During the last decade, chemotherapy has gained more and more value in cancer treatment. An example of this is gastric cancer treatment. Today neoadjuvant chemotherapy plays an important role, along with the staging laparoscopy. These indications are now part of worldwide cancer treatment guidelines. Are these good guidelines?
Chemotherapy also plays a role in colorectal liver metastases (CRLM) treatment. However, some questions are arising. Is chemotherapy being used in excess? Is there any benefit to the patients?
An opinion paper written by Dr. Storeid from Norway published in the last issue of the British Journal of Surgery got my attention. As we know, if surgical resection and multimodal therapy are possible, CRLM are potentially treatable. The remaining liver is paramount for hepatic resection. The future liver remnant and its function must be life-compatible. The future liver remnant must have at least two contiguous segments, good blood input and blood output, and good biliary drainage. Portal vein embolization and ALLPPS are available to increase resectability without liver function impairment. Systemic chemotherapy increased the number of tumors eligible for resection, but most of these patients experience recurrence.
According to Dr. Storeid, there is controversy in perioperative chemotherapy for resectable CRLM. The efficacy has been extrapolated from studies in unresectable metastases and adjuvant chemotherapy. Several guidelines for different issues present ideas extrapolated from studies for different diseases. The idea is: if it works for one, it must be good for the other. Having guidelines based on bad quality science is harmful to patients. (Read post - Dissecting ERAS).
Dr. Storeid presents us with crucial data that should make us stop and think. EPOC trial concluded that the usage of chemotherapy in patients with resectable CRLM did not affect survival. The NEW EPOC added cetuximab to the perioperative treatment of resectable CRLM. The survival decreased. We must say that these studies included low-burden diseases. (Read the article for more information). Another trial concluded postoperative oxaliplatin did not increase survival. The JCOG0603 trial concluded that most patients had side effects from adjuvant chemotherapy, and many for a long time. Intuitively, doctors think chemotherapy is better than surgery alone. Although studies to validate that conclusion are lacking, that belief is probably tailoring the guidelines. From the studies presented by Dr. Storeid, chemotherapy does not improve survival in patients with limited disease (≤ 4 CRLM). The author says that surgery alone offers excellent results in disease control for this group of patients.
And he goes on. Why do doctors insist on overtreatment if adjuvant chemotherapy has no proven benefit in survival, yet side effects exist? According to the author, the "more is better" feeds the doctors must do something idea, over doing nothing. But sometimes less is better! "As it stands, the liberal use of perioperative chemotherapy in patients with resectable CRLM should be questioned."
This article reminded me of a sentence from Dr. Costa Maia during a hands-on course of liver metastases treatment held several years ago in Hospital São João, Portugal. Questioned if we could treat a metastasis with radiofrequency instead of surgery, his answer could not be clear. "If a tumor is resectable, surgery is the best option." I frequently ask myself if the present-day treatment for gastric cancer is the correct one. This tumor is not a great responder to chemotherapy. In locoregional disease, for a medically fit patient with a potentially resectable cancer staged as cT2 or higher (any N), the NCCN Guidelines advise surgery or perioperative chemotherapy or preoperative chemoradiation. Following that decision, the NCCN presents us with the response assessment guideline. A previously resectable cancer can progress to unresectable or metastatic disease during perioperative treatment. So, tumor resection is no longer possible because of perioperative chemo, and the patient became a good candidate for palliation. Exploring the NCCN guidelines for esophageal cancer treatment, the problem is identical. Did the quality of life improve for this patient? Did the survival rate increase? Many say that if a patient does not respond to perioperative treatment, the outcome is the same. Is it? Are there any good-quality studies supporting this? I believe resecting the tumor will avoid future bleeding, and improve quality of life even if survival does not.
This doubt led me to another article in the British Journal of Surgery about a very hot and actual theme. Target therapy and tailored medicine are probably the future for all cancer treatments. The article written by Dr. Rachel Guest from Edinburgh (UK) talks about cholangiocarcinoma, its poor prognosis, the demanding procedures with a high rate of recurrences, the increasing mortality, and the target therapies as the upcoming "El Dorado". To the present date, pharmaceutical companies had low interest in developing agents for a small group of patients with short survival. The high-volume centers perform less than 20 procedures a year. It means that all trials usually have a small group of individuals to study. However, "times they are a-changin". Extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, and gallbladder cancer have different mutations which respond differently to treatments. An important fact is that they have druggable mutations, suggesting a precision approach can have good results. Several trials have already demonstrated the efficacy of target medicine in palliative treatment. A study of the target approach showed an overall survival of 6 months in the placebo group and ten months in the treatment group. FDA has already approved the use of Pemigatinib (oral inhibitor of FGFR1, 2, and 3) for advanced cholangiocarcinoma with FGFR2 fusions or rearrangements. It is the first target therapy approved, and testing FGFR2 fusion/rearrangements is now the standard of care in the US and Europe. Studies testing the effects of target therapies to HER2, BRAF, and NTKR are on the go.
It is "tailored medicine". This medical practice delivers a specific agent to treat specific cancers, depending on their molecular and genomic characteristics. This practice will probably tell the doctor if the cancer is or is not a responder, avoiding unnecessary chemotherapy and avoiding losing resection possibility. I believe this approach will decrease todays' systematic and liberal use of chemotherapy and increase the response rate to chemotherapy. Additionally, it will increase the usage of surgical resection as first-line therapy for those cancers that won't be responders. Eventually, the molecular and genomic analysis of cancer will tell the surgeon which resection fits each and only patient. "Tailored medicine" and "target medicine" will probably change cancer treatment.
Link to articles:
Dr. Carlos Eduardo Costa Almeida
General Surgeon
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