Raising the Bar: Where Do We Go From Here? - Advanced Studies ...

CASE STUDY

RAISING THE BAR: WHERE DO WE GO FROM HERE? — Discussion led by Michael A. Choti, MD

Dr Choti: The articles in this monograph have discussed shifting the mindset in oncology to one of curative intent rather than palliative treatment for many patients with colorectal hepatic metastases. Let us apply this curative treatment model to a real case. Suppose the following patient is referred to you: a 58-year-old male with rectal cancer who is asymptomatic. His carcinoembryonic antigen measures 18 ng/mL. The tumor is located 10 cm from the anal verge. In addition to the primary tumor, preoperative imaging demonstrates a solitary 2-cm metastasis in the right lobe of the liver (Figure 1). COURSE OF TREATMENT Dr Choti: What first course of treatment would the panel recommend for this patient? The options in this case would be to perform a proctectomy followed by staged hepatectomy then chemotherapy, or alternatively to perform a combined low anterior resection with right hepatectomy followed by chemotherapy. Would anyone consider initially approaching this patient with chemotherapy? Dr Grothey: Clearly, we would give adjuvant chemotherapy to this patient. Dr Fong: I agree. This patient should receive adjuvant chemotherapy. However, the more challenging treatment questions involve the sequencing of chemotherapy and surgery. Would this patient benefit from neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy? Certainly, it would be advantageous to operate on the rectum and the liver at one time to minimize complications. Dr Choti: Yes, the controversial part would be whether to perform a combined resection. This decision often depends on the location and extent of the liver resection and colorectal resection, in addition to the health of the patient. Our group would often con-

S388

sider combined resections in many cases. In this case, we would likely favor starting with chemotherapy if the patient was not significantly symptomatic from the primary tumor. Dr Fong: My hospital would treat this patient the same way. We favor neoadjuvant treatment in asymptomatic patients, and I would try 2 or 3 months of neoadjuvant chemotherapy in this patient, thus I could preserve as much liver as possible because it is always better to leave the patient with more liver. If this tumor were larger, requiring the entire right lobe to be removed, I would favor chemotherapy and portal vein embolization to grow the left side of the liver before surgery. Dr Choti: Where would the panel recommend this patient be treated to optimize the outcome? Dr Althaus: Any patient who presents with synchronous rectal or sigmoid cancer and hepatic metastasis should be treated at a tertiary care center.

Figure 1. 58-Year-Old Male with Rectal Cancer

Vol. 6 (5A)

n

May 2006

CASE STUDY

Dr Grothey: This patient needs to be treated in a multidisciplinary environment to have the best outcome. The patient will need to have his chemotherapy regimen optimized and may also require regional chemotherapy. All patients with stage IV disease will require complex treatment approaches if they are to be cured, and those decisions need to be made at a tertiary center. RADIATION THERAPY Dr Choti: Would the panel recommend radiation therapy for this patient? Dr Grothey: For overall survival considerations, I would not use radiation in the stage IV patient if I could avoid it. However, if there is a high risk of local recurrence, it is good idea to include radiation therapy. Dr Berlin: Local response rates for chemotherapy are approximately 60%, and the range is 60% to 70% for chemoradiation. Therefore, radiation is perhaps the last treatment that should be considered for many patients. Dr Choti: In this case, the tumor is relatively high in the rectum where sphincter preservation is not a concern. Let’s say now it is 4 or 5 cm from the verge, where preoperative chemoradiation may improve the likelihood of low anterior resection. Should preoperative chemoradiation therapy be encouraged in a case of a synchronous rectal cancer with a solitary resectable metastasis that is nonobstructing and not bleeding? Let’s get an opinion from the group. Dr Berlin: I would not favor radiation. We can’t do both at the same time. I still think the liver metastasis should be removed first and then wait to take the next step. Dr Fong: Let’s say endorectal ultrasound reveals T3N1, and the PET (positron emission tomography) scan shows uptake in the pelvis and solitary metastasis. Dr Grothey: I like the idea of nonradiation in the stage IV patient for overall survival. Having said that, we have a 50% chance of cure in this patient. And, if it is an N1 patient, we still have a significant risk of local recurrence. With an N1 patient, T3N1 is probably in the range of a 50% chance of cure, and a 15% chance to develop local recurrence, which you may be able to reduce to 10% with radiation. Local recurrence of rectal cancer is associated with high morbidity. Dr Berlin: Therefore, how would you manage this patient? Dr Grothey: If it is a low anterior resection, and it’s

Johns Hopkins Advanced Studies in Medicine

n

mid rectal, with no question of sphincter preservation, I would probably resect both sites and then do postoperative chemoradiation therapy. If sphincter preservation is an issue, preoperative chemoradiation is certainly an option. I recently managed a case of a patient in which we took a very different approach. The patient had an obstructing, bleeding rectal tumor and widely metastatic disease. Unlike this case scenario, we did not have time to observe for 4 or 8 weeks. We placed a stent just to control bleeding and obstruction, and then we put the patient on FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) without bevacizumab first cycle, then with bevacizumab second cycle. The patient’s liver was at the umbilicus when I first saw him. After 2 weeks, his liver size markedly reduced in size and I couldn’t palpate it anymore after 2 cycles. We rescoped him after 2 cycles of FOLFOX, 1 with bevacizumab, and the tumor was gone. With the liver now potentially resectable, the next question was whether we should then resect the primary tumor? Dr Berlin: We are also seeing dramatic responses in the primary tumors in some cases with chemotherapy alone. In such cases, it is unclear what the role of radiation therapy is. Dr Grothey: It is a matter of our mindset. Once we are thinking curative intent, we should not focus only on the metastasis, but also be concerned about local recurrence. Dr Fong: And, here is a patient that you were clearly thinking in this mode. It does not mean that these patients are all initially resectable; more that there may be a potential for complete resection with a significant response to chemotherapy. Dr Grothey: Generally speaking, this is not a new approach in oncology. For example, in lymphoma therapy, this is often how we approach the patient. Most often we take an aggressive curative approach. In cases when we have an elderly patient in which a curative approach isn’t appropriate, you will keep them alive with sequential therapies. The same applies to breast cancer management. Not that we can cure metastatic breast cancer, but we treat the primary tumor and then design our chemotherapy approaches. We now acknowledge that some patients initially considered for palliative treatment will be recognized as having curative potential. As in the patient I just described, I never would have guessed he would respond that well.

S389

CASE STUDY

Dr Choti: Back to our discussion case. So, how would you proceed, Dr Fong? You would go do a combined resection? Dr Fong: Yes, synchronous rectal and liver resection, for reasons of practicality. THE CHEMO-NAÏVE PATIENT Dr Choti: How would the chemotherapy be managed at Memorial Sloan-Kettering Cancer Center? Dr Fong: In our oncology department, we use a multidisciplinary approach. We would use neoadjuvant chemoradiation, unless the liver tumor is out of control. A small tumor, as in this case, would receive neoadjuvant chemoradiation. Oftentimes, the liver lesion will progress because of suboptimal chemotherapy, but the pelvic disease will most likely be controlled. The next step would then be a single operation to deal with both sites, followed by postoperative chemotherapy. I agree that we would likely recommend high-intensity chemobiologic therapy in this setting as a better way to control the entire systemic disease. Dr Grothey: Right now, I agree this is probably the approach that is most evidence-based. However, when I look at the latest studies that include oxaliplatin as a component of the radiotherapy, the dose they use (50 mg or 60 mg weekly/m2) is actually an effective systemic therapy. That is one of the reasons that I like this combination approach. In the future, we may see cetuximab and bevacizumab combined with radiation. We will be able to control systemic disease while still administering radiation therapy, which will make the discussion around this issue a little bit easier. Dr Berlin: Our approach in this patient would be systemic chemotherapy first, probably FOLFOX with or without bevacizumab for a relatively short duration, look for progression, look for response, then try to do both operations at the same time, without preoperative radiation. Then, we would wait for the final pathology. If there is minimal nodal disease, node-negative disease, or a complete response, then we would not favor radiation but give chemotherapy only afterwards. If it looks like N2 disease in the pelvis, or a similar pathologic finding suggesting a high risk for pelvic recurrence, I would favor postoperative radiation therapy, perhaps during a holiday from postoperative systemic therapy. Dr Grothey: With the primary tumor in place, we need to consider the results from the bevacizumab registry, in which 15% of 1986 patients were treated with bevacizumab-containing regimen, primarily FOL-

S390

FOX. There were no increased bleeding complications and no increased perforations in this group. In this registry, whether the patient still had a primary tumor, it did not matter for bevacizumab therapy. MULTIDISCIPLINARY APPROACH Dr Choti: Clearly, management of these patients require input from many specialties. At Johns Hopkins, we discuss such at our multidisciplinary conferences. First, we consider whether the patient is potentially curable. Depending on this, our management algorithm may be very different (Figure 2). Even the intensity and duration of chemotherapy may be very different, depending on whether there may be an option for resection. Let me ask the panel, how important is the role of the multidisciplinary team in treating patients with metastatic disease? Dr Grothey: The team approach will bring more patients off of palliative treatment because the team will more likely recognize the curative potential in some of these patients. By treating the primary disease and tailoring chemotherapy approaches to the patient, we will increase response rates. Dr Fong: I agree. For the case we are discussing, the team at my hospital would try to control the pelvic disease with neoadjuvant chemoradiation. Then, the patient would have one operation to resect both areas, and we would also give postoperative adjuvant chemotherapy.

Figure 2. Proposed Treatment Algorithm

Potentially Curable?

“CURATIVE” INTENT

yes

Initially Resectable?

“PALLIATIVE” INTENT

no

no Induction Chemo

yes Resect

“Adjuvant” Chemo (6 mo)

“Neoadjuvant” Chemo (2–3 mo)

Induction Chemo (until resectable)

Resect

Resect or ablate

“Adjuvant” Chemo (3–4 mo)

Consider “Adjuvant” Chemo

Maintenance Chemo

Multiple Lines

Vol. 6 (5A)

n

May 2006

CASE STUDY

Dr Berlin: Our approach would be very similar. However, we would not give the radiation up front. After the final pathology reports, we would decide on the benefit of radiation. Dr Grothey: I think what we are saying is that the standard of care should be to render patients disease free, if at all possible. That goal will require cooperation among all the oncology subspecialties, which is most likely to occur at a cancer center. Dr Kim: Although we may discuss the intricacies of treatment options and modalities, all of the information discussed in this case study suggests there are many more options and a much higher cure rate in

Johns Hopkins Advanced Studies in Medicine

n

colorectal cancer than we previously thought and have been taught for so many years. Dr Choti: There is clearly a shift to earlier diagnosis and screening prevention. Although the conventional wisdom is that metastatic disease is a death sentence, there is reason for optimism. We have a long way to go, but with aggressive approaches and multidisciplinary management of patients, there is reason to believe colorectal cancer may not be fatal in all patients. Rather than a fatal disease, I think with these new aggressive approaches, we may be moving toward turning advanced colorectal cancer into chronic disease for many patients.

S391