TNM (tumor, nodes, metastases) classification was developed in France by Prof Pierre Denoix at the Gustave-Roussy Institute between 1943-1952. It has been used for several decades as the standard classification for tumors, allowing for patient stratification, survival prognostication, and uniformization of trials. However, CRCs are heterogeneous and have different metastatic potential. According to Dr. Jenny Seligmann from the Department of Oncology of the University of Leeds (UK), the TNM classification is insufficient, although it is still central to decision-making. Why is this true? Where is TNM classification failing? What do we know that makes TNM outdated?
Treatment of CRC is evolving fast because of the increasing understanding of tumor biology and genomics. TNM only gives doctors the extent of tumor spread (T), number and location of nodes (N), presence or absence of metastases (M). Today, this information is used to decide which treatment fits better for that group of patients according to a staging (pretreatment – clinical staging; and after surgery – pathological staging). The first problem presented by the author is that clinical staging (by imaging - CT and/or MRI) has no optimal concordance with pathological staging. So, this lack of concordance causes concerns regarding under and over treatment. Secondly, tumor biology is not assessed by the TNM classification. Precision medicine (tailored medicine) is here to stay. Tumor biology gives prognostic information, and the likelihood of systemic treatment response. Dr. Jenny Seligmann states that tumor biology influences treatment decision by “selecting patients for adjuvant chemotherapy, identification of suitable patients for organ preservation or limited surgery in locally advanced rectal cancer”. This is crucial since this information may avoid unnecessary surgery or reduce surgical morbidity. Additionally, tumor biology will help doctors identify “metastatic patients who would benefit from extensive surgery such as cytoreductive surgery for peritoneal metastases or liver transplantation for liver-limited metastatic disease”.
Testing all CRC patients for deficient mismatch repair (dMMR) or microsatellite instability (MSI) will identify patients who will respond to immunotherapy. This is a gamechanger since immunotherapy for metastatic CRC patients with dMMR is associated with over 50% 5-year survival rate. The use of immunotherapy in locally advanced CRC is raising the potential for a non-operative management, avoiding surgery and radiotherapy, and their long-term consequences. Patients say, “thank you”! Molecular markers such as RAS, BRAF, and HER2 also give information on prognostic and who will benefit from target therapy (whether it is a metastatic or a locally advanced CRC). Dr Jenny Seligman gives us some insights about a new area of increasing interest, the use of circulating tumor DNA (ctDNA) to guide the treatment. This technique to determine ctDNA in the bloodstream, not associated with cells (free DNA), allows doctors to detect minimal residual disease and monitor response to therapy. The determination of ctDNA gives accurate prognostic information and identifies those patients who will benefit the most from adjuvant chemotherapy or molecular target therapy. Although this is experimental yet, stage II tests show that a ctDNA-based decision on chemotherapy is not inferior to the standard of care when ctDNA-negative patients are not given chemotherapy. This approach avoids unnecessary chemotherapy, and all side-effects associated with its use.
From the data presented by the author, it is evident that TNM classification may not be enough to guide the treatment decision in CRC patients. Genetics and molecular profile need to be included in the treatment-decision algorithm, and this is where TNM fails. Whether it identifies patients who will benefit from organ-preserving surgery, extensive surgery, or non-operative management, whether it identifies those patients who benefit from chemotherapy and those who will not need it, whether it identifies patients fit for immunotherapy, the tumor molecular profile and genetics are crucial in nowadays CRC treatment. In that setting, I leave you with the final idea from Dr Jenny Seligmann’s work: “(…) multimodality assessment of risk beyond TNM will better allow us to tailor our treatments and provide the best advice for patients”.
Once again, cancer treatment is changing and evolving because of medical treatments and not because of new nor better surgical techniques. CRC surgery is now "sailing" without an engine on a wide sea wherever the wind takes it, and the wind is the oncology. It appears that less invasive surgery or no surgery at all is the ultimate goal of new cancer treatments. Will oncology be successful? Whether the answer is yes or no, surgery will always have a role to play.
Link to article:
Dr. Carlos Eduardo Costa Almeida
General Surgeon
Comments