Simple Summary: The aim of our study was to estimate the rate of overall survival (OS) in patients undergoing hepatectomy compared with those treated exclusively with chemotherapy in cases of disease progression (PD) after perioperative chemotherapy for colorectal liver metastases. One hundred and five patients with PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection; the rest prosecuted chemotherapy. After inverse probability weighting, the OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). When feasible, hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only, even in the case of PD after perioperative treatment. Disease progression (PD) at neoadjuvant chemotherapy for patients with colorectal liver metastases (CLMs) is considered a contraindication to hepatic resection. Our aim was to estimate the overall survival (OS) in patients undergoing surgery compared with those treated exclusively with chemotherapy in cases of PD. Patients from a single centre with PD were analyzed and subdivided into two groups: hepatectomy (HEP) versus chemotherapy (CHT). An Inverse Probability Weighting (IPW) was run to balance the baseline differences between the two groups. A Cox regression was carried out on identifying factors predicting mortality. From 2010 to 2020, 105 patients in PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection. After a median follow-up of 30 (IQR 14–46) months, 61.9% were dead. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 95 and 46.8% for HEP (p < 0.001). After IPW, two balanced pseudopopulations were obtained: HEP = 85 and CHT = 103. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). After IPW, in the multivariate model, surgery resulted in the only protective variable (HR 0.198, 95%CI: 0.08–0.48, p = 0.0016). Our results show that hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only in originally resectable patients.
Keywords: colorectal liver metastases; liver resection; disease progression
Colorectal cancer (CRC) is the fourth most frequent tumor and the second most common cause of death worldwide [[
A still-debated issue remains the therapeutic approach to resectable patients who experience disease progression (PD) after preoperative chemotherapy.
Adam et al. [[
Our aim was to report the results from the experience of a single centre, exploring the eventual overall survival improvement in patients undergoing liver surgery despite a PD at the first or second line of preoperative chemotherapy protocols.
The present research is a retrospective study based on a prospectively collected institutional dataset from Humanitas Research Hospital IRCCS (Rozzano, Milan, Italy). The results are reported according to the principles of Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [[
Patients included in the study were further divided among those who were submitted to hepatectomy (HEP) and those who proceeded with chemotherapy alone (CHT). The primary endpoint of the study was to estimate overall survival (OS) among the two groups.
As described in our previous publications, in our centre liver surgery is performed according to a strict parenchyma-sparing surgical policy [[
The indication to hepatectomy despite PD after neoadjuvant chemotherapy was established in all cases because of intolerance to drugs or patients' refusal of systemic therapy prosecution, regardless of having acknowledged its potential benefit. For such patients, a deep discussion was organized, explaining all the risks of stopping or refusing neoadjuvant chemotherapy. Once their will to submit to surgery was firmly established, the procedure was planned. Surgery was scheduled for four to six weeks after the end of chemotherapy (six weeks in patients receiving anti-VEGF targeted therapies). The number and size of nodules were assessed using multiphase contrast computed tomography (CT) and/or magnetic resonance imaging (MRI) by expert and dedicated radiologists. Tumors located within 4 cm from the caval confluence and in contact with the hepatic veins were defined as tumors in the H-zone, while nodules in contact with the first or second order portal branches were defined as tumors in the P-zone [[
All patients were followed up using local protocols, which included measurement of serum tumor markers (Ca19.9 and CEA), abdominal ultrasound, CT or MRI and outpatient visits. OS was defined as the time from the date of the assigned treatment to any cause of death. Patient surveillance was closed at the end of April 2022.
Normal distribution was tested using the Kolmogorov–Smirnov test. Data were presented as frequency and percentage in the case of categorical variables, or median and interquartile range (IQR) in the case of continuous variables. Mann–Whitney and Fisher tests were used to compare baseline patient characteristics between the two treatment groups, respectively. The issue of unmeasured values in some covariates (reasonably due to a "missing at random" (MAR) mechanism [[
All tests were two-tailed, and the accepted level of significance was 5%. Analyses were made using R open software (4.0.6, libraries: MICE, WeightThem, cobalt).
Between 2010 and 2020, a total of 847 patients with CLM were discussed at our weekly multidisciplinary meetings. Five hundred and eighty-nine patients were resectable and candidates for perioperative chemotherapy. Of them, 105 (12.4%) patients were classified as having PD after at least four cycles of chemotherapy. Seventy-eight (74.3%) were treated with chemotherapy prosecution (with a second or further lines), while 27 (25.7%) were submitted to hepatectomy.
Among the HEP group, six patients (22.2%) underwent a one-stage hepatectomy (OSH); 14 (51.8%) patients were submitted to a parenchymal-sparing resection (PSR); seven (25.9%) cases were treated with major standard hepatectomy. In eleven patients (40.7%), metastases were removed in a single resection area. R1-vascular resection was performed in 12 (44.4%) patients: seven (25.9%) patients had vascular contact in the P-zone, while in six (22.2%) it was in the H-zone. Minor complications (Clavien–Dindo 1–2) occurred in seven (25.9%) cases, and major ones (Clavien–Dindo 3–4) in three patients (11.1%). Ninety-day mortality was 0 (Table S1).
At the baseline, the two groups were different for a few variables: the CHT group had a lower rate of primary tumor staged as T3 (50.0% versus 70.4% in HEP group) and a higher rate of T4 (19.2% versus 3.7%, respectively, p = 0.016). KRAS wild type was more frequent for those in the HEP group (59.3%) than those in the CHT one (28.2%, p = 0.008). Liver metastases were bilobar in 74.4% of cases in the CHT group and 48.1% in the HEP one (p = 0.027). The median number of liver metastases at the diagnosis was four (IQR 2–7) for CHT and two (IQR 1–4) for HEP (p = 0.016). The median number of neoadjuvant chemotherapy cycles before restaging was eight (IQR 5–12) and six (IQR 3–6) for CHT and HEP, respectively (p = 0.007). The types of drugs employed in both groups are summarized in Table 1.
After restaging, the median number of liver metastases was six (IQR 3–14) and three (IQR 2–5), respectively (p = 0.008); median tumor size was 4.8 cm (IQR 3.7–6.8) and 3.3 cm (IQR 2.0–4.5) for CHT and HEP groups (p = 0.004). Among the patients in the CHT group, 16 patients (20.5%) had numeric and dimensional progression, nine (11.5%) had biological and dimensional PD, while 33 (42.3%) had concomitant biological, numeric, and dimensional PD. Among the patients in the HEP group, eight (29.6%) had dimensional progression, five (18.5%) numeric and dimensional PD, four (14.8%) biologic and dimensional PD, and nine (33.3%) had biological, numeric and dimensional progression. These and other parameters are reported in Table 1.
After a median follow-up of 30 months (IQR 14–46), 65 (61.9%) patients were dead. The overall survival values at one and three years were 53.6% and 10% for CHT, and 95.0% and 46.8% for HEP (p < 0.001). Survival curves are depicted in Figure 1A.
Regarding the HEP group, at the end of follow-up, 23 patients (85.2%) had a recurrence. The median recurrence-free survival time was 4.5 months (95%CI: 3–8). Among these patients, in 16 (69.6%) cases the recurrence was intrahepatic, in two (8.7%) extrahepatic, and in five (21.7%) cases the relapse was both intra- and extrahepatic (lymph nodes and lung).
After univariate analysis, an overall mortality prediction model was developed. A KRAS wild type (HR 0.54, 95%CI: 0.31–0.93, p = 0.028) and being submitted to liver resection (HR 0.21, 95%CI: 0.10–0.44, p < 0.001) were the only independent protective factors, while the value of CEA at the diagnosis (HR 1.0, 95%CI: 1.0–1.0, p = 0.001) was the only independent risk factor. The Cox uni- and multivariate regression is summarized in Table 2.
To reduce the risk of selection bias, an IPW was conducted. The T status of the primary tumor, the KRAS status, the bilobar localization of the liver metastases, their number at the diagnosis, the number of chemotherapy cycles before restaging, and the number and size of the liver metastases after restaging were all significantly different at the baseline among the two groups, and consequently, they were weighted. The mean difference among those variables before and after the IPW is reported in Figure 2A.
Using this method, two pseudopopulations were created: 103.35 cases in the CHT and 84.51 in the HEP group. OS values at one and three years were 54.4% and 10.6% for CHT and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). The survival curve is depicted in Figure 1B.
In the multivariate Cox regression, being submitted to liver resection (HR 0.198, 95%CI: 0.08–0.48, p = 0.0016) and a numeric and dimensional disease progression (HR 7.582, 95%CI: 2.80–20.49, p = 0.0017) were the only independent prognostic factors for overall mortality. The results are reported in Table 2.
Among the presented cohort, 93 (88.6%) patients received a second line of chemotherapy after PD at the first line. All of them were also staged as PD after the second line. Of them, 20 (21.5%) were then submitted to hepatectomy, while 73 (78.5%) prosecuted with chemotherapy alone. The baseline comparing CHT versus HEP in this subgroup is summarized in Table 3.
The significant differences were the rate of bilobar disease (75.3% in CHT versus 45.0% in HEP, p = 0.020), the median number of hepatic lesions at diagnosis (5 IQR 2–11 and 2 IQR 1–3.5 for CHT and HEP, respectively, p = 0.009) and the number of hepatic tumors at the restaging (8 IQR 3–20 for CHT and 3 IQR 2–4.3 for HEP, p = 0.004). OS values at one and three years were 55.4%, 10.7% for CHT and 92.9%, 43.3% for HEP (p = 0.006). The variables that were significantly different at the baseline were employed to weight the cohort, producing two pseudopopulations of 93.14 in the CHT and 90.50 in the HEP groups. A Love plot depicting the weighting among variables is depicted in Figure 2b.
Survival analysis in the weighted subgroup demonstrated OS values at 1–3 years of 55.8, 10.5% and 96.3%, 32.9% for CHT and HEP, respectively (HR 0.416, 95%CI: 0.21–0.81, p = 0.013). Curves before and after the weighting are reported in Figure 3A,B.
After the selection of the variables using univariate analysis, a multivariate Cox regression model predicting overall mortality was developed in the weighted pseudopopulation. Being treated by liver resection (HR 0.259, 95%CI: 0.09–0.70, p = 0.011) and the values of CEA at the diagnosis (HR 1.01, 95%CI: 1.001–1.002, p = 0.013) were the only independent risk factors.
Considering the number of patients available per each type of disease progression recorded, subgroup comparison was possible only in the cases of dimensional progression, numeric and dimensional progression, and numeric, dimensional, and biological progression.
In case of dimensional progression, OS values at 1–3 years were 36.4%, 18.2% in CHT and 100%, 66.7% for HEP (p = 0.009). For patients classified as biologic, numeric and dimensional progression, OS values at 1–3 years were 63.9, 16.9% and 100%, 42.9% for CHT and HEP, respectively (p = 0.093). In the case of numeric and dimensional progression, OS values at 1 year were 38.3% and 75.0% for CHT and HEP, respectively (p = 0.014). When the progression was concurrently numeric, dimensional and biologic, OS rate was 63.9%, 16.9% for CHT and 100%, 42.9% for HEP at 1 and 3 years (p = 0.093).
In the present series, hepatectomy for patients with PD after neoadjuvant therapy significantly increases overall survival when compared with prosecution of chemotherapy. To the best of our knowledge, this is the first observational study comparing hepatectomy versus chemotherapy prosecution for resectable patients in progression after neoadjuvant chemotherapy. The prognostic role of tumor response to chemotherapy has been reported, and poor outcomes have been associated with PD [[
The routine use of neoadjuvant chemotherapy remains debated, because of the risk of progression in patients with a resectable disease at the diagnosis. Despite modern improvements in chemotherapy regimens, the rate of progression during therapy has been reported to be 7–8% [[
The type of progression during neoadjuvant chemotherapy has never been extensively explored. The RECIST criteria provided a morphological system to estimate tumor response, considering a percentage increase/decrease of the size of the target nodules or an increase in the total number of lesions [[
The present study had several limitations. First, although the weighting strategy was employed, the risk of selection bias could not be ruled out completely. Furthermore, the low number of patients may have created an increased risk of type-II error. Therefore, our results cannot be considered conclusive, due to the design of the study. However, this analysis represents at least an interesting and provocative snapshot, weakening the theoretical lack of advantage in performing surgery concomitant of PD. Indeed, it is worth mentioning that more than 70% of these patients remained in PD even after a second line of chemotherapy, thereby probably losing any surgical perspective. Meanwhile, modern parenchyma-sparing surgery has enhanced the feasibility of liver resection [[
Our study supports a strong survival advantage for those resectable patients who were submitted to hepatectomy after PD following neoadjuvant chemotherapy. It is our conviction, emphasized by these results, that in the case of resectability a PD after perioperative chemotherapy should not be considered an absolute contraindication for surgery.
Graph: Figure 1 Overall survival among patients treated with hepatectomy following perioperative chemotherapy (HEP) and prosecution of chemotherapy alone in case of disease progression: (A) before the inverse probability weighting, and (B) after it.
Graph: Figure 2 Love plots representing the effect of the weighting in terms of mean differences among the weighted variables. An optimal weighting has been reached if the green point falls between the vertical dashed lines. (A) the effect of IPW among patients who were in PD after a first line of chemotherapy and (B) the effect of IPW among those who were in PD even after a second line of chemo.
Graph: Figure 3 Overall survival among hepatectomy following II-line perioperative chemotherapy (HEP) and prosecution of chemotherapy alone in case of disease progression: (A) before the inverse probability weighting and (B) after it.
Table 1 Baseline characteristics of the cohort before weighting.
CHT HEP 78 27 63.50 [55.25, 71.00] 65.00 [60.00, 72.50] 0.313 51 (65.4) 20 (74.1) 0.553 0.192 1 16 (20.5) 6 (22.2) 2 12 (15.4) 0 (0.0) 0.016 1–2 4 (5.2) 5 (18.5) 3–4 54 (69.2) 20 (74.1) 0.164 1 19 (24.4) 11 (40.7) 2 25 (32.1) 6 (22.2) 40 (51.3) 10 (37.0) 0.008 24 (30.8) 12 (44.4) 0.291 58 (74.4) 13 (48.1) 0.027 29 (37.2) 9 (33.3) 0.226 8.00 [5.00, 12.00] 6.00 [3.50, 6.50] 0.007 70 (89.7) 20 (74.1) 0.002 7.50 [4.00, 12.00] 5.00 [4.00, 6.00] 0.271 Irinotecan (%) 15 (19.2) 3 (11.1) 0.335 Oxaliplatin (%) 61 (78.2) 20 (74.1) 0.66 Capecitabine (%) 25 (32) 13 (48.2) 0.134 Anti-VEGF (%) 22 (28.2) 4 (14.8) 0.165 Anti-EGFR (%) 3 (3.8) 3 (11.1) 0.161 Irinotecan+oxaliplatin (%) 5 (6.4) 0 (0) 0.178 Irinotecan (%) 41 (65.1) 12 (60) 0.68 Oxaliplatin (%) 13 (20.6) 5 (25) 0.68 Capecitabine (%) 7 (11.1) 3 (15) 0.642 Anti-VEGF (%) 23 (36.5) 10 (50) 0.283 Anti-EGFR (%) 4 (6.3) 1 (5) 0.825 Irinotecan+oxaliplatin (%) 1 (1.6) 0 (0) 0.571 0.298 Numeric 4 (5.1) 0 (0.0) Dimensional 12 (15.4) 8 (29.6) Biologic + Numeric 0 (0.0) 1 (3.7) Numeric +Dimensional 16 (20.5) 5 (18.5) Biologic + Dimensional 9 (11.5) 4 (14.8) All 33 (42.3) 9 (33.3) 4.00 [2.00, 7.25] 2.00 [1.00, 4.00] 0.016 3.00 [2.00, 4.80] 2.20 [1.35, 3.90] 0.121 27.00 [16.20, 132.25] 28.35 [12.00, 86.00] 0.613 218.00 [17.50, 1128.00] 48.00 [13.95, 495.15] 0.577 6.50 [3.00, 14.00] 3.00 [2.00, 5.00] 0.008 4.80 [3.70, 6.80] 3.30 [2.00, 4.50] 0.004 40.60 [17.50, 161.00] 29.80 [6.62, 63.75] 0.236 103.10 [16.95, 430.25] 76.10 [15.78, 147.75] 0.379
Table 2 Univariate and multivariate Cox regression analysis to assess the risk factors for overall mortality before and after IPW.
PRE IPW POST IPW HR (Univariable) HR (Multivariable) HR (Univariable) HR (Multivariable) 0 - - - 1 1.19 (0.61–2.32, - 0.775 (0.24–2.45, - 2 1.14 (0.48–2.68, - 1.452 (0.47–4.47, - 1 - - - - 2 1.42 (0.60–3.37, - 1.629 (0.13–19.43, - 3 1.60 (0.64–4.02, - 2.735 (0.22–33.36, - 1 - - - - 2 0.74 (0.24–2.35, - 0.608 (0.09–3.93, - 3 0.72 (0.30–1.71, - 0.496 (0.09–2.71, - 4 1.55 (0.59–4.06, - 1.156 (0.20–6.47, - 0 - - - - 1 1.11 (0.59–2.08, - 0.619 (0.21–1.75, - 2 1.28 (0.70–2.33, - 0.835 (0.33–2.06, - Mut - - - - WT 0.52 (0.31–0.88, 0.54 (0.31–0.93, 0.757 (0.33–1.71, - no - - - - yes 0.94 (0.55–1.62, - 1.182 (0.55–2.53, - no - - - - yes 1.44 (0.82–2.54, - 1.117 (0.50–2.48, - no - - - - yes 0.76 (0.46–1.28, - 0.797 (0.34–1.85, - Biologic - - - - Numeric 2.26 (0.23–21.86, - 2.398 (0.67–8.47, 2.85 (0.61–13.23, Dimensional 0.90 (0.11–7.04, - 0.457 (0.13–1.60, 1.323 (0.39–4.45, N+D 2.72 (0.35–20.94, - 2.139 (1.41–3.24, 7.582 (2.80–20.49, Bio+D 1.62 (0.20–12.93, - 1.362 (0.60–3.09, 3.548 (1.65–7.62, All 1.04 (0.14–7.70, - 0.917 (0.48–1.72, 1.838 (0.97–3.45, CHT - - - - HEP 0.25 (0.12–0.50, 0.21 (0.10–0.44, 0.256 (0.08–0.78, 0.198 (0.08–0.48, Mean (SD) 1.00 (0.98–1.03, 1.02 (1.00–1.04, 1.002 (0.97–1.03, - Mean (SD) 1.03 (0.99–1.06, - 1.002 (0.97–1.03, - Mean (SD) 1.09 (1.01–1.17, 0.98 (0.90–1.06, 1.142 (1.00–1.29, - Mean (SD) 1.00 (1.00–1.00, 1.00 (1.00–1.00, 1.00 (0.99–1.01, - Mean (SD) 1.00 (1.00–1.00, - 1.00 (1.0–1.0, - Mean (SD) 1.00 (0.99–1.02, - 0.991 (0.95–1.02, - Mean (SD) 1.07 (1.00–1.15, - 1.101 (0.98–1.23, - Mean (SD) 1.00 (1.00–1.00, - 1.0 (1.0–1.0, - Mean (SD) 1.00 (1.00–1.00, - 1.0 (1.0–1.0, -
Table 3 Baseline characteristics of the cohort submitted to second line chemotherapy before being considered for surgery.
CHT HEP 73 20 63.00 [54.00, 71.00] 68.00 [62.50, 73.25] 0.101 46 (63.0) 14 (70.0) 0.753 NaN 50 (68.5) 15 (75.0) 16 (21.9) 5 (25.0) 7 (9.6) 0 (0.0) 0.085 12 (16.4) 5 (25.0) 61 (83.5) 15 (75.0) 0.309 19 (26.0) 5 (25.0) 24 (32.9) 10 (50.0) 30 (41.1) 5 (25.0) 27 (37.0) 11 (55.0) 0.232 22 (30.1) 11 (55.0) 0.073 55 (75.3) 9 (45.0) 0.02 28 (38.4) 8 (40.0) 1 5.00 [2.00, 11.00] 2.00 [1.00, 3.50] 0.009 3.60 [1.40, 7.10] 1.95 [1.20, 4.35] 0.071 56.00 [5.00, 825.00] 57.60 [4.50, 600.75] 0.885 85.00 [1.00, 3557.00] 1629.00 [9.43, 2429.00] 0.463 8.00 [5.00, 12.00] 6.00 [4.00, 7.25] 0.023 12.00 [5.00, 14.00] 6.00 [4.75, 14.00] 0.4 0.415 1 (1.4) 0 (0.0) 3 (4.1) 0 (0.0) 13 (17.8) 4 (20.0) 0 (0.0) 1 (5.0) 17 (23.3) 4 (20.0) 8 (11.0) 4 (20.0) 31 (42.5) 7 (35.0) 8.00 [3.00, 20.00] 3.00 [2.00, 4.25] 0.004 4.80 [2.00, 9.20] 3.55 [2.15, 5.70] 0.21 41.00 [17.00, 383.00] 42.35 [11.05, 82.50] 0.333 166.00 [5.00, 12,000.00] 76.10 [10.70, 205.57] 0.583
Conceptualization, F.M., M.C. and G.T.; Data curation, F.M., M.C., E.P.T. and F.M.B.; Formal analysis, S.F.; Funding acquisition, A.P.; Investigation, S.F., F.M., M.C., F.P., G.C. and J.G.; Methodology, S.F. and F.M.; Project administration, M.D. and G.T.; Resources, A.P.; Supervision, M.D. and G.T.; Visualization, S.F. and F.M.; Writing—original draft, S.F., F.M., M.C., F.P., G.C., J.G., E.P.T. and F.M.B.; Writing—review & editing, S.F., M.D. and G.T. All authors have read and agreed to the published version of the manuscript.
The study was conducted in accordance with the Declaration of Helsinki. Being a retrospective study based on medical chart review and standard follow-up data, a formal institutional review board was not required.
Informed consent was obtained from all subjects involved in the study.
The retrospective analysis was made by using data of the adult patients enrolled in the liver unit registry and was conducted according to the guidelines of the Declaration of Helsinki. The data sets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
The authors declare no conflict of interest.
The following supporting information can be downloaded at: https://
By Simone Famularo; Flavio Milana; Matteo Cimino; Fabio Procopio; Guido Costa; Jacopo Galvanin; Elisa Paoluzzi Tomada; Francesca Margherita Bunino; Angela Palmisano; Matteo Donadon and Guido Torzilli
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