A 42-year-old woman with hematochezia and altered bowel movements is found to have a T3, node-positive rectal tumor six centimeters above the anal verge with two synchronous right hepatic lesions in segments V and VII, measuring three and two centimeters, respectively. PET confirmed no evidence of extrahepatic disease. She underwent six weeks of neoadjuvant chemoradiation therapy with infusional 5-FU/weekly oxaliplatin, resulting in primary tumor downstaging and partial response in her liver. She then proceeded to simultaneous low anterior resection with sphincter preservation and dual wedge excisions of liver metastases. Postoperatively she was treated with six cycles of FOLFOX. Eight months after surgery, she remains free of disease.
Case Discussion:
DR HALLER: A 42-year-woman with a history of altered bowel movements and blood in her stool was found to have a rectal cancer located six centimeters above the anal verge. An endoscopic ultrasound showed a fairly advanced T3, node-positive tumor. Imaging of the abdomen revealed two hepatic lesions in the right lobe in segments V and VII, measuring three and two centimeters, respectively. PET confirmed no evidence of extrahepatic disease.
The tumor was in the mid to low rectum and we wanted to preserve the sphincter, so we treated her with neoadjuvant chemoradiation therapy, based on the German trial that showed superior outcome, particularly in toxicity. She received infusional 5-FU and weekly oxaliplatin, which we felt would be a great treatment for the liver lesions. We believed this approach would simultaneously provide good control of the metastases and optimal management of her rectal cancer.
She tolerated the treatment well. We restaged her six weeks after she completed chemotherapy and found that both of the hepatic lesions had decreased by more than 50 percent.
This patient did not need a tumor response in the liver before surgery. It was nice to see, but the tumor looked resectable and we could have proceeded with the surgery without neoadjuvant therapy. The reason we treated her preoperatively was that we wanted her to start systemic treatment for the rectal cancer and not wait until she recovered from liver surgery. Also, it would be beneficial to know up front whether the cancer was responsive to chemotherapy and we felt the likelihood of her liver disease progressing and converting to nonresectable in the next six to 10 weeks was zero, which was an important consideration.
We didn’t use bevacizumab in this patient because few clinical data exist for concurrent radiation therapy and bevacizumab, which is problematic. Lee Ellis has some data from MD Anderson, and he told me that it appears that more toxicity occurs with this approach. I’m concerned about an anti-angiogenic drug and a treatment that may have vascular toxicity as a late effect, so I would not do it off protocol.
As we gain more information about the wild-type K-ras tumor and first-line therapy, especially for patients who need a response in the liver — considering the data that are now evolving from the CRYSTAL and other trials for response, which is 69 versus 40 percent — it’s likely that we will be using this to select therapies for patients with wild-type tumors.
For a patient with rectal cancer like this one, in whom the primary tumor and the metastases are the same biology, the biopsy at the time of diagnosis would be suitable for K-ras analysis. If the status is wild type, we might consider cetuximab with chemotherapy, either FOLFIRI or FOLFOX. I would choose FOLFOX if it was to be administered concurrently with radiation therapy, because of the synergistic diarrheal toxicity with irinotecan.
Also, we have a research trial in which we are intentionally administering cetuximab with radiation therapy. This is based on the preclinical data showing synergy between EGFR antibodies and radiation therapy, in addition to the positive data in head and neck cancer — albeit squamous cell — that suggests a survival advantage when cetuximab is added to standard radiation therapy and platinum chemotherapy.
After this patient’s disease was restaged, she underwent a low anterior resection with sphincter preservasion and fairly simple wedge excisions of the liver metastases. Whether one performs simultaneous rectal and hepatic surgery is controversial and a number of variables need to be considered. One is the experience of the
Performing both surgeries at the same time can lengthen anesthesia. In a patient with a number of comorbidities who requires an APR with colostomy, I believe most surgeons would shy away from performing a liver resection at the same time, particularly if the hepatic metastasectomy requires more than simply a wedge resection.
We discussed this case in our multidisciplinary gastrointestinal clinic before surgery and we felt the conditions were optimal for her to undergo a single-stage procedure. She was young, had no comorbidities and had adequate tumor shrinkage. The surgeons thought that there was enough space between the anal verge and rectal tumor, and an APR would not be necessary. The liver surgery added about 45 minutes to her procedure and it was fairly easy.
Response to treatment gives us some prognostic information and in this patient’s case, we had two good indicators. One is that in response to six weeks of infusional 5-FU and five doses of oxaliplatin, she experienced an excellent partial remission in the liver. This is always a good sign and indicated to us that her disease was sensitive to this regimen.
Secondly, pathology showed that the primary rectal lesion was downstaged to a T1N0 tumor. While this is not as good as a complete response, data from the German trial and others have shown that the better the downstaging, the better the prognosis. It’s a marker and a good prognosticator.
Pathology found some residual tumor cells in her liver lesions, but we know from a number of series that even with complete clinical responses in the liver, viable tumor almost always remains. Chemotherapy alone will not cure these patients, so these lesions need to be resected. Still, this patient did have significant downstaging of the metastases and the resections were R0, so the margins were negative. It’s critical in liver surgery that the resections are R0, rather than R1 with positive margins.
Because of the proven sensitivity of her cancer to 5-FU/oxaliplatin, the patient received six cycles of FOLFOX postoperatively. In total she received close to the 12 total cycles of FOLFOX as provided in the Nordlinger trial. She completed the FOLFOX eight months ago and remains free of disease.
I believe this patient has a good prognosis. In terms of her rectal cancer, her relapse-free survival rate is probably at least 80 percent and with regards to her hepatic metastases, she certainly has in excess of 50 percent likelihood of remaining free of disease.
Although this was a fairly straightforward case, a single plan of action was not outlined at the beginning. Rather, her care revolved around multiple sequential decisions based on response to prior treatment and the involvement of the multidisciplinary team, including the rectal surgeon, radiologists, pathologist and medical oncologist. It illustrates the essence of rectal cancer care and the need for a team approach, especially when complicated by liver metastasis.
In gastrointestinal cancers, the patients that most require multidisciplinary care are gastroesophageal, pancreatic and rectal cancer. For optimal care, they necessitate a high-volume hospital, a physician who sees a lot of these cases and a team approach. In almost every one of these instances, trimodality care is required and trimodality experience and superiority requires a fairly large center — you can’t do it alone.
I believe that more institutions are adopting the multidisciplinary approach. As I participate in tumor boards in medium-sized hospitals across the country, I see that they are on board. The pressure to do so is coming from insurance carriers — who may require surgical second opinions in many instances — and it’s coming from patients. The consumer will drive the medical community to develop such programs. We saw it happen in breast cancer and now even the smallest hospital has a breast clinic. In our newer facilities, the surgeons and radiation oncologists are no longer separate — they all have offices on the same floor.
I doubt that in the United States we will ever see adoption of the European approach, where the states will designate what facilities can and can not do. We’re too diverse a society and not as happy about governmental regulation. However, Americans usually succeed by evaluating what works and being pragmatic. Rectal cancer is common enough that I believe people can see the differences in care from one institution to another, particularly with regard to rectal surgery. Patients are willing to travel for a good surgery.
Within the trimodality approach, I believe superior surgery and, therefore, the surgeon is the most important driver of outcome in terms of survival and quality of life when caring for patients with liver metastases and rectal cancer. The second most important person is the radiation therapist. This field is quite technical and a lot of decisions need to be made. At the bottom of the chain is the medical oncologist. If a patient tells us that they live too far away to come to our institution for all three modalities — surgery, radiation therapy and chemotherapy — then we recommend they have their surgery here and we will try to find the best hospital close to them to administer the chemoradiation therapy.
