancer Network [26] do not distinguish among different sites of metastatic disease, and they recommend adjuvant therapy if there was no previous chemotherapy, and a variety of options for those who have received chemotherapy, including upfront resection or neoadjuvant chemotherapy. 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 CANCER — Initial management of the primary site in patients who present with stage IV disease 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' below.)
●For 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 elsewhere. (See "Hepatic resection for colorectal cancer liver metastasis".)
●For patients with asymptomatic primary tumors and unresectable metastatic disease, we agree with consensus-based guidelines of the National Comprehensive Cancer Network (NCCN) [26], and do not advocate primary site resection. (See 'Incurable metastatic disease' below.)
Surgical issues
Symptomatic primary — 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 stage IV disease. Although with the newer chemotherapeutic regimens there may be a response in the primary tumor, this response may not be as robust in the primary site as it is in the liver metastases [27]. 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 "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)
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 — In practice, the decision to pursue surgical resection of an asymptomatic primary site is based on the curability of metastatic disease.
Potentially curable metastatic disease — 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 [28,29].
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 [30]. This subject is discussed in detail elsewhere. (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 [27]. 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 [31-38]. 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 after colorectal cancer treatment", section on 'Diagnosing second cancers and polyps'.)
Incurable metastatic disease — For patients with incurable metastatic disease who are receiving systemic chemotherapy and who are asymptomatic from the primary tumor, there is no benefit for initial resection of the primary tumor, and we suggest not pursuing this approach.
The decision as to whether to resect the primary tumor is more complex for asymptomatic patients who have unresectable metastatic disease compared with those with potentially curable metastases; in such patients, the risk to benefit ratio of resecting the primary tumor must be carefully considered. Resecting the primary is not without risk. For patients with metastatic CRC who undergo surgery, there is a 20 to 30 percent risk of postoperative morbidity, and a 1 to 6 percent risk of perioperative mortality [39-41]. Postoperative complications typically delay (or even preclude) chemotherapy.
The two most important issues are whether deferring surgery increases the risk of an emergent presentation with a bowel obstruction, perforation, or bleeding; and whether there is any survival benefit for upfront resection of the primary.
●What is the risk of bleeding or obstruction/perforation with an intact primary tumor? – The available data suggest that there is a relatively low risk of bleeding (3 percent) or obstruction/perforation (7 to 14 percent) in patients who present with stage IV disease and an intact asymptomatic primary who are managed at least initially without resection [39,42-46]. As examples:
•In one large series, only 16 of 233 patients (7 percent) initially unresected patients required emergency surgery for obstruction or perforation [42]. For those who did require emergency surgery, the perioperative mortality rate was relatively high (13 percent).
•Additional data are available from a phase II trial of the National Surgical Adjuvant Breast and Bowel Project (NSABP C-10 trial) in which all enrolled patients were treated with fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in combination with bevacizumab without resection of the primary tumor [46]. The primary objective of the study was to determine the rate of major morbidity, while the secondary objectives included survival, chemotherapy-related toxicity, and determination of the specific events related to the primary tumor that require hospitalization or major intervention, but not surgery. In this study, the majority of patients with metastatic disease and an asymptomatic primary tumor could be safely spared an initial resection. At a median follow-up of 20.7 months, the cumulative incidence of major morbidity was 16.3 percent, and only 10 of the 86 enrolled patients (12 percent) required surgery (eight for obstruction, one for perforation, and one for pain). There were two patient deaths (one from obstruction and one from perforation) and four secondary events, of which three were obstruction and one was percutaneous drainage of an abscess. Survival did not appear to be compromised by leaving the primary tumor intact (median overall survival 19.9 months).
There are no specific criteria for identifying patients with unresected CRC who are likely to suffer complications and require surgery during systemic therapy. The risk of future obstruction may be lower with right as compared with left-sided tumors. However, others have shown that even patients who appear to be at high risk for subsequent complications because of tumor site or colonoscopic findings (ie, a nearly obstructing lesion or inability to advance the scope beyond the tumor) can be well controlled with modern chemotherapy, obviating the need for palliative surgery [47].
Largely because of these issues, and the high rates of morbidity with primary tumor resection in patients with unresectable distant metastases (12 and 21 percent for major and minor morbidity, respectively, in one report [43]), guidelines from the NCCN [26] suggest that bowel resection be considered in asymptomatic individuals with unresectable metastatic disease only if there is an imminent risk of obstruction or significant bleeding.
●Is there a survival benefit for palliative resection? – The philosophy of deferring primary site resection in asymptomatic patients with incurable metastatic disease has been called into question by several analyses suggesting that resection of the primary may slow progression and favorably impact survival. However, the results of the meta-analyses that have taken the use of systemic chemotherapy into account have been conflicting [45,48].
A lack of a survival benefit for primary tumor resection has been shown in several randomized trials, one of which suggests that survival may in fact be adversely impacted [49-51]. As examples:
•In the Japan Clinical Oncology Group [JCOG] trial 1007 165 patients with incurable stage IV CRC and no symptoms attributable to the primary tumor were randomly assigned to primary tumor resection plus modern oxaliplatin-containing chemotherapy versus chemotherapy alone [49]. At a median follow-up of 22 months, neither three-year overall survival (33 versus 32.9 percent) nor median progression-free survival (10.4 versus 12.1 months) was significantly improved with resection of the primary tumor. Furthermore, there were three postoperative deaths among the 81 patients allocated to primary tumor resection due to postoperative complications. Rates of primary site complications were not reported, but secondary palliative surgery was only needed in 11 (13 percent) of the 84 patients randomized to chemotherapy alone.
Notably, the initial sample size to detect a survival difference of 24 versus 20 months for the addition of primary tumor resection to chemotherapy was 780 patients; study accrual was stopped prematurely after a preplanned interim analysis, which recommended termination of the trial based on futility.
•The CAIRO4 trial randomly assigned 198 patients with synchronous unresectable metastatic CRC and few or no symptoms related to the primary tumor to systemic fluoropyrimidine plus bevacizumab based-chemotherapy only or primary tumor resection followed by systemic chemotherapy [50]. Sixty-day mortality was significantly higher among those undergoing primary tumor resection (3 versus 11 percent, p = 0.03). Notably, only one of the 11 deaths in the primary tumor resection arm was directly related to surgery while four were related to disease progression shortly after surgery. The median time between surgery and start of systemic treatment was 29 days (interquartile range 25 to 35 days). Overall survival results were not mature.
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 [52-54].
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 [55]. 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 elsewhere. (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 [56-63]. Laser ablation is effective in restoring luminal patency in 88 to 97 percent of patients with obstructive symptoms [61-63]. 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 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 in patients not receiving neoadjuvant therapy", section on 'Stage II to III disease following 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 elsewhere. (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 small number of patients using multimodality approaches such as aggressive cytoreductive surgery (CRS) with or without heated (hyperthermic) intraperitoneal chemotherapy (HIPEC) [64], 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 [65-67]) 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 modern 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 should not yet be considered a standard approach for treatment of metastatic CRC with 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 [68,69]. 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 PCI) [68]. If upfront CRS is chosen, postoperative adjuvant chemotherapy appears to be safe [70], and is a reasonable approach, particularly for those with synchronous peritoneal metastases [71].
●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 considered for alternative approaches [72].
●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 [73]. 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 [74].
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 [75,76]. Until more recently, most oncologists viewed peritoneal carcinomatosis as a terminal condition, to be palliated only with systemic chemotherapy. (See "Systemic therapy for metastatic colorectal cancer: General principles", 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 [77-79]. 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 [75].
Randomized trials of CRS with or without HIPEC — To date, four randomized controlled trials have been conducted of surgical cytoreduction with or without HIPEC for patients with peritoneal dissemination of CRC, none of which provide definitive results [80-83]. Only two used modern 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 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 [80]. 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, 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 [84].
This trial has a number of flaws that limit interpretation. Patients were relatively unselected for enrollment. A chest x-ray 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 modern standards. The use of a modern 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", 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) [81]. 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 modern 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 [82]. 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 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 very small 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 stage IV CRC, isolated peritoneal metastases and a peritoneal cancer index (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 [83]. 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 [73], is discussed elsewhere. (See "Epithelial tumors of the appendix", section on 'Patient selection'.)
At a median follow-up of 64 months, HIPEC did not increase median overall survival (median 41.7 versus 41.2 months; five-year survival 39 versus 37 percent), relapse-free survival, or 30-day morbidity relative to cytoreductive surgery 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 overall survival benefit for those with a PCI between 11 and 15 with a hazard ratio 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 as compared with modern systemic chemotherapy alone remains uncertain. Randomized trials are still needed to assess the benefit of CRS relative to modern systemic chemotherapy alone, preferably stratified according to PCI.
Expert group recommendations — Recommendations for the utility of CRS with or without HIPEC in patients with metastatic CRC are available from the National Comprehensive Cancer Network (NCCN), Society of Surgical Oncology, and the American Society of Clinical Oncology (ASCO).
●NCCN guidelines state that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for select patients with limited peritoneal metastases, for whom R0 resection can be achieved [26].
●A year 2007 consensus statement from the Society of Surgical Oncology endorses early referral to a peritoneal surface malignancy center for completeness of cytoreduction assessment for those without extraperitoneal disease after a rigorous diagnostic workup, and CRS with HIPEC for those deemed amenable to complete cytoreduction [85]. These guidelines have not been updated since the publication of PRODIGE 7.
●A year 2022 ASCO guideline on metastatic CRC [86] recommends CRS in conjunction with systemic for selected patients with colorectal peritoneal metastases (evidence-based, benefits outweigh harms, evidence quality moderate, strength of evidence weak), largely based on the randomized Dutch trial and the long-term outcomes of PRODIGE 7 [80,83]. This recommendation applies to patients who are deemed amenable to complete resection, and who have no extraperitoneal metastases, and is regardless of prior treatment. Patients being considered for this approach should be referred to specialized centers with substantial clinical expertise, and decision making should include both multidisciplinary input, and a discussion with the patient about the potential impact on quality of life and the rate of adverse events associated with CRS. They also recommend against the addition of HIPEC to CRS based on the PRODIGE 7 trial (evidence-based, harms outweigh benefits, evidence quality moderate, strength of recommendation: strong).
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 colorectal cancer 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 [87]. 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: Colorectal cancer treatment; metastatic 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.
•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. (See 'Introduction' above.)
●Potentially resectable hepatic, lung, adrenal, and ovarian metastases and retroperitoneal lymph nodes
•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 elsewhere. (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".)
•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.)
•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 metastases' above.)
•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 stage IV disease should be guided by the presence or absence of symptoms from the primary tumor and whether or not the metastases are potentially resectable:
•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' 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'.)
•For most patients who present with potentially curable stage IV disease and who are not symptomatic from the primary tumor we suggest initial systemic chemotherapy rather than upfront resection to allow the natural history of disease progression to become manifest (Grade 2C). 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' above.)
•For patients with incurable metastatic disease who are receiving systemic chemotherapy and who are asymptomatic from the primary tumor, there is no benefit for initial resection of the primary tumor, and we suggest not pursuing this approach (Grade 2B). (See 'Incurable 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 HIPEC should not yet be considered a standard approach for treatment of 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.
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