Primary Gross Tumor Volume (pGTV) and Tumor Response in Locally Advanced Rectal Cancer (LARC). Is There Any Correlation?

This article refers to:

The Relationship between Primary Gross Tumor Volume and Tumor Response of Locally Advanced Rectal Cancer: pGTV as a More Accurate Tumor Size Indicator

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision has been established as the recommended treatment for locally advanced rectal cancer (LARC), leading to an improved loco-regional control [1]. nCRT offers an important advantage due to the fact that blood flow to the pGTV is maintained and a higher percentage of cancer cells are normoxic and radiosensitive [2].

The existing evidence supports the use of single agent fluoropyrimidines in combination with RT as the standard of treatment while the addition of oxaliplatin has not added a significant survival benefit, not to mention the increased toxicity [3]. Predictive factors to better characterize and stratify patients according to the clinical and biological characteristics are needed to intensify neoadjuvant treatment for rectal cancer where needed and de-escalate dose intensity whenever appropriate.

The clinical tumor size can predict pathologic complete response (pCR) following nCRT [4]. Patients with a tumor diameter less or equal to 5 cm, are more likely to achieve pCR [4]. However, the methods used for measurement of the tumor size do vary, the time points to define disease free or overall survival can be different, and the single-dimension measurement, as that of the diameter, commonly used in the different studies, cannot reflect the three-dimensional actual tumor volume. At the same time, it is increasingly recognized that pGTV measurement during radiotherapy planning may serve a more reliable way to assess actual tumor size [5].

The tumor regression grade (TRG) system was used as a metric system for histological stratification of tumor response to nCRT [6, 7], in a way that TRG3-4 was classified as superior response (SR) group and TRG0-2, as inferior response (IR) group.

The study [6] reported that pGTV was significantly associated with tumor response (p = 0.002) and it could be used as an independent predictive factor. According to a logistic regression analysis based on a multivariate regression model, pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were resulted to be independent predictive factors of superior tumor response. Nevertheless, only pGTV can be used as an independent predictor of pCR (p = 0.036).

Tumor volume in different tumor types, like head and neck, has a prognostic value and correlates with tumor differentiation, body weight and general status of the patient, as well as the clinical symptoms [8, 9]. The adverse influence of increasing tumor volume and clonal radio resistance on local-regional control is obvious and several studies in the past have revealed that tumor size was an independent predictive factor of tumor response [8, 9].

Does the size really matter though? It is not uncommon that small tumors to behave more aggressively than larger ones or the differential response within the same tumor to be witnessed. Tumor volume cannot accurately predict tumor biology and this is the actual unmet need; how to radiologically predict the biological behavior of a neoplasm. Different ways to go around this problem have been considered. Mid-treatment scans or alternative imaging techniques have been suggested as an accurate way to assess end of treatment response [10, 11]. Even with this approach, most of the studies are generating hypotheses and in the majority of cases the findings need validation.

What about the location of the tumor? Does this make the difference? In the study [6], authors suggested that DAV could predict tumor response but not pCR. DAV has been discussed in the literature as a surrogate marker to predict response and pCR [12] although conflicting results do exist [13]. Both lower and higher rectal tumors have been reported to predict pCR but it is uncertain if this is a biological or treatment effect.

Tumor compactness (defined as the ratio of the volume and the surface area) is a good prognostic predictor of rectal pCR after nCRT. Negative predictors are the clinical nodal status and real tumor volume (RTV) (contouring of the lesion from every cross-sectional area of each slice through magnetic resonance imaging or contrast-enhanced computed tomography and multiplying each cross-sectional area with the section thickness [14].

Other negative prognostic predictors for pCR are reported to be the following: depth of submucosal invasion, poorly differentiated adenocarcinomas (as signet-ring cell carcinoma and mucinous carcinoma, the presence of muconodules at the deepest area of invasion, and lymphovascular space invasion [2].

The carcinoembryonic antigen (CEA) clearance pattern represents another independent predictor of tumor response. Patients with CEA exponential decrease after nCRT have a higher adequate rate of pathologic complete response and downstaging [15].

Overall, predictive markers to further guide the management of rectal cancer remain an unmet need. Researchers will need to systematically and consistently address the scientific questions in a reproducible way to identify better markers to guide treatment decisions. The biological rational to explain the role of surrogate markers will need to be considered as well, aiming for the best clinical outcomes.

DECLARATION OF INTEREST

No potential conflicts of interest. No financial support.

AUTHOR CONTRIBUTIONS

All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.