A 54-year-old obese man underwent resection for T3N2 colon cancer followed by nine cycles of adjuvant FOLFOX (complicated by Grade II neuropathy). Two years later, a rise in CEA levels prompted PET/CT, which revealed a solitary 2-cm lung nodule and three right-sided hepatic metastases, all smaller than three centimeters. No further disease was identified. He underwent immediate wedge resection of the lung lesion by VAT, followed by six cycles of FOLFIRI/bevacizumab. He then proceeded to right hepatic resection with six additional cycles of postoperative FOLFIRI/bevacizumab. Eight months later follow-up PET/CT showed multiple recurrent pulmonary nodules treated with systemic therapy alone.
Case Discussion:
DR HALLER: This is an obese 54-year-old man who underwent surgery for T3N2 cancer in the descending colon. He received FOLFOX, but discontinued after nine cycles because of Grade I neuropathy. After stopping therapy, it progressed to Grade II, which is fairly common.
Two years later, his CEA level was 4.5, and imaging showed a solitary, 2-cm lung nodule and three hepatic lesions in the right lobe, all less than three centimeters in size. The PET scan showed the lung lesion had a SUV of 8.5, pretty much confirming malignant disease, and each of the liver lesions had a SUV greater than six. No other disease was detected outside the liver or lung.
In the past, I might have treated with preoperative chemotherapy and then, if the patient had a complete response, say to the thoracic surgeon, “Aren’t you proud of me? Can you remove it?” The surgeon’s response would have been, “Remove what?” While a complete response in the liver is desirable, the lung is a different organ. First of all, the liver is a fixed organ with segments, so if the lesion was in segment VII, even if it disappears, the surgeon can remove segment VII. Secondly, the liver regenerates.
With lung metastases, if the patient has a single nodule, the surgeon can probably perform a wedge resection, but if he can’t find it while in the operating room, he can’t perform a VAT for exploration purposes alone. He’s not going to perform a whole lobectomy either, because the lung doesn’t regenerate.
So, this patient went to surgery without preoperative therapy and the lung lesion was removed by a VATS procedure. Pathology confirmed metastatic disease and a R0 resection. He received six cycles of FOLFIRI with bevacizumab postoperatively. We chose FOLFIRI because he still had some residual neuropathy from the FOLFOX administered two years prior. We deleted bevacizumab from the last cycle in anticipation of his next surgery.
When he completed therapy, he was reimaged. He had no new lesions and the liver lesions were stable by RECIST criteria. He went to surgery for the hepatic resection approximately four to six weeks after his last dose of bevacizumab and about four weeks after his last dose of chemotherapy. The data are strong to suggest that approach is safe.
Postoperatively, the patient received another six cycles of systemic therapy. We stopped at that point because he had already received nine cycles FOLFOX two years prior in addition to the six cycles of FOLFIRI before and after the hepatic resection. We knew he might develop another liver metastasis and undergo another resection, which is being done more frequently, and we didn’t want to treat with so much chemotherapy that he developed hepatotoxicity. That was a particular concern in this case because obese patients may already have steatohepatitis and fatty livers and they are more susceptible to chemotherapy-induced liver toxicity.
The message we want to send to clinicians is that when you first see a patient, with or without liver metastasis, you need to define your goals of treatment and strategize your treatment plan over the life of the patient. Are you seeking response or survival?
Realize that the morbidities associated with systemic therapy will impact your ability to perform a liver resection in the future. If any chance exists that the patient’s disease will ever be resected, you do not want to treat with continuous FOLFOX or FOLFIRI until treatment failure. Don’t shoot for a complete response expecting to see it on the twelfth cycle. If you don’t see it by the sixth cycle, it’s not going to happen.
We know that patients tend to respond to chemotherapy around cycle three. That’s when they hit their maximal velocity, if you will, so six cycles may be okay. Bernard Nordlinger has published data from the EORTC trial on the impact of six cycles of neoadjuvant chemotherapy on the normal liver, so we have some sense of at least pathologically, if not clinically, how much damage takes place in that population. The data showed that the hepatic morbidity was higher in the patients who received neoadjuvant therapy, compared to those that did not. Even merely six cycles led to increased biliary leaks and other liver-related toxicities of surgery. Therefore, at our institution, we review the case and if there’s even a chance that a patient may one day go to surgery, then we limit the number of treatment cycles.
In this case eight months after treatment, imaging revealed multiple pulmonary nodules, and no relapse in the liver. Since the patient had received FOLFIRI so recently, we began FOLFOX with calcium and magnesium to prevent worsening of his peripheral sensory neuropathy, which was now Grade I. We have reasonable data from the North Central adjuvant trial — randomizing between calcium and magnesium versus placebo — which showed these agents significantly reduced Grade II sensory peripheral neuropathy.
I would have estimated that the likelihood of cure in this patient with his original T3N2 colon cancer with three hepatic lesions and a solitary lesion in the lung was possibly in the range of 10 to 20 percent. Since this was a 54-year-old obese but otherwise healthy patient, that was a reasonable risk to take. Certainly, colon cancer is notable for having a reasonably large number of patients who are curable with metastatic disease. That is not a common state with other solid tumors. And we are extending our indications for curability, by asking, “Why should we not attempt to do something?”
We know that patients with limited liver metastases can be cured with surgery alone. The second most likely location for colorectal metastases is the lung and now we even have a cure rate for patients who have a solitary pulmonary nodule or even a few nodules. The real question is whether we can cure patients who have both pulmonary and hepatic metastases. Do they biologically present an incurable situation, or do they appear to be incurable simply because we don’t treat them and, therefore, the inevitable happens and their disease progresses? I believe we are rewriting history.
