Dr. Cathy Eng:
Welcome to The ASCO Post Roundtable Series on Updates in Colorectal Cancer. I'm Dr. Cathy Eng at Vanderbilt Ingram Cancer Center. Joining me today are two of my colleagues.
Dr. Arvind Dasari:
Hello, I'm Arvind Dasari. I'm a medical oncologist in the Department of GI Medical Oncology at MD Anderson Cancer Center.
Dr. Smitha Krishnamurthi:
I'm Smitha Krishnamurthi. I'm a GI oncologist at Cleveland Clinic.
Dr. Eng:
Thank you so much for joining us today. Today, we will be discussing recent updates in colorectal cancer and integrating these new developments into four patient case studies. Our second installment will focus on the role of neoadjuvant therapy in T4 colon carcinoma, a unique setting, and we're going to start it off with case number two.
Patient is a 65-year-old woman with obesity, diabetes, hypertension, and chronic kidney disease. She has a history of stage I endometrial cancer status post-hysterectomy 8 years ago. She presents with syncope and was found to have paroxysmal SVT. On a diagnostic imaging, she had multiple distal pulmonary emboli, and ultrasound of her lower extremities reveals left lower extremity DVT. A head CT non-contrast was unremarkable, her echocardiogram was unremarkable, and apixaban was started. Her performance status is equal to 2, and she has only a cancer of unknown origin in her mother based upon family history, who was diagnosed the age of 60. On colonoscopy, she has an ulcerated inflamed mucosa in the rectosigmoid colon. Biopsy is consistent with moderately differentiated adenocarcinoma and it is MSI-stable. Flexible sigmoidoscopy with her colorectal surgeon reveals an ulcerated fungating lesion located about 20 cm from the anal verge. Her CT scan, chest, abdomen, and pelvis, demonstrates no evidence of distant metastatic disease, and her CEA is with the normal limits, at 1.6. These are her baseline diagnostic imaging. Dr. Krishnamurthi, do you want to comment on this case and these images you provided?
Dr. Krishnamurthi:
Yes. Thank you so much. On CT scan, thank god for the radiologist pointing out for us this tumor. It's pretty subtle. It's in the rectosigmoid region, 2.6 cm, and the colorectal surgeon ordered an MRI because of the proximity of the tumor to potentially the rectum. So to clarify, this was rectal versus colon cancer. And so we can see here on the MRI, there is a mass with the blue arrow on the sagittal image, and actually, the perineal reflection is not on this image because it's a few centimeters below. But the tumor was found to have extension into the peritoneal fat and it was considered a clinical T4a tumor, node-negative. And so, it was at our tumor board we were discussing this and I thought, "This might be a good patient for preoperative therapy based on this finding."
Dr. Eng:
So, what are your treatment options for this patient? What would you consider?
Dr. Krishnamurthi:
Typically, finding that this is not a rectal tumor, our standard approach has been, the patient would go for surgery, because it looks resectable, and then we would base our adjuvant treatment on the pathologic staging. But, in light of evidence indicating that patients with T4 disease have higher risk of recurrence, new approaches are definitely of interest.
We know from the idea of pooled analysis that the 3-year disease-free survival for patients with T4 tumors and N2 tumors was only 60%, despite the adjuvant fluoropyrimidine and oxaliplatin chemo. IDEA analysis also showed for high-risk stage II, that patients who have T4 tumors have poorer 5-year disease-free survival. And just at ASCO 2022, there was an analysis from the ACCENT database looking at three studies of fluoropyrimidine with or without oxaliplatin for patients with stage III disease, and they found that patients who had T4 tumors had no overall survival benefit from the oxaliplatin. So, that's not to change our practice. I would still use a double chemotherapy adjuvantly, but it all this data suggests that we need to look at more innovative or intensified approaches for patients with T4 cancers.
The FOxTROT trial was a large study in the UK, over 1,000 patients enrolled. They enrolled patients who, on CT scan, appeared to have T3 or T4 colon cancer, so clinical staging, and then they were randomized to like a straight to surgery approach, followed by adjuvant chemotherapy or just three doses of FOLFOX or 6 weeks of CAPOX, and then proceed to surgery followed by adjuvant therapy. Their primary outcome was relapse or persistent disease at 2 years. They were targeting a hazard ratio of 0.75.
Importantly, the study found that there was no increase in perioperative complications with this short course of 6 weeks of chemotherapy pre-op, and they found there was a decreased risk of surgery without an R0 resection. So it was 4.8% versus 11% for the patients who went straight to surgery. Looking at subsets, they found that there was really no benefit for the patients with deficient mismatch repair. And so in the patients who have proficient mismatch repair, MSS tumors, the risk of recurrence, the relative risk was 0.72 with the preoperative therapy, and that was a significant finding. So our current NCCN guidelines do include to consider preoperative chemotherapy for patients with like T4b disease or N2 disease.
Looking further at FOxTROT, this was the overall finding of risk of recurrence or persistent disease for the entire study population, with the relative risk of 0.72. Importantly, they found that the better tumor regression achieved with the chemotherapy, the smaller risk of recurrence. So, for the 3% of patients that have pathologic complete response, there was no recurrence for over 5 years, compared to patients that had no response, where they had a 31% risk of recurrence.
We just heard at ASCO 2022, this presentation of the OPTICAL trial, which is conducted in China, in which patients were enrolled, again, based on clinical staging of advanced T3 or T4 disease, randomized to 3 months of preoperative FOLFOX or CAPOX, followed by surgery and another adjuvant course of treatment of 3 months, compared to just the surgery first approach and adjuvant therapy.
This study, similar to FOxTROT, found that the preoperative therapy results in tumor down-staging. With 3 months of treatment, they had 7% of patients having a pathologic CR, and again, just like FOxTROT, no increase in surgical complications. Patients had fewer distant metastases. But in this study it was a little puzzling because the disease-free survival was really no different between the two arms, but there was a significant improvement in overall survival, which is shown in the lower graph.
So, we had these two large randomized trials, both indicating some benefit for preoperative therapy. I had proposed at our tumor board to treat the patient with a few doses of preoperative therapy, and the surgeon was only too happy in light of her multiple comorbidities, her recent PE, and, of course, scheduling difficulties. He immediately said, "Yeah, sure. Go ahead."
Dr. Eng:
I have to say, that's a very, very interesting case. I remember when FOxTROT was originally proposed and people thought they were out of their minds, because they never think about taking a potentially surgical resectable colon carcinoma in patient straight to chemotherapy versus going to surgery. And so, I just find it so intriguing and I did not see this OPTICAL data until you've presented it here. So I do find it intriguing as well. Do you want to elaborate? There's so much discussion about immunotherapy nowadays, and it's not been a home run in the MSI stable population, but what are your thoughts regarding the role of immunotherapy for our patients in general? And maybe you can elaborate upon this.
Dr. Krishnamurthi:
Oh, yeah. Thank you. I think that's a great question because, especially thinking about patients with clinical T4 disease, high-risk of recurrence, what can we do besides chemotherapy? If we could, of course get the immune system to recognize the cancer and eradicate it, that could certainly lead to improvement in cure rates. Of course, all of us are interested in ways to get the immune system to respond to our patients with MSS colon cancer, which is the majority. And we've actually got a couple of studies showing a signal for activity for neoadjuvant immunotherapy for patients with MSS or proficient mismatch repair, early-stage colon cancers. I think this is so fascinating, because immunotherapy has not worked well for these patients in the metastatic setting, but there's a lot of interest in using it neoadjuvantly while the primary tumor is still there as a source of neoantigens, and the immune system may be more robust, because somebody who has metastatic disease, their immune system has allowed the metastasis to take place. So these drugs could work better in the neoadjuvant setting.
There's one trial, NICOLE from Naples, where these investigators bravely gave nivolumab, two doses, to patients before surgery at early-stage colon cancer, and among 18 proficient mismatch repair patients, there was one complete response and one 90% tumor regression. So, certainly not a home run, but definitely a signal of activity.
And then we just heard an update of the NICHE trial from the Netherlands, this was at ASCO 2022, where they also, very bold to give immunotherapy to patients with proficient mismatch pair tumors. They gave one dose of ipilimumab and two doses of nivolumab before surgery, and they found that 7 out of 31 patients had a major pathologic response, which meant that there is less than 10% viable tumor left. So this is a definite sign of activity in this setting. Small study, but it's very impressive. 4 of the patients had a complete pathologic response with these two doses of immunotherapy. So, of course, this is of great interest.
We need more studies, we need to be able to identify who could respond to this, and so I think there's a lot of interest in developing clinical trials of preoperative therapy and incorporating this immunotherapy, but not yet ready for prime time.
Dr. Eng:
Intriguing regarding the data, and I'm so glad you put this together in a small synopsis. Let's go back to your patient. So, what transpired with your patient?
Dr. Krishnamurthi:
The patient actually ended up receiving four cycles of FOLFOX, and I did get a followup CT, but not an MRI, and the radiologist had noted that the previously noted sigmoid mass was not visualized, but radiology did say it is pretty hard to see on CT. MRI was definitely better. The patient underwent surgery without any complications and the pathology revealed a ypT3N1a tumor, no sign of metastases, margins were negative, and she had a regression score of 2, indicating a partial response. And so we're going to finish up the adjuvant chemotherapy now after surgery, and I hope her outcome will be better because she got this preoperative therapy.
Dr. Eng:
It's really quite interesting, and obviously so helpful to the patient to be downstaged.
I was just curious, Arvind, have you ever given neoadjuvant therapy in the setting of a T4 tumor? I have to say, I have. I've had similar scenarios where the surgeon really didn't feel very comfortable taking the patient to the OR because of the degree of involvement noted on the imaging or just coordination of OR dates. And in fact, I've had some very, very nice responses. I've actually found it quite helpful. But Arvind, can you just give us little subtle hint of any of your own personal experience?
Dr. Dasari:
Absolutely. As was highlighted in this case, patients with comorbidities in whom we need to have a little more time to optimize preoperative risk would be one situation. And then secondly, down-staging the tumors and bulky tumors, especially those with T4b tumors, and other situations, which we've based increasingly during COVID and continuing to do so to a lesser extent is logistical scheduling issues, where personnel or OR dates are not available. So, go ahead and start these patients on treatment. Like we've seen in this patient's case, A, it's safe to give neoadjuvant therapy without affecting operative outcomes, and B, you do see gratifying tumor regressions.
Dr. Eng:
Thank you so much. I think it's really important to also take into account, sometimes our patient's performance status is rather poor because the degree of tumor burden. And so sometimes by providing them neoadjuvant chemotherapy, they actually feel better and the performance status improves, which optimizes their ability to go to surgery when it's appropriate. I think that's important to keep in mind.
Some of the key clinical takeaways from this. T4 colon carcinoma has significant risk of recurrence, even with adjuvant treatment. For FOxTROT, 6 weeks of preoperative FOLFOX resulted in reduced risk of recurrence or incomplete resection. The OPTICAL study demonstrated 3 months of fluoropyrimidine plus oxaliplatin resulted in no increase in disease-free survival, but 3-year overall survival was significantly increased. Ipilimumab for one dose and nivolumab for two doses in proficient MMR colon carcinoma results in a 29% pathological response in 31 patients. Preoperative chemotherapy can be safely given to patients with clinical T4 tumors to reduce risk of recurrence, and more study is needed in valuing the role of preoperative immunotherapy for proficient mismatch repair colon carcinoma, especially in regards to response rate and predictive markers to determine benefit of response.
In conclusion, this brings us to the end of this case. Please see the other segments for further discussion on the latest data in colorectal cancer or visit ASCOpost.com. Thank you so much.
