Local and Regional Control
Almost half of the patients undergoing curative resection will ultimately die of metastatic disease as a result of residual microscopic disease not evident at the time of surgery. Patients with stage II colon cancer at high risk of relapse have been defined by the National Comprehensive Cancer Network (NCCN) as those individuals with T4 tumors (stage IIB/IIC); poorly differentiated history (excluding MSI-H cancers); lymphovascular invasion; perineural invasion; bowel obstruction; localized perforation; margins that are close, indeterminate, or positive; and inadequate sampling of lymph nodes (<12 nodes examined) (23).
Surgical Management of Colon Cancer
Resection for localized colon cancer removes the affected segment of bowel, the adjacent mesentery, and the draining lymph nodes. Asymptomatic patients with stage IV disease with their primary malignancy intact do not require surgical resection of their primary except for impending bowel obstruction. Laparoscopic colectomy was noninferior to an open colectomy in several prospective randomized studies, with the laparoscopic surgery group having a shorter perioperative recovery, hospital stay, duration of parenteral narcotic use and oral analgesics, as well as comparable intraoperative complications and postoperative mortality (24).
Evidence Regarding Adjuvant Therapy for Colon Cancer
Patients with stages II and III colon cancer have a risk of relapse after surgical resection of macroscopic disease. Systemic chemotherapy has been employed to eradicate micrometastases. Currently, patients with stage III colon cancer (node positive without clinically detectable metastases) receive 6 months of adjuvant chemotherapy. The MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial demonstrated an improved 5-year disease-free survival (DFS) from 67% to 73% for patients receiving FOLFOX (5-fluorouracil [5-FU], leucovorin calcium, and oxaliplatin) versus 5-FU and leucovorin alone (25) with the DFS and overall survival (OS) benefits achieving statistical significance in patients with stage III disease.
The evidence for adjuvant therapy for stage II disease is less robust. To date, the largest study of patients with stage II disease, QUASAR (Quick and Simple and Reliable), showed a modest survival benefit of 3.6% in patients receiving adjuvant 5-FU versus observation following surgical resection (26). The 2012 subset analysis of the 889 patients with stage II disease in the MOSAIC (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) trial showed no statistically significant benefit in either OS or DFS with the addition of oxaliplatin to 5-FU in the adjuvant setting for stage II (27). Furthermore, the analysis of the patients with low- and high-risk stage II demonstrated that neither subgroup unequivocally derived benefit from the addition of oxaliplatin.
Multigene assays have been in development for prognostic and predictive value in patients with stage II colon cancer. Among the assays furthest along in development is the Oncotype Dx colon cancer assay (Genomic Health, Inc.), which provides a prognostic classification of low, intermediate, or high risk of recurrence based on the expression of seven recurrence risk genes and five reference genes. In two large trials, QUASAR and NSABP C-07, of patients with stage II and III disease, this score was validated as prognostic for recurrence, DFS, and OS but not predictive of benefit from chemotherapy (28).
A second assay, ColoPrint (Agendia), identifies the expression of 18 genes and produces one of two recurrence risk categories, high or low. Although it was studied in stages I-IV, it has emerged to be of the most value in patients with stage II in identifying the risk of recurrence between high- and low-risk groups (hazard ratio [HR] 3.34, P = .017) (29). It is currently being prospectively validated in patients with stage II in the PARSC trial, which will predict the 3-year recurrence-free survival using ColoPrint and clinical factors (30). Both assays share limitations particularly the inability to predict clinical benefit from chemotherapy.
Irinotecan has no established role in the adjuvant setting. Three randomized phase III trials failed to show an improvement in DFS or OS in the adjuvant setting (31,32,33). An exploratory analysis of CALGB 89803 (IFL versus bolus 5-FU/LV) indicates that patients with MSI-H may have an improved DFS from irinotecan-based therapy (HR 0.76; 95% CI, 0.64-0.88; P = .03). However, the PETACC 3 study confirmed that while patients with stage II disease with MSI-H tumors have a survival advantage over MSS patients with a 5-FU-based treatment, the addition of irinotecan produced no additive benefit, affirming the overall consensus against using an irinotecan-based regimen in the adjuvant setting (34).
Furthermore, data have not supported the addition of bevacizumab, cetuximab, or panitumumab in the adjuvant setting. The NSABP trial C-08 showed no improvement in DFS or OS with the addition of bevacizumab to adjuvant FOLFOX6 in stage II and III colon cancer (35). A second phase III randomized controlled study, the bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT) trial of resected stage III or high-risk stage II colon cancer (36) also failed to show any improvement in DFS and, in fact, suggested a poorer OS with the addition of bevacizumab.
The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration is a prospective combined analysis of phase III trials investigating duration of adjuvant chemotherapy (3 vs 6 months) for stage III colon cancer (37). The ongoing US CALGB/SWOG 80702 colon trial, which is among the six trials that are part of the IDEA collaboration, further randomizes patients beyond the duration of adjuvant therapy to 3 years of celecoxib versus placebo (37). Overall, few therapeutic changes appear to be on the horizon for the treatment of adjuvant colon cancer.
The MDACC Approach to Nonmetastatic Colon Cancer
When patients present to MDACC with a diagnosis of colon cancer, a detailed history, including family history; routine laboratory tests, including CEA level; and imaging (CT chest, CT or MRI abdomen, pelvis) are obtained. Previous endoscopic findings and pathology are reviewed and are tested for MSI by IHC or by PCR. Patients without metastatic disease or contraindications to surgery should undergo primary resection with curative intent (Fig. 24-3). If there is an obstruction, colonoscopy is usually performed. Surgery may consist of segmental resection or subtotal colectomy, depending on the underlying colonic pathology (multifocal cancer, FAP, HNPCC, etc.); pathologic staging is then determined from the surgical specimens, which is the standard for all such resections at MD Anderson irrespective of age. Patients with stage 0 or I tumors are placed on surveillance only. Patients with stage II colon cancer have a 75% to 80% chance of long-term DFS with surgical resection alone. Patients with stage II colon cancer are referred for discussion of adjuvant chemotherapy with full consideration provided to all patients with stage III disease.
Diagnostic and therapeutic algorithm for colon cancer.
Our current approach favors FOLFOX or XELOX (Table 24-6) for 6 months for all stage III patients unless chemotherapy is contraindicated. Those who are better candidates for a single-agent fluoropyrimidine are offered capecitabine over intravenous 5-FU. Adjuvant therapy should begin within 4 to 8 weeks after surgery, unless postoperative complications warrant a delay.
Table 24-6Summary of Common Chemotherapy Regimens Used at MDACC for Colorectal Cancer ||Download (.pdf) Table 24-6 Summary of Common Chemotherapy Regimens Used at MDACC for Colorectal Cancer
|Adjuvant Chemotherapy |
|Capecitabine: 1,000 mg/m2 by mouth twice daily on days 1-14 (3-week cycle, total 8 cycles) |
|5-Fluorouracil/leucovorin: Leucovorin 400 mg/m2 IV on day 1; 5-fluorouracil 400 mg/m2 IV bolus on day 1, followed by 5-fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (2-week cycle, total 12 cycles) |
|Modified FOLFOX 6: Oxaliplatin 85 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-fluorouracil 400 mg/m2 IV bolus on day 1, followed by 5-fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (2-week cycle, total 12 cycles) |
|XELOX: Oxaliplatin 130 mg/m2 on day 1; capecitabine 850 mg/m2 by mouth twice a day on days 1-14 (3-week cycle, total 8 cycles) |
|Therapy for Metastatic Disease |
|Capecitabine: 1,000 mg/m2 by mouth twice a day on days 1-14 (3-week cycle) |
|• With or without bevacizumab (7.5 mg/kg IV every 3 weeks) |
|5-Fluorouracil/leucovorin: Leucovorin 400 mg/m2 IV on day 1; 5-fluorouracil 400 mg/m2 IV bolus on day 1, followed by 5-fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (2-week cycle) |
|With or without bevacizumab (5 mg/kg IV every 2 weeks) |
|Modified FOLFOX 6: Oxaliplatin 85 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-fluorouracil 400 mg/m2 IV bolus on day 1, followed by 5-fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (2-week cycle) |
|• With or without bevacizumab (5 mg/kg IV every 2 weeks) |
|• With or without cetuximaba (400 mg/m2 IV first infusion followed by 250 mg/m2 IV weekly or 500 mg/m2 IV every 2 weeks) or panitumumaba (6 mg/kg IV every 2 weeks) |
|XELOX: Oxaliplatin 130 mg/m2 on day 1; capecitabine 850 mg/m2 by mouth twice a day on days 1-14 (3-week cycle) |
|With or without bevacizumab (7.5 mg/kg IV every 3 weeks) |
|• With or without cetuximaba (400 mg/m2 IV first infusion followed by 250 mg/m2 IV weekly or 500 mg/m2 IV every 2 weeks) or panitumumaba (9 mg/kg IV every 3 weeks) |
|Modified FOLFIRI: Irinotecan 180 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-fluorouracil 400 mg/m2 IV bolus on day 1, followed by 5-fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (2-week cycle) |
|• With or without bevacizumab (5 mg/kg IV every 2 weeks) |
|• With or without cetuximaba (400 mg/m2 IV first infusion followed by 250 mg/m2 IV weekly) or panitumumaba (6 mg/kg IV every 2 weeks) |
|Irinotecan: 180 mg/m2 IV on day 1 (2-week cycle) or 300-350 mg/m2 IV on day 1 (3-week cycle) |
|• Cetuximaba 400 mg/m2 IV first infusion followed by 250 mg/m2 IV weekly + irinotecan 350 mg/m2 IV on day 1 (3-week cycle) or 180 mg/m2 IV on day 1 (2-week cycle) |
|• Cetuximaba 500 mg/m2 IV every 2 weeks ± irinotecan 180 mg/m2 IV every 2 weeks |
|Panitumumaba: 6 mg/kg IV every 2 weeks or 9 mg/kg IV every 3 weeks |
Surveillance for Patients With Resected Colon Cancer
Once active therapy is completed, patients undergo clinical evaluations every 3 to 4 months for the first 3 years during the period of highest risk of recurrence, then every 6 months for the following 2 years, and annually thereafter. Of all recurrences, 80% occur within the first 3 years following surgical resection (38). Colonoscopy is recommended 1 year after surgery and every 3 years thereafter at a minimum. Laboratory studies, including CEA level, are checked every 3 to 6 months; abdominopelvic CT or MRI and a chest x-ray/CT of the chest are obtained at 12 months. At 5 years, patients are followed with surveillance colonoscopy (every 3 years), annual physical examination, and CEA level.
Local Therapy for Rectal Cancer
In general, over two-thirds of the patients with rectal cancer will be able to have a sphincter-saving procedure whether it is a low anterior resection or a proctectomy with a coloanal anastomosis (CAA). An abdominoperineal resection (APR), which includes removal of the rectum, anus, sphincter muscles, and a permanent colostomy is reserved for patients with tumor involvement of sphincter muscles or with poor preoperative sphincter function. A sharp mesorectal excision should be performed; there is no role for blunt dissection in the pelvis in rectal cancer surgery.
Radiotherapy improves survival in patients with locally advanced rectal cancer. Standard radiotherapy doses are 45 Gy in 25 fractions, followed by a 5.4-Gy boost. Concurrent protracted venous infusional (PVI) 5-FU provides similar efficacy with lower gastrointestinal and hematologic toxicity rates than bolus 5-FU or a high-dose infusion of 5-FU (39). A phase III intergroup trial demonstrated inferiority for bolus 5-FU during radiation therapy versus prolonged infusional 5-FU and resulted in higher OS rates (P = .005) (22).
Preoperative Therapy for Rectal Cancer
Two European studies have supported the use of preoperative therapy for resectable rectal cancer. The German Arbeitsgemeinschaft Internistische Onkologie (AIO) trial comparing preoperative and postoperative chemoradiation in T3 or T4 tumors showed a lower pelvic recurrence rate in the preoperative chemoradiation arm (6% vs 13% postoperative, respectively, P = .0006) (40). In patients who, based on pretreatment clinical evaluation, were believed to require APR, chemoradiation also led to increased sphincter preservation rates (39% vs 19%, P = .004). Only 54% of patients in the postoperative arm received the full radiation dose, and 50% received full-dose chemotherapy, compared with 92% and 89%, respectively, in the preoperative arm (P < .001).
Neoadjuvant chemotherapy with concurrent radiotherapy has been extensively studied. NSABP R-04, a four-arm phase III trial of 5-FU, capecitabine, 5-FU/oxaliplatin, and XELOX showed no improvement in locoregional recurrence, DFS, or OS with the addition of oxaliplatin (41). Two phase III trials (Studio Terapia Adiuvante Retto and Action Clinique Coordonnées en cancérologie Digestive [STAR and ACCORD, respectively] 12) did not have higher rates of pCR with the addition of weekly oxaliplatin (42,43).
Another treatment principle under investigation is induction chemotherapy, defined as administration of chemotherapy prior to chemoradiotherapy and surgery in resectable stage II or III rectal cancer. One small study out of the United Kingdom evaluated neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in patients with MRI-defined poor-risk rectal cancer (44). Overall, 77 patients received neoadjuvant capecitabine and oxaliplatin, with 88% demonstrating a radiologic response and 86% a symptomatic response after just one cycle of therapy. The response rates increased to 97% on completion of chemoradiation. Then, 66 of 67 patients who then underwent a TME had R0 resection, with a pathologic complete response seen in 16 patients and only microscopic disease noted in 32 patients (48%).
To investigate the sequence of therapies, the randomized phase II study from Spain, the Grupo cancer de recto 3 (GCR-3) study, randomized 108 patients into two arms: arm A for preoperative concurrent chemoradiation with capecitabine and oxaliplatin followed by surgery and four cycles of adjuvant capecitabine and oxaliplatin or arm B for induction capecitabine and oxaliplatin followed by chemoradiation and surgery (45). Rates of pathologic complete response, which was the study’s primary end point, were not significantly different in the arms; however, patients who received induction capecitabine/oxaliplatin combination had fewer grade 3 or 4 adverse events occur during the induction period when compared to those in the adjuvant chemotherapy arm.
The addition of the neoadjuvant bevacizumab was also investigated in a randomized, noncomparative phase II study in locally advanced T3 resectable rectal cancer (46). Arm A incorporated bevacizumab plus FOLFOX4 as induction prior to bevacizumab–5-FU–RT and then TME; arm B did not have the induction component but did include bevacizumab–5-FU–RT prior to surgery. While the pathologic CR end point was not met in arm B, arm A did show a statistically significant improvement in pathologic CR (23.5%; 95% CI, 12.1% to 39.5%) when compared to a defined standard rate of 10% (P = .015).
In studies incorporating cetuximab, the EXPERT-C trial was a multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in high-risk rectal cancer, with high risk defined by the high-resolution, thin-slice MRI (3 mm) finding of tumor within 1 mm of mesorectal fascia, T3 tumor at or below levators, extramural extension of 5 mm or greater, T4 tumor, or presence of extramural venous invasion (47,48). This study showed higher response rates and OS with cetuximab in KRAS/BRAF wild-type (WT) rectal cancer; however, the primary end point of improved pathologic or radiologic complete response was not met.
A potentially pivotal ongoing study led by the Alliance (N0148) is a phase II/III trial that evaluates the need for chemoradiation therapy versus induction FOLFOX in patients with mid–high-lying rectal cancers (NCT01515787).
Adjuvant Therapy for Rectal Cancer
Since the mid-1970s, studies have shown that combined-modality therapy offers a clear benefit for patients with stage II or III rectal cancer. The Gastrointestinal Tumor Study Group (GITSG) performed a randomized trial in patients with rectal cancer undergoing surgery with curative intent. Patients were randomized to four arms: observation, chemotherapy alone, radiotherapy alone, or chemoradiotherapy. The rates of DFS and OS were higher in the combined-modality therapy group than in the other arms (49). Currently, standard adjuvant therapy for patients with stage II or III rectal cancer should consist of fluoropyrimidine-based chemotherapy and external-beam radiotherapy of the pelvis.
The MDACC Approach to Nonmetastatic Rectal Cancer
The approach to rectal cancer is outlined in Fig. 24-4. At MD Anderson, patients see a multidisciplinary team of radiation, medical, and surgical oncology specialists for a thorough history, including family cancer history, physical exam with a digital rectal exam, inguinal lymph node exam, rigid proctoscopy, and staging studies. The patency of the colonic lumen is evaluated by proctoscopy, flexible sigmoidoscopy, or colonoscopy before starting systemic chemotherapy.
Diagnostic and therapeutic algorithm for rectal cancer.
For patients with nonmetastatic disease, EUS and MRI of the pelvis are obtained as pretreatment staging. Capecitabine is given as the radiation sensitizer (825 mg/m2 twice daily, Monday-Friday, on days of radiation therapy only). Bowel exclusion techniques during simulation minimize the small bowel in the field. We conduct a toxicity evaluation every 1 to 2 weeks during radiation to ensure symptom control. Electrolytes, renal function, and hematologic parameters are checked weekly. Topical barrier creams are prescribed for grades 1 to 3 perineal radiation dermatitis. Should grade 2 or higher nonhematologic toxicity develop (excluding radiation dermatitis), concurrent chemotherapy is held until resolution but radiation is continued.
After chemoradiation, perianal pain and ulceration, anorexia, and diarrhea typically subside within 2 to 3 weeks. Approximately 6 weeks after completion, patients undergo repeat physical examination with proctoscopy and then surgical resection. We recommend reversal of the diverting ileostomy after the completion of adjuvant chemotherapy due to erratic bowel managements. For those patients who recover fully from surgery, postoperative chemotherapy is delivered for a total of 4 months.
In the adjuvant setting, patients with stage III rectal cancer and no contraindication to oxaliplatin are advised to receive it as a component of FOLFOX or XELOX. In select cases, a patient with a pCR after preoperative 5-FU–based chemoradiation may receive single-agent 5-FU–based adjuvant therapy rather than FOLFOX. The choice of adjuvant therapy may vary based on degree of response to single-agent fluoropyrimidine-based therapy and the patient’s underlying comorbidities.
Patients who have undergone surgery as their initial intervention may require postoperative chemoradiation and systemic therapy when they present to MD Anderson after surgery. For patients with T3N0M0 or T2N1 disease, radiotherapy is often omitted if the tumor was located in the high pelvis (>10 cm from the anal verge), there is good nodal sampling (>12 lymph nodes) (50), and the radial margin is negative (>2 mm) because pelvic tumor control is excellent without the use of chemoradiation (51). In all other stage II and III rectal cancer cases, local failure is high enough to warrant the use of chemoradiation. In addition, 4 months of systemic therapy with either capecitabine or 5-FU/leucovorin is typically integrated with chemoradiation. Patients at higher risk of distant metastasis often receive chemotherapy first with FOLFOX.
Surveillance for Patients With Resected Rectal Cancer
Follow-up for patients with resected rectal cancer is very similar to that for colon cancer. Patients with a sphincter-preserving procedure also require periodic proctoscopies for local relapses and anastomotic strictures. A rising CEA without other clinical or CT evidence of relapse prompts a pelvic MRI or PET/CT particularly for local recurrence.
Patterns of Spread and Recurrence After Primary Therapy
Among patients who undergo surgical resection, at least 25% will have a recurrence, with most (60%) relapsing at multiple sites; the remaining relapse in the liver (15%), lung (4%), and locally (21%) (52). Relapse in multiple sites is generally managed with palliative systemic chemotherapy, while surgery can be considered for oligometastatic disease.
Management of Locally Recurrent Disease
Locally recurrent rectal cancer presents a therapeutic challenge for which salvage surgery may not be feasible. The collective experience at MD Anderson suggests that systemic therapy has limited activity against locally recurrent disease with few durable responses. Palliative radiation is delivered as external-beam radiotherapy or brachytherapy catheters. Aggressive use of narcotics and intrathecal analgesics or neurolytic blocks is employed for pain control concurrently with aggressive bowel management.
For the subset of patients who may be surgical candidates, treatment planning is vetted in the weekly multidisciplinary conference at MD Anderson. In our experience, pelvic MRI is superior to CT for distinguishing posttreatment changes from viable tumor while identify resectable disease. Biopsy confirmation of recurrence is always recommended; EUS has not been particularly useful with locally recurrent rectal tumors.
Prior to salvage surgery, additional chemoradiation may be considered using a hypofractionated schedule to a total dose of 39 Gy (if at least 1 year has elapsed since prior pelvic radiation). Radiosensitization with 5-FU or capecitabine is also considered. Approximately 6 to 8 weeks after completion of chemoradiation, a final decision about surgery is made. In most cases, the operative strategy may also include intraoperative radiotherapy or insertion of brachytherapy catheters for high-dose afterloading. Postoperative chemotherapy after aggressive preoperative chemoradiation is at the discretion of the treating physician. However, there is broad agreement that surgery for locally recurrent disease is not indicated in those patients with unresectable metastatic disease, given the overall poor prognosis, significant morbidity, and prolonged recovery associated with this complex pelvic surgery.
Systemic Therapy for Metastatic Disease: A Rapidly Changing Therapeutic Landscape
Since the late 1950s, systemic chemotherapy with 5-FU has been the mainstay of palliative treatment for patients with metastatic disease not amenable to surgical intervention. During the ensuing decades, a variety of 5-FU schedules have been employed, including bolus injections administered either weekly (Roswell Park regimen) or daily for 5 days (Mayo regimen) and continuous infusion given via central catheter and portable pump. Objective response rates have ranged from 15% to 25% with these schedules. When 5-FU is administered as a bolus injection, leucovorin is often added to enhance binding of 5-FU to its target, thymidylate synthase. After a long period of uncertainty regarding the optimal dose and schedule of 5-FU with leucovorin, infusional 5-FU regimens have been recognized as superior to bolus regimens. However, prior to the advent of irinotecan and oxaliplatin, while infusional delivery of 5-FU led to better response rates compared with bolus therapy, no clear survival advantage was ever demonstrated. Given the barriers to delivery of infusional 5-FU, including the need for a central venous catheter and its associated risks, bolus 5-FU with leucovorin was widely accepted in the United States as frontline therapy for metastatic colorectal cancer well into the 1990s.
Since that time, therapeutic options for metastatic disease have been rapidly evolving, and oncologists now have access to several drugs with activity in the first-, second-, and even third-line settings. In addition to cytotoxic drugs, the targeted agents cetuximab, panitumumab, and bevacizumab have emerged as clinically relevant components of systemic therapy for advanced disease. It is important for oncologists to have a general understanding of these drugs and their roles in the treatment of metastatic disease.
Capecitabine: An Orally Bioavailable Fluoropyrimidine
Capecitabine is an oral fluoropyrimidine that is converted to 5-FU primarily in tumor tissues. It passes through the intestinal mucosa essentially unchanged and is subsequently metabolized by a sequential three-enzyme pathway (53). First, capecitabine is converted to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase (primarily in the liver). The 5′-DFCR is then converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase, which is found in both the liver and tumor tissues. The metabolism of 5′-DFUR to the pharmacologically active agent 5-FU is mediated by thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor. Concentrations of TP are relatively higher in tumor tissue than normal tissue, which accounts for the preferential intratumoral release of 5-FU. Two large phase III trials compared capecitabine with a bolus regimen of 5-FU (54,55), and the results were subsequently pooled. The response rates were superior with capecitabine, and the median survival was equivalent, with less neutropenia and mucositis among those patients receiving capecitabine.
In patients with contraindications to combination chemotherapy, capecitabine monotherapy is a reasonable alternative to 5-FU and leucovorin in the metastatic setting.
Irinotecan, an inhibitor of topoisomerase I, was originally developed as second-line chemotherapy for patients in whom 5-FU was ineffective (56,57,58). In phase II trials of irinotecan performed in the United States, response rates in patients refractory for 5-FU were approximately 15% superior to those reported prior to the advent of irinotecan; this led the Food and Drug Administration (FDA) to approve the drug as a second-line therapy in patients with advanced 5-FU-refractory disease (59). The survival benefit of second-line irinotecan was subsequently verified in a European trial, in which patients who had been previously treated with 5-FU were randomized to receive irinotecan every 3 weeks or best supportive care (BSC) (60). Patients randomized to BSC were allowed to receive infusional 5-FU. This trial demonstrated a survival advantage for patients in the irinotecan arm compared to those in the BSC arm (9.2 vs 6.5 months; P = .0001).
Shortly thereafter, studies were performed to investigate the potential benefit of irinotecan as a component of frontline therapy in patients with metastatic colorectal cancer. Two large, randomized trials were conducted in the United States and Europe comparing 5-FU and leucovorin with 5-FU, leucovorin, and irinotecan as first-line treatment of metastatic colorectal cancer (61,62). Both studies demonstrated that the response and OS rates for the group treated with triple-drug therapy were superior to those for the group treated with 5-FU and leucovorin. The response rates for the triple-drug combination ranged from 35% to 40%, the median time to disease progression was 7 months, and median survival was prolonged by 2 months. These results prompted the FDA in 2000 to approve the use of these irinotecan-based combinations for first-line treatment of colorectal cancer. For a brief period of time, the IFL regimen (bolus 5-FU at 500 mg/m2, leucovorin 20 mg/m2, and irinotecan 125 mg/m2, administered weekly for 4 weeks on a 6-week cycle) became standard first-line therapy for patients with metastatic colon cancer in the United States. However, as these studies were being performed, a novel platinum analog, oxaliplatin, was also showing impressive activity in combination with 5-FU and leucovorin, generating great interest in the drug.
Oxaliplatin is a third-generation platinum derivative that has shown additive or synergistic antitumor activity in combination with a variety of standard antineoplastic agents, including 5-FU; oxaliplatin is ineffective without 5-FU (63). While irinotecan was being studied in the United States, oxaliplatin was already approved in Europe. In 2000, de Gramont and colleagues reported the results of a phase III trial of infusional 5-FU/leucovorin and oxaliplatin (FOLFOX4), versus 5-FU/leucovorin alone, as first-line treatment in advanced colorectal cancer (64). Four hundred twenty patients were randomized to the study, and progression-free survival (PFS) was the primary end point. Progression-free survival and response rates were significantly better for the FOLFOX arm compared to the 5-FU/leucovorin arm (9.0 months and 50% vs 6.2 months and 22%, respectively). Even though the FOLFOX arm experienced more grade 3 and 4 neutropenia, diarrhea, and neurosensory toxicity, this did not impair quality of life. The primary objective of median OS was not met (14.7 months for the 5-FU/leucovorin arm and 16.2 months for the FOLFOX arm, P = .12); consequently, initial approval by the FDA failed.
Goldberg and associates subsequently compared the activity and toxicity of three different drug combinations in untreated patients with metastatic colorectal cancer. Seven hundred ninety-five patients were randomized to receive IFL, FOLFOX, or IROX (irinotecan + oxaliplatin) (65). The results favored FOLFOX for all end points, including time to progression, response rate, and OS. Median survival in the FOLFOX, IFL, and IROX groups was 19.5, 15.0, and 17.4 months, respectively. The authors concluded that FOLFOX should be considered a standard first-line regimen for advanced colorectal cancer. A limitation of this study was that 60% of the patients treated with oxaliplatin received irinotecan in the second-line setting, but only 24% of patients in the IFL arm could get oxaliplatin as second-line treatment because it was not approved in the United States at the time of the study.
Tournigand and colleagues answered the important question of how to sequence these regimens. They reported the results of a phase III study investigating 5-FU, leucovorin, and irinotecan (FOLFIRI), followed by FOLFOX6 (see Table 24-6) on progression of disease, versus the opposite sequence (FOLFOX6 followed by FOLFIRI) (66). The two sequences were equivalent in terms of progression-free and OS, although the toxicity profiles were different. Median survival was 21.5 months in the FOLFIRI-FOLFOX arm (109 patients) and 20.6 months in the FOLFOX-FOLFIRI arm (111 patients) (P = .99).
An aggressive approach is the combination of oxaliplatin, irinotecan, and 5-FU/leucovorin (FOLFOXIRI) (67). An impressive response rate of 66% was noted in a phase III trial of FOLFOXIRI versus FOLFIRI, fulfilling the primary end point of PFS. However, a serious adverse toxicity reaction associated with this regimen is severe myelosuppression. Concerns about this regimen are largely due to discussion of limited options for second-line therapy if the patient’s disease should progress. Furthermore, an earlier phase III Greek trial failed to note an improvement in OS, perhaps due to the limited second-line chemotherapy options for patients treated with FOLFOXIRI (68). Common chemotherapy regimens for both colon and rectal carcinoma are listed in Table 24-6.
Therapeutic use of the immune system against cancer has been studied for decades but remained elusive until recently due to technical difficulties. The fact that tumor cells are recognized as a part of the normal host makes the development of vaccines difficult, and the logical alternative would involve development of foreign antibodies that could be delivered to the patient. The development of those antibodies was not possible until 1975, when the hybridoma technique was perfected by Kohler and others, allowing the development of specific antibodies against antigens restricted to, or overexpressed in, tumor cells (69). Initially, the development of these antibodies was proposed as a direct immunologic and cytotoxic approach for treatment of malignant disease. While such efforts continue, this strategy has been refined to include the development of antibodies that target specific proteins critical to intracellular signaling, tumor cell function, or the host-tumor interface. Three new monoclonal antibodies have been recently approved in the United States for treatment of metastatic colorectal cancer.
Cetuximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody directed against the epidermal growth factor receptor (EGFR), also known as ErbB-1 (70). In the colorectal cancer arena, it was primarily studied in previously treated patients. Cetuximab monotherapy yielded a response rate of 9% and median survival of 6.4 months in a small group of irinotecan-refractory patients (71). When compared to BSC in a treatment-refractory patient population, single-agent cetuximab resulted in superior OS (6.1 vs 4.6 months) and quality of life. Two phase III randomized trials (Bowel Oncology and Cetuximab Antibody, Erbitux Plus Irinotecan for Metastatic Colorectal Cancer [BOND, EPIC]) subsequently confirmed the efficacy of cetuximab in combination with irinotecan in previously treated patients (72,73), with response rates of approximately 20%. Improvement in OS versus BSC has since been validated in heavily pretreated patients (74). The reason for the apparent synergy between cetuximab and irinotecan is not well understood; it is known that EGFR mediates not only proliferation signals but also a number of other processes whose inhibition may render cells more sensitive to apoptotic stimuli, such as chemotherapy.
The EGFR inhibition is fraught with potential treatment-related toxicities, including a pustular acneiform rash of the upper torso and scalp. Hence, identification of a predictive marker for efficacy of anti-EGFR therapy would decrease unnecessary drug exposure and financial burden. It is now recognized that EGFR expression does not correlate with efficacy of therapy (75). However, mutation of the KRAS oncogene is present in 35% to 50% of all patients with colorectal cancer and has an early role in the transition of adenoma to carcinoma, with reported concordance between the primary and the metastatic site (76). The mutations are commonly G>A transitions and G>T transversions; codons 12 and 13 are the most frequently affected and rarely codons 61 and 146. In addition to KRAS, mutations in NRAS have been recently identified as a potential predictive indicator of anti-EGFR efficacy. The NRAS mutation may be present in 10% of patients and was also associated with reduced response to panitumumab (77). Patients with KRAS WT and NRAS WT tumors had improved PFS (HR = 0.39, 95% CI = 0.27, 0.56) compared with those receiving BSC, whereas those with NRAS mutant tumors did not appear to benefit from panitumumab (HR = 1.94, 95% CI = 0.44, 8.44).
The Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal (CRYSTAL) phase III trial randomized nearly 1,200 patients with untreated metastatic colorectal cancer to FOLFIRI with or without cetuximab. Median PFS (8.9 vs 8.0 months) and response rate (47% vs 39%) were modestly improved with cetuximab. Most important, however, investigators later discovered in an unplanned retrospective analysis that clinical benefit was limited to those patients with KRAS WT tumors. In this group of patients, the findings were impressive; cetuximab improved the response rate from 43% to 59% and median PFS from 8.7 months to 9.9 months (78). Updated results of the CRYSTAL trial were recently presented, indicating an OS advantage for FOLFIRI and cetuximab in the KRAS WT group (23.5 vs 20.0 months) (79). This is the first trial to demonstrate an improvement in OS with cetuximab in combination with chemotherapy in treatment-naïve patients. In addition, OPUS, a randomized phase II trial in treatment-naïve patients, compared FOLFOX4 plus cetuximab to FOLFOX4 alone and also showed improvement in response rate and PFS with cetuximab. Once again, analysis revealed that this benefit was restricted to patients without KRAS mutations (80). Neither study has indicated what percentage of specimens analyzed was from the primary versus the metastatic site and if true concordance existed. Despite the current evidence supporting KRAS testing, the FDA delayed mandating KRAS testing largely due to the retrospective unplanned analyses. Soon after, the American Society of Clinical Oncology (ASCO) released a provisional clinical opinion advising against use of EGFR monoclonal antibodies in colorectal cancer patients with KRAS mutant tumors (81); subsequently, the FDA revised the label of cetuximab and panitumumab in July 2009.
The most significant toxicities associated with cetuximab include diarrhea, hypomagnesemia, hypocalcemia, and an acneiform rash. Traditionally, the risk of an allergic hypersensitivity reaction is reported to be <5%. However, life-threatening anaphylactic hypersensitivity reactions have been reported in up to 30% of patients residing in select geographic locations (82). Immunoglobulin E antibodies against cetuximab have been discovered and may allow screening for patients at risk for this reaction.
Development of the skin rash appears to be a clinical predictor of response and survival, but the mechanisms involved in this process are poorly understood (83). The Dose-Escalation Study of Cetuximab for Metastatic Colorectal Cancer (EVEREST), which was undertaken to address the association between skin rash and clinical response to cetuximab, stratified patients with no or mild rash to standard-dose or dose-escalated cetuximab. Dose escalation increased the response rate from 13% to 30%. Although these results are intriguing, firm conclusions about the dose–response relationship with cetuximab cannot be drawn from this small phase II trial, and the final results have not been reported. Recent data support that the pharmacokinetics of cetuximab is not compromised with administration every 2 weeks rather than weekly (82). Furthermore, a small phase II trial indicated that preemptive dermatological care may improve patient outcome when using EGFR inhibitors (84).
Cetuximab is currently FDA approved as monotherapy for patients with metastatic colorectal cancer who are intolerant of irinotecan-based regimens or in combination with irinotecan after progression of disease. The findings of the CRYSTAL trial will likely result in an FDA application for approval for cetuximab in the frontline setting.
Panitumumab is a fully human IgG2 monoclonal antibody directed against the EGFR. In a randomized phase III trial, patients with refractory metastatic disease received BSC with or without panitumumab. The response rate and stable disease rate with panitumumab were 10% and 27%, respectively, compared to 0% and 10%, respectively, with BSC alone. An OS difference could not be demonstrated in this trial, likely due to crossover from the BSC group (85). Subsequent analysis revealed that only patients with KRAS WT tumors benefited from panitumumab (86). Although cetuximab and panitumumab have not been compared head to head, they appear to have similar efficacy and toxicity in patients. Infusion reactions are uncommon with panitumumab because it is a fully human monoclonal antibody. It is now FDA approved as a single agent for patients failing irinotecan- and oxaliplatin-based chemotherapy. Two phase III trials have recently been reported of FOLFOX or FOLFIRI with or without panitumumab for both treatment-naïve and previously treated patients, respectively (87,88). Both studies reported superior response and PFS for the combination and will likely also result in an application for approval in combination with chemotherapy in the front- and second-line setting.
In studies dating back more than 40 years, Dr. Judah Folkman demonstrated that tumors cannot grow beyond 1 mm without creating new vessels to deliver oxygen and nutrients. He therefore predicted that a drug capable of blocking angiogenesis would be able to arrest the growth of tumors (89). Among the several angiogenic factors isolated to date, vascular endothelial growth factor (VEGF) seems to be particularly important, with elevated circulating levels associated with poor prognosis in patients with colorectal cancer (90,91). Bevacizumab is a humanized monoclonal antibody that binds all isoforms of circulating VEGF, thereby inhibiting permeability and angiogenesis mediated by this factor (92).
Bevacizumab is currently FDA approved in multiple tumor types, including lung, breast, and colorectal cancer. A randomized phase II trial compared weekly 5-FU/leucovorin with the same chemotherapy combined with either 5 mg/kg or 10 mg/kg of bevacizumab. Both experimental arms performed better than the control 5-FU/leucovorin arm (93). However, the best results were seen with the lower dose of bevacizumab, leading the investigators to recommend a dose of 5 mg/kg for a phase III trial in colorectal cancer.
The phase III trial compared the IFL regimen, which was considered the standard regimen for metastatic colorectal cancer at that time, with IFL plus bevacizumab (5 mg/kg) (94). A third arm with 5-FU/leucovorin plus bevacizumab was added as a precaution, but it was dropped after the first 100 patients were treated safely. Patients on the exploratory arm were allowed to continue bevacizumab with their second-line chemotherapy regimen following progression of disease. When compared to IFL alone, the addition of bevacizumab resulted in a 10% increase in overall response rate (35%-45%). More important, patients randomized to IFL plus bevacizumab had a median survival of 20.3 months, while patients randomized to IFL alone had a median survival of 15.6 months (P < .0004). The absolute improvement in OS was superior to any incremental survival advantage observed using conventional combination chemotherapy alone. As a result, bevacizumab became the first drug of its class to receive FDA approval for colorectal cancer.
These promising results in the frontline setting have been confirmed in other trials. In the phase II TREE-2 study, Hochster and colleagues demonstrated the safety and efficacy of bevacizumab in combination with oxaliplatin-based chemotherapy (mFOLFOX6, bFOL, or XELOX) (95). This trial was not powered for direct comparisons among the three arms, but time to progression (9.9 and 10.3 months, respectively) and OS (26.1 and 24.6 months, respectively) were virtually identical in the mFOLFOX6 and XELOX arms. In the NO16966 trial, untreated patients were randomized in a 2 × 2 design to FOLFOX4 or XELOX (noninferiority) with or without bevacizumab (96). The pooled analysis revealed superior median PFS (9.4 vs 8.0 months, P = .002) in the bevacizumab-containing groups, but a difference in response and OS did not achieve statistical significance. Surprisingly, when PFS was stratified by chemotherapy regimen, the XELOX regimen fared better. In both of these trials, bevacizumab did not increase the toxicities of chemotherapy. However, it may exist when bevacizumab is combined with an oxaliplatin-based regimen, and the use of antiangiogenic therapy in conjunction with oxaliplatin-based chemotherapy is not well understood as originally believed. The most significant adverse events associated with bevacizumab were hypertension, proteinuria, thrombosis, and rare instances of bleeding (mostly epistaxis), delayed wound healing, and gastrointestinal perforation.
The Bolus, Infusional, or Capecitabine With Camptosar-Celecoxib (BICC) trial was a phase III trial that evaluated the role of bevacizumab in combination with irinotecan-based regimens (IFL, FOLFIRI, and CapeIri). During patient enrollment, bevacizumab was subsequently approved, requiring an amendment to the trial design. An expanded cohort of 117 patients randomized to IFL or FOLFIRI plus bevacizumab was created. No statistical difference in PFS or response was noted, but an impressive median OS was reported for the FOLFIRI plus bevacizumab arm (28.0 vs 19.2 months, P = .037).
The efficacy of bevacizumab as an adjunct to chemotherapy has been validated in the second-line setting as well. ECOG 3200 randomized over 800 patients with metastatic colorectal cancer previously treated with 5-FU and irinotecan (but not oxaliplatin or bevacizumab) to one of three arms: FOLFOX4, bevacizumab, or the combination. The arm receiving bevacizumab as monotherapy was closed to accrual after an interim analysis revealed inferior outcomes compared to the other two arms. Ultimately, the addition of bevacizumab to chemotherapy resulted in improved PFS (median 7.3 vs 4.7 months, P < .0001) and OS (median 12.9 vs 10.8 months, P = .0011) (97).
A recent large patient registry trial (Bevacizumab Regimens: Investigation of Treatment Effects and Safety [BRiTE]) suggested that continuation of bevacizumab following first-line progression of disease will have a positive impact on patient outcome versus no therapy or continuing second-line chemotherapy without continuing bevacizumab (98). These data are intriguing but were not collected in a prospective randomized fashion. Regardless, ongoing clinical trials have adopted this methodology of bevacizumab as the control arm. Admittedly in the patient with KRAS MT tumor, consideration of continuing bevacizumab is an option given the limitations of biologic therapy in a KRAS MT tumor–type patient, but it should be considered with a note of caution given the lack of evidence-based medicine and potential toxicities associated with bevacizumab.
The role of bevacizumab in the adjuvant setting is questionable at this time. A large phase III trial (NSABP C-08) was completed in patients with both stage II and III (99). Patients were randomized to FOLFOX (6 months) versus FOLFOX plus bevacizumab (5 mg/kg × 12 months). After a median follow-up of 35.6 months, the investigators failed to meet their primary end point of DFS (HR = 0.89, P = .15). The AVANT trial is a three-arm randomized study of FOLFOX4 (6 months) versus FOLFOX4 plus bevacizumab (5 mg/kg × 12 months) versus XELOX plus bevacizumab (7.5 mg/kg × 12 months) in the adjuvant treatment of patients with stage III or high-risk stage II colon cancer. Preliminary toxicity results have been reported with final efficacy results pending (100).
Unlike the EGFR inhibitors, predictive markers for the efficacy of initial anti-VEGF therapy have not been identified. Intriguing data from a phase II study of bevacizumab in treatment-naïve patients has noted a possible correlation with levels of basic fibroblast growth factor (101).
Bevacizumab represents a significant step for the use of antiangiogenesis agents in the treatment of colorectal cancer. It was FDA approved for use in combination with fluorouracil-based regimens as a first- or second-line treatment for metastatic colorectal cancer. Because bevacizumab has essentially no clinical activity as monotherapy in colorectal cancer, it cannot be recommended as a single agent in colorectal cancer and should not be considered for adjuvant therapy outside a clinical trial.
Dual Antibody Anti–Vascular Endothelial Growth Factor and Anti-Epidermal Growth Factor Receptor Therapy
Based on compelling preclinical data suggesting additive antitumor efficacy, the concept of dual inhibition of VEGF and EGFR has been investigated in several clinical studies. The BOND-2 trial randomized 83 irinotecan-refractory, bevacizumab-naïve patients to cetuximab plus bevacizumab with or without irinotecan (CB vs CBI). The CBI arm showed a better response rate (37% vs 20%) and time to progression (7.3 vs 4.9 months). In addition, the concurrent use of monoclonal antibodies did not result in any unexpected safety signals. These encouraging data prompted two large phase III trials (Capecitabine, Irinotecan, Oxaliplatin 2 [CAIRO2], Panitumumab Advanced Colorectal Cancer Evaluation [PACCE]) to examine the efficacy of dual biologic therapy in metastatic colorectal cancer. The CAIRO2 trial randomized 755 untreated patients to XELOX/bevacizumab with or without cetuximab. Unexpectedly, the patients receiving cetuximab experienced shorter PFS (9.4 vs 10.7 months, P = .01). Furthermore, in subgroup analyses, cetuximab-treated patients with KRAS mutant tumors had significantly inferior PFS (8.1 vs 12.5 months, P = .003) and OS (17.2 vs 24.9 months, P = .03) compared to patients with KRAS mutant tumors who did not receive cetuximab. Even in the subset of KRAS WT patients, the addition of cetuximab did not produce a PFS benefit (102).
The PACCE trial investigated dual biologic therapy in the first-line setting by randomizing patients receiving oxaliplatin- or irinotecan-based chemotherapy (investigator’s discretion) to bevacizumab plus or minus panitumumab (103). The panitumumab arms were discontinued after a planned interim analysis of patients in the oxaliplatin cohort revealed inferior PFS (8.8 vs 10.5 months, P = .04) with the addition of panitumumab. The final results showed worse OS (19.4 vs 24.5 months) and significant excess toxicity with dual-antibody therapy. The negative clinical impact of panitumumab was seen irrespective of KRAS status. In light of the data from PACCE and CAIRO2, dual VEGF and EGFR inhibition currently has no role in the treatment of patients with colorectal cancer and should not be pursued outside a clinical trial.
Decision Making for Potential Surgical Resection in Patients With Metastatic Colorectal Cancer
Despite therapeutic advances, the estimated 5-year OS for a patient unable to be surgically resected will remain at 11%. Therefore, when surgical resection with curative intent is a possibility for a patient with metastatic colorectal cancer, it is best to initiate discussion with your colleagues in the other disciplines. It is imperative discussion regarding each individual patient is initiated early if there is a potential for surgical resection with curative intent to optimize patient outcomes. Maximizing diagnostic imaging capabilities has an important role when considering surgical resection, such as MRI, PET/CT, and volumetric imaging. The use, choice, and duration of neoadjuvant chemotherapy should be determined by the treating medical oncologist and surgeon in a multidisciplinary fashion. Prior studies indicated that patients who have a partial response or stable disease to neoadjuvant therapy will fare better than those with progression of disease (104). Prior studies have indicated a trend in DFS and OS for adjuvant single-agent 5-FU–based chemotherapy versus observation following hepatic resection (105). Hence, clinical trials are under way to modify the neoadjuvant and adjuvant approach for candidates of hepatic resection. Challenges remain in the setting of a patient with a primary rectal cancer and the timing and role of radiotherapy.
In general, it is recommended that patients have KRAS testing completed early on in preparation for both immediate and subsequent chemotherapy treatment planning. When considering hepatic resection, it is crucial that patients are not treated until the point of radiographic CR. It is well known that a radiographic CR harbors microscopic disease that is only appreciated on the tissue specimen once surgically resected (106). Furthermore, if patients are not surgically resected following path CR or near-path CR, progression of disease will develop. In addition, prolonged chemotherapy may have a negative impact on surgical mortality (107).
Follow-Up for Patients With Resected Metastatic Colorectal Cancer
Following metastasectomy, patients are followed closely with physician visits, CEA level analysis, and diagnostic imaging. Patients undergo clinical evaluations every 3 to 4 months for the first 3 years, every 6 months for the following 2 years, and annually thereafter. Colonoscopy will continue to be completed every 3 years thereafter (some patients require more frequent examinations based on endoscopic findings or high-risk status). Computed tomography of chest, abdomen, and pelvis (or MRI) is the standard recommended cross-sectional imaging modality. Use of PET/CT is completed only if inconclusive findings are noted on CT/MRI or if a rising CEA is noted without measurable disease on CT/MRI. All patients are encouraged to maintain a relationship with a primary care physician for optimal surveillance and health care.
The MDACC Approach to Patients With Metastatic Disease
It is difficult to articulate a general treatment algorithm for patients with metastatic disease, but individual consideration of each patient’s case is always taken into account. For the majority of patients with metastatic colorectal cancer, surgical resection of metastatic disease will not be technically possible or clinically appropriate. Whenever possible, patients with good performance status and no significant problems related to local tumor are offered therapy as part of a clinical trial.
Once patients fail frontline therapy, a period of observation may ensue, or second-line therapy may be instituted. Previous analyses have suggested a survival advantage for patients treated with all three active conventional cytotoxic agents (5-FU, irinotecan, and oxaliplatin) during the course of their treatment (108), but the precise order of targeted agents in the therapeutic sequence has yet to be fully elucidated. However, KRAS tumor mutation status has become a core part of treatment decision making.
Broad principles have emerged as the foundation for therapeutic decisions at MDACC:
Asymptomatic patients with metastatic disease are usually offered systemic chemotherapy treatment. Systemic chemotherapy has served an integral role in our care of patients with metastatic disease with regard to quality of life, palliation of pain, and improvement in OS. A multidisciplinary approach is always considered when the primary malignancy remains in place. Evaluation of lumen patency is completed before initiating systemic chemotherapy. With the advent of newer agents such as irinotecan, oxaliplatin, and the monoclonal antibodies, OS of patients with metastatic disease has been steadily improving over the last several years. Moreover, frontline therapy is better tolerated and more likely to be beneficial in asymptomatic patients with good performance status. An exception to this principle applies to those patients with known metastatic disease that is either not evaluable or extremely low volume. In these cases, close follow-up with frequent cross-sectional imaging may be an appropriate initial strategy. Therapy is then initiated once measurable disease is evident or, in the oncologist’s judgment, further expectant follow-up is likely to lead to symptoms. Patients with a rising serum CEA level are usually not recommended to undergo treatment in the absence of clear clinical or radiographic evidence of metastatic disease and are followed closely. When deciding between an oxaliplatin- or irinotecan-containing regimen, the choice of chemotherapy is largely based on the objectives of treatment: surgical intent, borderline resectable, and unresectable for palliation. FOLFIRI and FOLFOX are comparable in terms of efficacy, but toxicities are distinctly different. When considering systemic chemotherapy for an unresectable patient, FOLFIRI is commonly selected at our institution given its lack of dose-limiting toxicities.
The initial treatment for metastatic disease may depend on the timing and residual toxicities of prior adjuvant therapy. Many patients who develop metastatic disease have received prior adjuvant therapy consisting of oxaliplatin, 5-FU, and leucovorin. When patients relapse, they should be considered refractory to this combination if fewer than 12 months have elapsed since the completion of adjuvant therapy. Irinotecan often becomes the primary cytotoxic agent in the treatment of relapsed disease after recent adjuvant therapy.
Patients should be treated to maximal benefit or until therapy becomes intolerable. When patients are receiving systemic therapy for metastatic disease, we usually continue treatment until the tumor becomes refractory to the regimen, toxicity dictates discontinuation, or patient deferment of therapy. Patients receiving oxaliplatin in conjunction with capecitabine or 5-FU, as part of a FOLFOX or XELOX regimen, may develop unacceptable peripheral neuropathy. A study performed in France suggested that there is no disadvantage to discontinuation of oxaliplatin, provided maintenance therapy with 5-FU and leucovorin continues. Oxaliplatin may be reintroduced as a component of the regimen once neuropathic symptoms subside or the tumor starts to progress (109).
This concept was analyzed in a prospective trial, Optimized 5-FU and Oxaliplatin Study (OPTIMOX1). It demonstrated that switching to a nonoxaliplatin maintenance regimen (5-FU/ leucovorin) after 6 cycles of FOLFOX, with reintroduction of oxaliplatin after 12 cycles of maintenance therapy or at disease progression, did not worsen clinical outcomes when compared to continuous FOLFOX until disease progression. In fact, patients on the maintenance arm experienced less grade 3 and 4 toxicities after the initial six cycles of treatment (110). A subsequent trial (OPTIMOX2) randomized patients to maintenance therapy (as in OPTIMOX1) or a chemotherapy holiday after six cycles of FOLFOX, with similar rules for oxaliplatin reintroduction. The maintenance arm showed superior median PFS (8.6 vs 6.6 months, P = .0017) and duration of disease control (13.1 vs 9.2 months, P = .046), with a trend toward improved overall (111). In clinical practice, however, the benefit of maintenance therapy must be weighed against potential toxicity, and patient preference must be considered as well. Therefore, a chemotherapy treatment holiday may be appropriate for patients after prolonged response or stability of disease.
Once frontline therapy has been exhausted, a period of observation may be advantageous. With newer drugs and combinations creating significant inroads as debulking agents, metastatic colorectal cancer can be viewed as a chronic illness for some patients, rather than a suddenly life-threatening disease. Therefore, immediate initiation of second- or third-line therapy after failing frontline treatment is not always necessary, and punctuating regimens with periods of observation has at least two advantages. First, it provides patients with a chemotherapy holiday, which may improve overall quality of life; second, it allows for more robust physiologic and hematopoietic recovery after prior treatment. Therefore, once a decision is made to restart cytotoxic therapy, timely delivery of full-dose therapy is more likely to proceed without interruption. As described previously, when we follow patients expectantly, restaging studies are performed every 8 to 12 weeks unless the clinical situation requires restaging sooner.
The need for local control should always be considered. Some patients with metastatic disease may also have intact primary tumors or locally recurrent disease. Recent experience with combination therapies suggested that the primary tumor may respond well to systemic therapy in some cases, obviating the need for local therapies. As a general rule, however, locally recurrent tumor at a site of previous surgery or radiotherapy is not particularly responsive to systemic therapy. Therefore, oncologists must continuously reassess whether local tumor control should take priority over treatment for disseminated disease. Such decisions are usually made with input from a multidisciplinary team, which may include radiotherapists, surgical oncologists, and gastroenterologists.
Challenging Clinical Management Problems
On occasion, an endoscopically removed polyp may demonstrate invasive adenocarcinoma within a villous or tubular adenoma. Treatment recommendations in this situation should be individualized based on features, including negative margins, no evidence of invasion beyond the submucosa, well- or moderately differentiated adenocarcinoma, and no evidence of lymphatic or vascular invasion. In this setting, the risk of lymph node metastases is low (5%), and follow-up with periodic colonoscopic examinations is reasonable (4). Unfortunately, retrieval of a sessile or bulky polyp distorts the depth of invasion or margin status. Furthermore, if pathology demonstrates poor differentiation, invasion into the muscularis, or lymphovascular invasion, surgical resection is advised. In particular, T2 tumors have a 20% likelihood of lymph node metastases, so continued endoscopic follow-up without further surgical intervention is not appropriate.
A malignant polyp in the distal or midrectum is often not amenable to further local staging because endoscopic rectal polypectomy leads to unreliable EUS imaging. Definitive surgical resection should be considered for a resected rectal polyp without clear margins or with adverse pathologic features. If margins are equivocal without muscle invasion, transanal excision may be feasible. Even when laparotomy is considered, a sphincter-preserving procedure is usually possible. Occasionally, an adequately informed patient will refuse surgery, or medical comorbidities preclude surgery as an option. In these special circumstances, nonstandard combined-modality chemoradiation is an alternative to definitive resection.
Nonsurgical Options for Partially Obstructing Tumors
The clinical diagnosis of bowel obstruction usually is based on an endoscopy or CT that may show obstructing mass(es). However, clinically significant bowel obstruction may not be present without proximal colonic dilation or evidence of perforation.
Bowel resection or diverting ostomy may be appropriate, but in patients with poor performance status, nonsurgical management should be considered, which includes expandable metal stents, especially in the rectosigmoid region. Obstructing sites higher in the colon can pose technical barriers to stent insertion. An endoscopically placed colonic decompression tube proximal to the obstruction may provide temporary relief. Endoscopic electrosurgical procedures, including argon plasma coagulation may recanalize the lumen. External-beam radiotherapy may then prevent complete obstruction while alleviating partial obstruction. Radiotherapy in rectal primaries may also relieve sacral plexus pain syndromes. Patients with impending bowel obstruction are hospitalized for bowel rest, nasogastric tube decompression, and intravenous hydration, followed by multidisciplinary evaluation by a gastroenterologist, surgical oncologist, medical oncologist, and radiotherapist. While stent insertion, photocoagulation of intraluminal disease, or radiotherapy may all rapidly reverse impending bowel obstruction, the use of systemic therapy in a patient with tenuous bowel patency should be discouraged.
Multidisciplinary Management of Poor Bowel Function After Curative Treatment
Segmental bowel resections particularly for rectal cancer lead to permanent alterations in the frequency and character of bowel movements. Loss of the rectal vault and subsequent radiotherapy lead to compromised stool storage and stricture formation at the anastomotic site, while sphincter function may not return to baseline, leading to functional and mechanical dysfunction manifesting as small, frequent bowel movements, with episodic fecal incontinence.
In general, patients are advised that bowel habits may improve for up to 1 year from the time of surgery or up to 6 months after completion of all adjuvant therapy. For patients with more chronic and severe problems (innumerable small bowel movements or fecal incontinence), a multidisciplinary team of surgeons, gastroenterologists, and enterostomal nursing staff recommends a personalized detailed bowel regimen that, with adequate adherence, can improve quality of life and satisfaction with sphincter preservation. On rare occasions, when a sphincter-preserving procedure leads to unbearable dissatisfaction with bowel function, a colostomy or ileostomy may be recommended to improve functional status and quality of life.
Carcinoma With Neuroendocrine Features
Histologically, a colorectal carcinoma may demonstrate neuroendocrine differentiation, which should be readily distinguished from small cell carcinomas or high-grade neuroendocrine tumors by additional stains for chromogranin and synaptophysin. Metastatic gastrointestinal neuroendocrine carcinomas have been treated with irinotecan/cisplatin or irinotecan/oxaliplatin at MDACC, with observed partial responses, but durable responses remain uncommon. Individuals with adenocarcinoma with focal neuroendocrine features are offered standard colorectal cancer chemotherapy.