Apr 22, 2015
By Sabha Ganai, MD, PhD
Director of Gastrointestinal Oncology, Southern Illinois University School of Medicine
Oligometastasis, which describes a disease state of limited metastatic potential, was first hypothesized to characterize a subset of patients with metastatic disease who demonstrate favorable outcomes after locally directed therapy.1 Particularly in colorectal cancer, evidence shows that many patients with limited metastasis can be cured with surgical resection, a remarkable finding that has on occasion been discounted due to selection bias. Indeed, one can argue that the act of selection is a responsibility and prerogative of an expert hepatobiliary surgeon, who, when weighing any potential for benefit versus the possibility of morbidity with surgery, must consider several factors, including anatomical features, patient considerations, and tumor biology.
While favorable anatomy and perioperative risk are relatively well understood by surgeons, determining the tumor biology that defines oligometastasis is still an imprecise art. Clinicians rely on clinicopathologic features, including disease-free interval and tumor number, to estimate tumor growth kinetics, yet an occult state of polymetastasis may only be truly recognized with the passage of time.2 Neoadjuvant chemotherapy has been advocated as a method of delivering the “test of time,” allowing clinicians to treat systemic disease and then use the response to therapy as a way to gain understanding of tumor biology and determine candidacy for resection. However, data supporting this approach is limited and conflicted.3
In this edition of Current Controversies in Oncology, expert hepatobiliary surgical oncologists debate the added benefit of neoadjuvant therapy for resectable hepatic colorectal metastases. While few would downplay the option of systemic therapy for a patient with bilobar metastases or bulky disease, this debate focuses on the patient with favorable features supporting resection and one unknown variable: tumor biology. While clinical trials of neoadjuvant therapy for resectable hepatic colorectal metastases have been challenging due to the complex interplay of variables in the equation, this is a topic that is ripe for further study. Ultimately, an understanding of what distinguishes oligometastasis from polymetastasis will allow us to start predicting outcomes, thus adding science to the art of selection.
1. Weichselbaum RR, Hellman S. Nat Rev Clin Oncol. 2011;8:378-82.
2. Ganai S, Winchester DP. Oncology (Williston Park). 2011;25:50-8.
3. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet Oncol. 2013;14:1208-15.
Dr. Ganai is the Director of Gastrointestinal Oncology at the Southern Illinois University Simmons Cancer Institute. She has been an ASCO member since 2011 and is a member of the Integrated Media and Technology Committee and the ASCO Connection Editorial Board. Follow Dr. Ganai on Twitter @DrSabha.
Perioperative Chemotherapy Is Preferable to Postoperative Adjuvant Chemotherapy in Patients with Resectable Hepatic Colorectal Metastases
By Pragatheeshwar Thirunavukarasu, MD
Oncology Fellow, Roswell Park Cancer Institute
Thomas A. Aloia, MD
Associate Professor of Surgical Oncology, The University of Texas MD Anderson Cancer Center
The rationale for the delivery of preoperative systemic chemotherapy to patients with colorectal liver metastases is informed by a number of sources, including the findings of a randomized trial (EORTC intergroup trial 40983) which compared pre- and postoperative FOLFOX [fluorouracil, leucovorin, and oxaliplatin] (sandwich) chemotherapy to surgery alone.1 Despite a significant three-year progression-free survival (PFS) advantage in the chemotherapy arm, ultimately, the trial found statistically similar five-year overall survival.2 Naturally, this result let the air out of the preoperative chemotherapy balloon.
The subsequent rush to abandon neoadjuvant strategies in this systemic disease is unfortunate on many levels, as a careful examination of the details within the EORTC 40983 trial reveals many important findings. First, enrollment was limited to patients with the lowest burden of disease, a result of the inclusion criteria for tumor size and number. A priori, it was going to be exceedingly difficult to demonstrate a survival advantage for chemotherapy in this patient population. Hopefully, the focus of this debate will not be on the rare patient with a solitary small metastasis—the type of patient who overpopulated the EORTC 40983 trial but is rarely seen in the hepatobiliary surgeon’s clinic.
In addition, the trial informed us about the natural history of clinical occult metastatic disease. We are aware that for patients who have multiple sub clinical intra- and/or extrahepatic metastases or who develop this shortly after diagnosis and initiation of therapy, about 10% will have an aggressive phenotype. To illustrate this point, within the surgery arm of the EORTC 40983 trial, 18 patients (11%) were explored and closed due to the finding of unresectability. In contrast, in the chemotherapy arm, only eight patients (5%) underwent a nontherapeutic laparotomy. An additional 12 patients progressed during preoperative therapy and avoided laparotomy. Biologically speaking, these are the exact same Sabha Ganai, MD, PhD Pragatheeshwar Thirunavukarasu, MD Thomas A. Aloia, MD Michael A. Choti, MD W.A. PARK patients in either arm; the only difference between them is that the surgery-first patients required an incision to determine unresectability.
The “con” side of this debate is bolstered by the data regarding surgical complications associated with preoperative systemic therapy. But while it is true that excessive preoperative systemic therapy (longer than three months, more than six cycles) increases the difficulty of surgery and recovery, no one would suggest giving more than this amount to the index “resectable” patient, who is the focus of this debate.3-5 So, then, we must ask: What is the impact of short-course systemic therapy on postoperative complications?
Impact of short-course systemic therapy on postoperative complications
Digging back into the EORTC 40983 trial, we see that 25% of patients in the perioperative chemotherapy arm experienced complications, compared to only 16% in the surgery-first arm. However, if we include nontherapeutic laparotomy as a complication, the scales tip to 30% versus 26%, with no statistical difference. Most importantly, the mortality rate in both groups was identical at 1%.
In addition to the opportunity to weed out bad biologic actors prior to laparotomy, preoperative therapy has a dramatic impact in two areas: margins and prognosis. It is now understood that the addition of preoperative therapy allows for smaller margins of resection, sparing more vital structures and liver parenchyma. Effectively, a preoperatively treated patient with R1 resection margins shares the same survival as an untreated patient with microscopically negative margins.6
In real-life cases, we typically see patients with a median of three tumors frequently abutting at least one of the major vascular structures within the liver; in these cases, a clear and present benefit of neoadjuvant chemotherapy is the ability to achieve equivalent oncologic outcomes with resection of only the tumor, thus sparing the patient the risks of overly aggressive resection. But more important than margin status is the prognostic information gained from the combination of preoperative therapy, surgical resection, and pathologic assessment of the treated tumor tissue.
Recent research indicates that pathologic tumor response is the single most powerful prognosticator of long-term oncologic outcome in this disease. Patients with major pathologic response have an almost 80% five-year survival compared to 55% for patients with minor response, and only 30% among patients with no response.7,8
In fact, when pathologic response is entered into a risk model containing the five components of the Memorial Sloan Kettering Cancer Center colorectal risk score, all five of these factors lose statistical significance as prognostic factors, leaving only margin status and pathologic response as meaningful indicators for long-term survival. In other words, pathologic response to neoadjuvant therapy is so prognostically powerful that it completely eliminates the relevance of other traditionally considered prognostic factors such as node positive primary tumor, synchronous presentation, elevated carcinoembryonic antigen level, metastasis tumor size, and even number of metastases.
Without preoperative therapy, this most important prognostic marker is lost, giving the surgeon and patient less information as they move forward. In summary, for patients presenting to surgeons and oncologists with resectable colorectal liver metastases, the benefits of short-course preoperative systemic therapy—including avoidance of nontherapeutic laparotomy, improved margin control, increased surgical flexibility, and the provision of critically important prognostic information—far outweigh the minor differences in postoperative complication rates.
Dr. Thirunavukarasu is a Fellow of Surgical Oncology at Roswell Park Cancer Institute.
Dr. Aloia is an Associate Professor in the Department of Surgical Oncology, Division of Surgery, at The University of Texas MD Anderson Cancer Center. He is currently a member of the Journal of Oncology Practice Editorial Board.
1. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet. 2008;371:1007-16.
2. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet Oncol. 2013;14:1208-15.
3. Karoui M, Penna C, Amin-Hashem M, et al. Ann Surg. 2006;243:1-7.
4. Aloia T, Sebagh M, Plasse M, et al. J Clin Oncol. 2006;24:4983-90.
5. Vauthey JN, Pawlik TM, Ribero D, et al. J Clin Oncol. 2006;24:2065-72.
6. Andreou A, Aloia TA, Brouquet A, et al. Ann Surg. 2013;257:1079-88.
7. Blazer DG 3rd, Kishi Y, Maru DM, et al. J Clin Oncol. 2008;26:5344-51.
8. Chun YS, Vauthey JN, Boonsirikamchai P, et al. JAMA. 2009;302:2338-44.
Postoperative Adjuvant Chemotherapy Is Preferable to Perioperative Chemotherapy in Patients with Resectable Hepatic Colorectal Metastases
By Michael A. Choti, MD, MBA, FACS
Professor and Chair, Department of Surgery, UT Southwestern Medical Center
Integrating chemotherapy and hepatectomy in patients with initially resectable colorectal liver metastases has the potential to improve survival beyond resection alone. Yet, questions remain regarding the optimal indications, regimen, and sequence of chemotherapy. Advocates for the use of routine neoadjuvant chemotherapy often cite the European multicenter randomized trial (EORTC 40983).1 Yet, one must keep in mind that this trial compared perioperative chemotherapy to surgery alone and did not assess whether the order of chemotherapy— pre- versus postoperative—affected patient outcomes. Moreover, this study failed to demonstrate any overall survival benefit to chemotherapy when administered perioperatively.2 Therefore, we have little high-level evidence to help guide recommendations regarding the optimal sequencing of chemotherapy in this setting.
Proponents of perioperative therapy argue that patients with resectable cancer have specific advantages in undergoing initial chemotherapy. For example, the delay in surgery can be used to identify those who progress and develop metastases at distant sites, thus selecting out those who will not benefit from hepatic surgery. Yet, several studies, including the EORTC trial, suggest that this strategy is a poor discriminator for patient selection, with less than 10% of patients progressing during preoperative chemotherapy and fewer than 3% becoming unresectable.1 Even among studies with a greater number of metastases and worse prognostic factors, progression on neoadjuvant chemotherapy occurs in fewer than 10% of patients, and rarely progresses to unresectable disease or precludes the possibility of eventual surgical therapy.3,4
Supporters of neoadjuvant therapy also emphasize the benefit of chemotherapy as a prognostic and predictive biomarker based in vivo chemosensitivity of the macroscopic disease. However, it is clear from multiple studies that the role of chemotherapy in noncurative settings cannot be directly extrapolated to the adjuvant setting. Reports on the prognostic value of macroscopic response are largely based only on regimens containing targeted therapies such as bevacizumab or cetuximab. As with adjuvant therapy for stage III disease, bevacizumab has not been shown to improve outcomes in resected, stage IV colorectal cancer and probably has a limited role in the resectable patient, before or after liver resection.
Importantly, a recent trial compared perioperative adjuvant systemic FOLFOX chemotherapy with and without cetuximab in patients with wild-type KRAS tumors.4 In spite of an observed 70% response rate, this study found that cetuximab did not improve outcomes, and moreover, was associated with worse PFS. Importantly, advocates argue that a response assessment is beneficial in tailoring postoperative management. Yet, the preoperative response yields little information to help guide modifications in the postoperative regimen and few clinicians use this information to change therapy.
Potential disadvantages to neoadjuvant therapy
There are several additional potential disadvantages to neoadjuvant therapy. For example, chemotherapy is associated with an increased risk of chemotherapy-associated liver injury.5 Whereas this adverse effect is more often associated with chemotherapy of a more prolonged duration, even limited cycles of chemotherapy can result in increased perioperative morbidity. Specifically, the EORTC randomized trial of six cycles of perioperative FOLFOX found that patients who received chemotherapy had a statistically increased risk of postoperative complications.1
Neoadjuvant chemotherapy may also reduce the surgeon’s ability to find and remove all initially evident macroscopic disease, thus paradoxically contributing to worse outcome than when initial surgery is performed. For example, a subset of patients, particularly those with small lesions, sometimes have a complete radiologic response.6 Although tumor response in these patients may be considered advantageous, all initial sites of disease must be resected to achieve optimal surgical therapy. Even among patients undergoing initial surgical therapy, intraoperative assessment with intraoperative ultrasound of the liver will find additional disease—even beyond those lesions seen with high-quality preoperative imaging—in up to 10% of cases. Therefore, additional disease that might have been found intraoperatively with initial surgery may be more likely to be missed if neoadjuvant chemotherapy is administered.
Until further trials are completed and shed more light on the benefits and disadvantages of pre- versus postoperative chemotherapy, the timing of therapy should be individualized and based on specific clinical situations. Specifically, neoadjuvant chemotherapy may be appropriate in highly selected situations: in patients with particularly high-risk features, in cases where medical preoperative optimization of comorbid conditions may be needed, or when indeterminate extrahepatic disease is found and preoperative chemotherapy response may help assess these sites.7 Preoperative chemotherapy may also be warranted in patients with marginally unresectable disease for whom a response would improve the likelihood of complete resection. However, for most cases in which hepatic metastases are initially resectable, neoadjuvant chemotherapy should be used highly selectively and should not be regarded as the standard of care.
Dr. Choti is a Professor and Chair of the Department of Surgery at UT Southwestern Medical Center. He has been an ASCO member since 1999 and has served on the Radiofrequency Ablation (RFA) Committee and the Cancer Education Committee.
1. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet. 2008;371:1007-16.
2. Nordlinger B, Sorbye H, Glimelius B, et al. Lancet Oncol. 2013;14:1208-15.
3. Viganò L, Capussotti L, Barroso E, et al. Ann Surg Oncol. 2012;19:2786-96.
4. Primrose J, Falk S, Finch-Jones M, et al. Lancet Oncol. 2014;15:601-11.
5. Zorzi D, Laurent A, Pawlik TM, et al. Br J Surg. 2007;94:274-86.
6. van Vledder MG, de Jong MC, Pawlik TM, et al. J Gastrointest Surg. 2010;14:1691-700.
7. Karagkounis G, Cai G, Johnson PT, et al. Ann Surg Oncol. Epub 2015 Jan 13.