Accomplishments in 2007 in the Management of Curable Metastatic Colorectal Cancer

SUMMARY

1. Overview of the Disease

   1. Incidence
   2. Prognosis
2. Current Therapy Standards

   1. Colorectal Liver Metastases (CRLM)

      1. Resectable Tumors
      2. Strategies To Convert Nonresectable Liver Metastases to Resectable Status
      3. Synchronous Colorectal Liver Metastases
      4. Predictors of Survival After Resection of CRLM
   2. Peritoneal Carcinomatosis (PC) From Colorectal Cancer
   3. Colorectal Pulmonary Metastases (CRPM)
   4. Colorectal Liver Metastases With Extrahepatic Disease
3. Accomplishments (or Lack of Accomplishments) During the Year

   1. Therapy

      1. New Staging System
      2. Preventive Measures for CRLM
      3. Systemic Chemotherapy
      4. Selective Internal Radiation Therapy (SIRT)
      5. Proposed Definition of Cure From CRLM
   2. Basic Science
4. What Needs To Be Done?

   1. Optimizing Patient Care
   2. Controversies and Disagreements
5. Future Directions

   1. Comments on Research
   2. Obstacles to Progress

I. OVERVIEW OF THE DISEASE

I-A. Incidence

Colorectal cancer (CRC) is the fourth most common cancer diagnosed worldwide and accounts for the second highest cancer-related mortality rate.¹ Approximately 35% of patients have stage IV disease at presentation and 20% to 50% with stage II or III disease progress to stage IV.²

I-B. Prognosis

New therapies and improved surgical techniques have continued to reduce the death rate by almost 1.8% per year. The overall 5- year survival rate for stage IV disease remains approximately 10%.³ In the natural course of the disease up to 50% of patients will develop metastases to the liver, making it the most common site of metastasis.⁴ Approximately one quarter of patients initially presenting with CRC has liver metastases (ie, synchronous liver metastases); the presence or absence of liver metastases primarily determines survival.⁵ Even in patients with an isolated liver tumor, the progression of the liver disease, rather than of the primary CRC, determines overall life expectancy.⁶ If left untreated, survival in patients with colorectal liver metastases (CRLM) is measured in months.^6–8

Peritoneal carcinomatosis may occur from transmural spread of the primary malignancy or from perforation at diagnosis and is associated with a poor prognosis.⁹ Pulmonary metastasis from CRC (CRPM) is also common but less intensively studied. Surgical resection of CRPM has increased in recent years, showing similar long-term benefit in selected groups of patients as seen with liver resection for CRLM.¹⁰ Although cerebral metastases are uncommon, CRC is responsible for approximately 5% of brain metastases, which generally occur at a later disease stage.¹¹

II. CURRENT THERAPY STANDARDS

II-A. Colorectal Liver Metastases (CRLM)

The main therapeutic modalities for CRLM comprise surgical resection, chemotherapy, and radiofrequency ablation; however, hepatic resection is currently the only potentially curative approach.¹²

II-A. 1. Resectable Tumors

At the time of presentation, only 15% to 20% of patients with CRLM are candidates for resection with intent to cure.¹³ Resectability is mainly defined by the ability to perform a curative hepatectomy, resecting all lesions while leaving at least 30% of nontumoral liver parenchyma.¹⁴ Five-year survival rates of 35% to 55% have been reported among patients undergoing hepatic resection.^2,15

II-A. 2. Strategies To Convert Nonresectable Liver Metastases to Resectable Status

Preoperative or conversion chemotherapy has become the primary treatment approach for nonresectable CRLM.¹⁶ This therapy helps to downstage liver disease, allowing more patients to undergo curative hepatectomy with a ≥ 30% nontumoral liver parenchyma remnant. Various chemotherapy regimens used include fluorouracil, leucovorin, oxaliplatin, and/or irinotecan. Modern chemotherapy allows 12.5% of patients with initially unresectable CRLM to be rescued by liver surgery. Despite a high recurrence rate and the requirement for repeat hepatectomies and extrahepatic resections, 5-year survival rate of 33% has been reported, approaching that of patients diagnosed with operable disease.¹⁴ However, hepatectomy is contraindicated in patients with potentially resectable CRLM receiving neoadjuvant chemotherapy whose tumors progress before surgery, due to the poor reported outcome, even after potentially curative hepatectomy.¹⁷

Preoperative portal vein embolization (PVE), first described by Kinoshita¹⁸ and then used by Makuuchi¹⁹ in the setting of hepatic resection of hilar cholangiocarcinomas, is an effective means of creating hypertrophy of the future liver remnant (FLR), thus allowing safe hepatic resection. The underlying principle involves blocking portal venous flow to the side of the liver ipsilateral to the lesion in order to cause hypertrophy of the contralateral side and increase the volume of the FLR. Long-term survival is comparable to that after resection without PVE.²⁰

Radiofrequency ablation (RFA) combined with hepatic resection is rarely necessary or applicable. However, in selected patients whose tumors are otherwise unresectable, additional use of ablation allows effective clearance of disease. In such patients with extensive bilobar disease, recurrence rates are high, but long-term survival is encouraging and may be improved with aggressive postoperative chemotherapy.²¹

Some patients with multiple hepatic CRLM are not candidates for complete resection by a single hepatectomy, even when downstaged by chemotherapy, after portal embolization, or combined with a locally destructive technique. In two-stage hepatectomy, the tumor clearance of one hemiliver is conducted first, as a noncurative intervention, and the remaining tumors of the contralateral hemiliver are resected in a second operation, after a period of liver regeneration.²² This approach had led to good outcomes in patients with multiple, bilateral CRLM.²³

II-A. 3. Synchronous Colorectal Liver Metastases

Treatment strategies for patients with synchronous CLRM are still unclear. Synchronous metastases usually indicate a more disseminated disease status and are associated with shorter disease-free survival than metachronous metastasis.²⁴ The timing of surgery for primary CRC and CRLM as well as that of chemotherapy is controversial. To date, studies comparing simultaneous surgical resection vs. staged resection have shown that simultaneous resection may be safe but no survival advantage has been demonstrated. Comparison is difficult because simultaneous resection is often restricted to patients with more limited hepatic disease. However, it has been proposed that one-stage resection achieves a better outcome.^25–27

II-A. 4. Predictors of Survival After Resection of CRLM

Much interest has focused on factors that may predict patient prognosis after major liver surgery for metastatic disease; one such factor is the tumor-free margin of the resected specimen. Currently, a width of >1 cm is considered optimal, and is an independent predictor of survival after resection for CRLM. However, subcentimeter resections have also been associated with favorable outcome and should not preclude patients from undergoing resection.²⁸ Another known factor is number of metastases²⁹: more than 8 are associated with early recurrences.³⁰ An elevated neutrophil-lymphocyte ratio (NLR) was found to be a prognostic indicator in primary CRC and to increase both risk of recurrence and death in patients undergoing surgery for CRLM.³¹ An interesting report by DeOliveira et al states that presence of hypoechoic lesions on intraoperative ultrasonography is associated with poor patient survival.³²

II-B. Peritoneal Carcinomatosis (PC) From Colorectal Cancer

PC is a common manifestation of CRC and has traditionally been regarded as a terminal disease with short patient survival. Over the past decade, a new local-regional therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy) has evolved, and promising survival results have been reported. In a recent retrospective multicenter study involving 506 patients, median survival was 32.4 months vs. 8.4 months in patients who completed vs. did not complete cytoreductive surgery.³³

II-C. Colorectal Pulmonary Metastases (CRPM)

Pulmonary metastasectomy remains a mainstay in the multidisciplinary management of patients with resectable lesions. Five-year survival rates up to 50% have been reported in patients with metastases limited to the lungs.³⁴ Chemotherapy is generally used in conjunction with resection.

II-D. Colorectal Liver Metastases With Extrahepatic Disease

After reasonable success of multimodality treatment for isolated liver and pulmonary metastases, interest is emerging for the treatment of more complex multi-organ metastases. Surgical resection of both hepatic and pulmonary colorectal metastases has been associated with prolonged survival in selected patients.^35,36 Elias et al stated that extrahepatic disease, when resectable, is no longer a contraindication to hepatectomy.³⁷ More important, the total number of metastases, whatever their location, has a stronger prognostic effect than the site of the metastases. However, further validation of this concept is needed.

III. ACCOMPLISHMENTS (OR LACK OF ACCOMPLISHMENTS) DURING THE YEAR

III-A. Therapy

III-A. 1. New Staging System

Management of advanced CRC and of CRLM has evolved dramatically in the past two decades. What was once considered stage IV (noncurable) disease has now become possibly curable, based on advances in surgical techniques, chemotherapy, and perioperative care. Poston et al³⁸ have proposed a new staging system in advanced CRC, which includes two major prognostic factors: the resectability of metastases, and the isolated or combined presence of hepatic and extrahepatic metastases. Furthermore, Minagawa et al³⁹ have proposed a simplified staging system for predicting prognosis of patients with resectable CRLM, which was developed after examining 22 clinopathologic factors in 369 consecutive patients who underwent curative liver resection for CRLM. This tool was also validated by data from 229 unrelated patients. Patients with hepatic lymph node metastasis are categorized as stage IV and the remaining patients are categorized according to number of risk factors, as shown in Figure 1. Further validation of this staging system is awaited before it can be universally accepted.

Figure 1.

New staging system for patients with liver metastases from colorectal cancer. Abbreviation: CEA= carcinoembryonic antigen. Reprinted with permission from Minagawa et al.³⁹ Copyright ©(2007), American Medical Association. All rights reserved.

III-A. 2. Preventive Measures for CRLM

Xu et al demonstrated the benefits of preoperative hepatic and regional arterial chemotherapy, in combination with surgical resection, in a prospective randomized controlled trial.⁴⁰ Patients with stage II or III CRC were randomly assigned to receive preoperative hepatic and regional arterial chemotherapy (PHRAC group, n = 110) or surgery alone (control group, n = 112). There were no significant differences in overall morbidity between the groups. During the follow-up period (median, 36 months), the median time from detection of CRC to development of liver metastasis for patients with stage III CRC was significantly longer in the PHRAC group (16 ± 3 vs. 8 ± 1 months, P = .01). Stage III patients treated with PHRAC also had a significant reduction in the incidence of liver metastasis (20.6% vs. 28.3%, P =.03), and increased 3-year disease- free survival (74.6% vs. 58.1%, P = .0096), 3-year overall survival (87.7% vs. 75.7%, P =.020), and median survival duration (40.1 ± 4.6 vs. 36.3 ± 3.2 months, P = .03) relative to control patients. In contrast, stage II patients showed no benefit from PHRAC.

III-A. 3. Systemic Chemotherapy

• Perioperative FOLFOX4 (5-fluorouracil [5-FU], leucovorin, oxaliplatin) chemotherapy for patients with potentially resectable CRLM: Final results of the European Organisation for the Research and Treatment of Cancer (EORTC) Intergroup randomized phase III 40983 study were reported in 2007.⁴¹ A total of 364 patients with up to four CRLM were randomized between perioperative FOLFOX4 (oxaliplatin 85 mg/m² and LV5FU2), six cycles before and six cycles after surgery (CT), vs. surgery alone (S). Eleven of 182 patients were ineligible in each arm, mostly due to more advanced disease; 31 and 30 patients in the CT and S arms, respectively, could not undergo resection. At a median follow-up of 3.9 years, progression-free survival (PFS) was significantly better in the CT group (Table 1).

• First-line chemotherapy with FOLFIRI ± cetuximab in patients with metastatic colorectal cancer: This randomized study included 1,217 patients and demonstrated that the combined use of cetuximab with FOLFIRI (5-fluorouracil, irinotecan, leucovorin) improved PFS (1-year PFS rate, 34% vs. 23%; median PFS, 8.9 vs. 8 months) and increased the resectability of patients with initially unresectable metastatic CRC (6% vs. 2.5%), through an increased response rate (46.9% vs. 38.7%).⁴²

• Rescue chemotherapy for CRLM previously refractory to conventional systemic therapy:

  • – A phase III trial compared FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) and FOLFIRI in 244 patients with unresectable metastatic CRC.⁴³ Patients in the FOLFOXIRI arm had a better rate of R0 secondary resection of metastases (6% vs. 15%, P = .033, among all 244 patients; and 12% vs. 36%, P = .017, among patients with liver metastases only) and a significantly improved PFS and overall survival (OS).
  • – A retrospective study also evaluated 151 patients with CRLM refractory to first-line conventional chemotherapy, who then received combination therapy with cetuximab.³⁶ Of these 151 patients, 25 (16%) underwent surgery after a median of six cycles of combination therapy with cetuximab. After a median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were disease- free. Median OS and PFS durations from initiation of cetuximab therapy were 20 and 13 months, respectively.

Table 1.

EORTC phase III 40983 study of perioperative FOLFOX4: Progression-free survival

	No. pts CT	No. pts Surgery	% Absolute Difference in 3-yr PFS	HR (CI)	P Value
All patients	182	182	+7.2% (28.1% to 35.4%)	0.79 (0.62–1.02)	P =.058
All eligible	171	171	+8.1% (28.1% to 36.2%)	0.77 (0.60–1.00)	P =.041
All resected	151	152	+9.2% (33.2% to 42.4%)	0.73 (0.55–0.97)	P =.025

Abbreviations: CI = confidence interval; CT = perioperative chemotherapy; EORTC = European Organisation for the Research and Treatment of Cancer; FOLFOX4 = 5-fluorouracil, leucovorin, oxaliplatin; HR = hazard ratio; PFS = progression-free survival.

III-A. 4. Selective Internal Radiation Therapy (SIRT)

SIRT spheres are biocompatible radioactive microspheres containing yttrium-90 that emits beta radiation. It delivers up to 40 times more radiation to liver metastases than would be possible using conventional radiotherapy, and has shown benefits in patients with liver metastases. These microspheres are delivered into the hepatic artery via a catheter inserted in the femoral artery. Typically, SIRT is used in combination with chemotherapy as multimodal treatment for unresectable CRLM. Complete eradication of hepatic metastasis from CRC after SIRT therapy was recently reported.⁴⁴

III-A. 5. Proposed Definition of Cure From CRLM

Surgical management has been used for patients with CRLM for about five decades, and interesting long-term follow-up data are emerging from high volume centers. One such center reported that patients who survive 10 years after liver resection for CRLM seem to be cured of their disease, whereas approximately one third of 5-year survivors die of a cancer-related cause.⁴⁵ In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CRLM. They also found that the presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.⁴⁵

III-B. Basic Science

The effects of hepatectomy and hepatic regeneration on intrahepatic and extrahepatic tumor growth are as yet unclear. Two interesting studies using animal models demonstrated that regeneration after major hepatectomy accelerates extrahepatic tumor cell engraftment, most likely by accelerating neovascularization and induction of tumor cell migration.⁴⁶ Moreover, the late phase of liver regeneration plays a significant role in tumor stimulation and metastasis; this observation may assist in the development and timing of adjuvant agents to minimize tumor recurrence during this phase.⁴⁷ These findings support the trend toward performing limited nonanatomic and segmental resections, whenever possible.

IV. WHAT NEEDS TO BE DONE?

IV-A. Optimizing Patient Care

Most patients with colorectal metastases still present to general surgeons and oncologists who are not specialists in their management. Because the treatment strategy frequently depends on the response to earlier therapies, and proper treatment of metastases at an early stage is associated with better outcome, certain procedures and systems are needed to provide optimal care for patients with metastatic CRC. These include regular surveillance and a multidisciplinary team (MDT) approach; computer programs such as Oncosurge⁴⁸ are also a step in this direction. Oncosurge helps to determine resectability of individual patients and define optimal treatment strategies. It can also be used for medical education.

IV-B. Controversies and Disagreements

Radiofrequency ablation (RFA) techniques are currently accepted for palliative purposes. The expected OS rate of patients undergoing RFA for unresectable or non-resected CRLM was improved compared with that reported following the natural course of disease (best supportive care) or chemotherapy.⁴⁹ Local tumor progression is common after percutaneous RFA; therefore, close follow-up and re-treatment are necessary to achieve optimal results.⁵⁰ Few studies have reported improved or equivalent outcome after RFA in patients with small CRLM. However, a recent report from Park et al showed that RFA for metachronous CRLM, in comparison with hepatic resection, was associated with higher local recurrence and shorter recurrence-free and OS rates, even in patients with solitary, small (≤3 cm) lesions.⁵¹ Aloia et al showed similar findings.⁵²

V. FUTURE DIRECTIONS

V-A. Comments on Research

Surgical resection with intent to cure is a standard therapy for selected patients with CRLM. However, optimal therapy for nonresectable CRLM, synchronous CRLM, metastases to organs other than liver, the role of RFA and/or chemotherapy as curative measures, and many other issues remain unanswered. Given the potential for remission and sometimes cure that can be achieved with surgery, the resectability of metastases, mainly hepatic, is emerging as a new end point in the treatment of patients with metastatic CRC. Whether potent chemotherapy regimens, including triplets or doublets with biologics, in patients with marginally unresectable metastases is a valid strategy for improving long-term outcome as compared with conventional chemotherapy remains an open question. Table 2 lists current key trials evaluating treatments for patients with metastatic colorectal cancer.

Table 2.

Key trials in the management of patients with metastases from colorectal cancer.

Trial Name	Stage	Status	Trial Schema
Phase III Trials
USCTU-4351	III	Recruiting	Neoadjuvant and adjuvant combination chemotherapy with vs. without cetuximab
GERCOR-C02-1	III	Recruiting	Adjuvant FOLFOX4 vs. FOLFOX7 and FOLFIRI
HEPATICA	III	Recruiting	Adjuvant XELOX + bevacizumab vs. XELOX alone
Sir-Spheres1	III	Recruiting	Hepatic intra-arterial injection of yttrium-90 microspheres vs. infusional IV 5-FU in patients refractory to standard IV chemotherapy
Adjuvant, Perioperative, or Neoadjuvant Trials
FRE-IGR-CHOICE	II	Recruiting	LV5FU2 simplified + cetuximab with intra-arterial hepatic oxaliplatin for potentially resectable metastases
EORTC-40051	II	Recruiting	Adjuvant FOLFOX + cetuximab vs. FOLFOX + cetuximab + bevacizumab
DUMC-5883-04-6RO	II	Recruiting	Active immunotherapy with PANVAC or autologous, cultured dendritic cells infected with PANVAC after complete resection
CHUV-CH-OCFL	II	Recruiting	Oxaliplatin-CPT-11-5-FU-leucovorin + bevacizumab and cetuximab (OCFL-BC) for potentially resectable liver and/or lung metastases
ACO-ASSO-LM1	II	Recruiting	Perioperative XELOX and bevacizumab for potentially resectable liver metastases
RMNHS-RMH-CCR-2676-BOXER	II	Recruiting	Neoadjuvant XELOX + bevacizumab
MSKCC 04-086	II	Recruiting	Hepatic arterial infusion with FUDR + DXM together with systemic chemotherapy ± bevacizumab in patients with resected liver metastases
Trials for Initially Unresectable Metastases
CCCGHS-CHEMO-SIRT	II	Recruiting	Chemotherapy with selective internal radiation treatment using Y-90 microspheres for unresected liver metastases
CELIM	II	Recruiting	FOLFOX + cetuximab vs. FOLFIRI + cetuximab for unresectable liver metastases
CHUG-ERBIFORT	II	Recruiting	FOLFIRI and cetuximab for unresected liver or lung metastases
NCI-04-C-0229	II	Recruiting	Isolated hepatic perfusion with melphalan for unresectable liver metastases
MSKCC-06075	II	Recruiting	Hepatic arterial infusion with FUDR and DXM in combination with best systemic chemotherapy plus bevacizumab

Abbreviations: CELIM = Cetuximab in Neoadjuvant Treatment of Nonresectable Colorectal Liver Metastases; CPT-11 = irinotecan; DXM = dexamethasone;

EORTC = European Organisation for the Research and Treatment of Cancer; FOLFIRI = 5-fluorouracil, irinotecan, leucovorin; FOLFOX = 5-fluorouracil, leucovorin, oxaliplatin; FUDR = floxuridine; GERCOR = French Oncology Research Group; IV = intravenous; LV5FU2 = 5-fluorouracil + leucovorin; MSKCC = Memorial Sloan-Kettering Cancer Center; XELOX = capecitabine + oxaliplatin.

K-ras mutation status appears to be a tool to predict response to anti-EGFR agents, and may help to select appropriate patients for these targeted therapies.⁵³ Patients with mutated K-ras appear to have no response to EGFR-directed therapy.

V-B. Obstacles to Progress

The number of patients with metastatic CRC who can be offered treatment with the intent to cure is low. Therefore, it is not feasible to conduct prospective randomized trials to answer the many remaining questions in management of this patient cohort. The majority of new studies involve retrospective analyses of data from high volume centers. A prospective worldwide registry was recently initiated (www.livermetsurvey.org) to more clearly determine the patterns of care and outcomes. Universally accepted definitions and classifications to compare results from different studies are also needed.