convert an unresectable patient to resectable status. The duration of treatment in these patients is

important. There is a need to balance the minimum time required to achieve a response that will make

the patient resectable, while avoiding hepatotoxicity from the chemotherapeutic agents. Both FOLFOX

and FOLFIRI increase resectability in 12.5% to 40% of patients initially considered unresectable. A

study has shown that adding irinotecan to FOLFOX (FOLFIRINOX) in patients with initially unresectable

metastasis increased the resection rate compared to FOLFOX alone.311 Adding EGFR inhibitors to

FOLFOX or FOLFIRI increased the resectability rate in patients with wild-type KRAS/NRAS tumors and

initially unresectable liver metastasis.312,313 Angiogenesis inhibitors combined with FOLFIRI modestly

increase resectability of initially unresectable liver metastasis compared to FOLFIRI alone, but have no

effect when combined with oxaliplatin-containing regimens.314,315 To limit FOLFOX- and FOLFIRIassociated toxicity, patients receiving systemic chemotherapy to increase resectability should be

evaluated for response every 2 months, and undergo surgery as soon as they become resectable.

Treatment of Peritoneal Carcinomatosis

Most patients with peritoneal carcinomatosis have widespread metastatic disease, and are treated with

systemic chemotherapy. The treatment of patients with the peritoneum as the only site of metastasis is

controversial.316,317 Complete cytoreductive surgery (CRS), with removal of all visible abdominal and

pelvic disease, and hyperthermic intraperitoneal chemotherapy (HIPEC) are now commonly used in

patients with peritoneum-only metastatic CRC. The most commonly used drug for intraperitoneal

chemotherapy is mitomycin C, which is minimally active against CRC. As experimental data do not

support any biologic benefit from the hyperthermia component, the role of HIPEC has been questioned.

Oxaliplatin, irinotecan, doxorubicin, paclitaxel, and carboplatin have also been tested. Comparative

studies have not shown a conclusive advantage of mitomycin C over oxaliplatin.318 This aggressive

treatment is associated with significant mortality (0.9% to 5%) and morbidity (12% to 52%), with the

most common complications being surgical site infection, hematologic toxicity, and intestinal fistula.

Many single institution case series have reported improved survival in patients treated with CRS and

HIPEC followed by systemic chemotherapy, compared to systemic chemotherapy alone. A recent review

of 19 studies conducted from 1999 to 2009 reported a median survival of 33 months for patients treated

with CRS and HIPEC versus 12.5 months for patients undergoing palliative surgery and/or systemic

chemotherapy.319 These studies have been criticized because of strong patient selection bias favoring

peritoneum-only disease in the CRS/HIPEC group, an undefined role for palliative treatment, and

suboptimal chemotherapy in the nonsurgical group. The only prospective trial published so far

randomized patients to 5-FU/LV with palliative surgery versus CRS, HIPEC, and postoperative 5-FU/LV.

OS was 12.6 months in the standard arm versus 22.2 months in the HIPEC group.320 This study has been

criticized because it also included patients with pseudomyxoma peritonei of appendiceal origin, and

because it was conducted before most of the drugs currently used in metastatic disease were available.

In spite of this criticism, CRS and HIPEC are commonly performed regimens for patients with

peritoneum-only colorectal metastasis.321

The selection criteria for this complex and potentially morbid treatment are not well defined. The

most important prognostic factors in patients undergoing CRS and HIPEC are the Peritoneal Cancer

Index (PCI), a grading of tumor burden at the time of surgery, and the completeness of cytoreduction

(CC) score. Unfortunately, the determinants of these scores are only available at the time of abdominal

exploration during surgery. Therefore, they have not been useful in selecting those patients more likely

to benefit from CRS and HIPEC. Recently, a Peritoneal Surface Disease Severity Score (PSDSS) that

includes patient symptoms, extent of peritoneal dissemination, and primary tumor histology has been

developed to stratify patients at the time of diagnosis, without the need of an operation.322 The PSDSS

score system has been found to be an independent prognostic factor in multivariate analysis, not only

for patients undergoing CRS and HIPEC, but also for patients treated with systemic chemotherapy. This

score may help eliminate selection bias in future comparisons of different treatments, in patients with

peritoneum-only metastatic CRC.

TREATMENT OF LOCALLY RECURRENT CRC

LR after curative-intent surgery is defined as a relapse of tumor in the surgical field of the initial

procedure, including the anastomosis, regional nodes, surgical scars, and drain tracts.323 While most

patients with LR also have distant metastasis, a few have isolated LR. A complete surgical resection is

the only curative option for patients with isolated locally recurrent CRC, but is associated with

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considerable morbidity and mortality.324 In spite of this criticism, CRS plus HIPEC is commonly

performed for patients with peritoneum-only colorectal metastasis.

The risk of LR is higher for rectal cancer compared to colon cancer, for advanced stage tumors (T4),

for tumors with high-risk histologic features (lymphovascular and perineural invasion, grade III or IV,

signet ring cell histology), perforating or obstructing tumors, and patients with close or involved CRM.

Most local recurrences present within 3 years after the primary surgery, but LR tends to occur later in

patients treated with CRT and surgery, compared to those treated with surgery alone. In the Dutch TME

trial, 10% of LRs occurred more than 3 years after surgery in patients treated with TME, versus 31% in

patients treated with preoperative RT and TME.325

While some LRs are detected though surveillance, while asymptomatic, most are diagnosed after they

become symptomatic. Symptoms of local recurrence include bowel obstruction, abdominal distension,

rectal or vaginal bleeding, and urinary problems.326 Pelvic pain is common, and is a predictor of

reduced long-term survival.327 A common manifestation in patients who have had abdominoperineal

resection (APR) is a nonhealing perineal wound. Whenever symptoms suggestive of recurrence arise, a

detailed history and complete physical examination must be done. This includes DRE in patients who

have undergone sphincter-preserving surgery, and a pelvic examination in females. If recurrent tumor is

identified, endoscopy and imaging studies will help assess extent of disease and surgical risk. A

complete colonoscopy should be performed if possible. Intraluminal recurrences are easily diagnosed

with endoscopy and biopsy. Cystoscopy is required for patients who present with urogenital symptoms,

as these strongly indicate tumoral invasion of the ureters and bladder.328 CEA is routinely measured

during follow-up surveillance after primary rectal cancer resection. Elevation of this tumor marker is

frequently the first sign of recurrence329; however, elevated CEA is present in only about 50% of

patients. Patients with elevated CEA should undergo further work-up with imaging studies.

A CT scan of the chest, abdomen, and pelvis is the primary imaging modality used in these patients,

and it is especially helpful in identifying metastases in the liver, lung, and peritoneum, and evaluating

regional adenopathy.330 MRI is more accurate than CT in detecting and staging pelvic LR331; although it

has been ineffective when added to routine follow-up in detecting ERUS it may be useful in diagnosing

LR after LE of distal rectal cancer.332 Positron emission tomography (PET) using the glucose analog

fluorodeoxyglucose (FDG), particularly when combined with a CT scan, is helpful in distinguishing

between postsurgical changes and tumor recurrence. In a recent meta-analysis comparing FDG-PET,

FDG-PET/CT, CT, and MRI in the detection of recurrent CRC in patients with high suspicion of

recurrent disease, based on symptoms or elevated CEA, FDG-PET and FDG-PET/CT performed more

accurately than CT scan.333 PET/CT also demonstrated greater accuracy than MRI in identification of

lymph node recurrence in a lesion levels analysis.334 Overall accuracy of FDG-PET/CT is slightly higher

than FDG-PET: 92.3% (94% sensitivity, 77.2% specificity) versus 89% (90.3% sensitivity, 80%

specificity).335 However, lesions measuring less than 1 cm in diameter are more difficult to detect with

PET scanning, as are mucinous tumors, due to poor FDG uptake. Finally, FDG-PET cannot be used to

detect or evaluate LR if there is residual inflammation of the tumor bed secondary to chronic leaks.

Regardless of the imaging studies used to help diagnose LR, histologic confirmation is imperative.

Anastomotic recurrences should be biopsied endoscopically; extraluminal recurrences can usually be

biopsied percutaneously, under radiologic (CT) guidance.

7 The treatment of locally recurrent CRC should be discussed in a multidisciplinary setting, since it

often involves colorectal surgical oncologists, radiation oncologists, medical oncologists, and other

specialists. Patients with multifocal LR should be treated with systemic chemotherapy, as in metastatic

disease. Only patients with localized LR and good performance status are candidates for surgical

resection. Even these patients may benefit from additional systemic chemotherapy or chemoradiation, if

they did not receive it at the time of treatment of the primary tumor.336 Some patients with recurrent

rectal cancer treated initially with standard doses of radiation (50.4 Gy in 180 cGy fractions, or

biologically equivalent total dose), can be re-irradiated to the gross tumor volume using small fractions

(180 to 200 cGy), with or without sensitizing chemotherapy.336 Re-irradiation seems to increase the

possibility of an R0 resection in patients with resectable disease, or provides good palliation in

unresectable patients. Following preoperative chemotherapy and/or radiotherapy, re-staging should be

done to exclude interim development of distant metastasis and to ascertain the extent of the LR.

Surgery is the only curative option for patients with locally recurrent rectal cancer. Without

treatment, median survival is typically 6 to 7 months

337; systemic chemotherapy can prolong survival,

similar to patients with systemic recurrence. Only patients with good performance status, with

recurrences that, based on anatomical location, are amenable to an R0 resection, should be considered

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surgical candidates. A resection with gross positive margins (R2) should not be attempted, because it

provides no oncologic advantage to the patient and is associated with significant morbidity. Patients

found to have microscopic positive margins (R1) may benefit from intraoperative radiation. However,

this modality is only available at some institutions, and requires preoperative planning. Therefore, the

treatment of locally recurrent CRC should be limited to institutions with appropriate expertise and

equipment.

Only about one-third of patients with isolated locally recurrent CRC are candidates for surgical

salvage with curative intent. In the Intergroup Study 0114, which investigated several chemotherapy

regimens in patients with locally advanced rectal cancer, only 159 (35%) of the 448 patients with

single-site first recurrences in the liver, lung, or pelvis had curative-intent surgery.326 The proportion of

patients undergoing resection was similar for liver, lung, or local recurrences. OS differed significantly

between the resected and nonresected groups, with 5-year OS of 27% and 6%, respectively (p < 0.001).

The 5-year DFS was in the range of 30% for patients undergoing resection of tumors in solitary sites of

the liver or lung, and 20% for those undergoing resection of LRs. Retrospective case series from

institutions with experience in the treatment of locally recurrent CRC report 5-year survival rates close

to 35% for patients with R0 resections, compared to 21% for patients with R1 resections.

Palliation is an important aspect of the treatment of patients with unresectable LR. Bowel obstruction

often requires palliative surgery, stomas, endoluminal stents, or percutaneous gastrostomy tubes.

Urinary obstruction is common, requiring stents or percutaneous nephrostomies. Pain is a common

symptom in these patients, often requiring the assistance of pain specialists and specialists in palliative

care.

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