Abstract
Background
There is a paucity of data on the current management and outcomes of liver directed therapy (LDT) in older patients presenting with stage IV colorectal cancer (CRC).
Objective
To evaluate treatment patterns and outcomes in use of LDT in the setting of improved chemotherapy.
Methods
We used Cancer Registry and linked Medicare claims to identify patients ≥66 undergoing surgical resection of the primary tumor and chemotherapy after presenting with stage IV CRC (2001–2007). LDT was defined as liver resection and/or ablative procedures.
Results
We identified 5,500 patients. LDT was used in 34.9% of patients; liver resection was performed in 1,686 patients (30.7%) and locoregional therapy in 554 patients (10.1%), with 322 patients having both resection and ablation/embolization. Use of LDT was negatively associated with increasing year of diagnosis (OR=0.96, 95% CI 0.93–0.99), age >85 (OR=0.61, 95% CI 0.45–0.82), and poor tumor differentiation (OR=0.73, 95% CI 0.64–0.83). LDT was associated with improved survival (median 28.4 vs. 21.1 months, P<0.0001); however, survival improved for all patients over time. We found a significant interaction between LDT and time period of diagnosis and noted a greater survival improvement with LDT for those diagnosed in the late (2005–2007) time period.
Conclusions
Older patients with stage IV CRC are experiencing improved survival over time independent of age, comorbidity and use of LDT. Greater gains in survival are seen with LDT for patients diagnosed in the later time period. These data suggest that improved patient selection may be positively impacting outcomes.
Keywords: metastatic colorectal cancer, liver directed therapy, synchronous lesions, colorectal cancer liver metastases
INTRODUCTION
Metastatic disease is present at the time of diagnosis in 20% of patients presenting with colorectal cancer, and for these patients, the liver is the most common site of metastatic disease.1, 2 Advances in chemotherapeutic regimens, surgical technique, and postoperative care have allowed for aggressive treatment of liver metastases in patients who previously would have only been candidates for palliative chemotherapy. Liver resection is the only potentially curative option and the preferred treatment modality in patients with isolated and resectable liver metastases. However, resection may not be possible in the case of multiple metastases, extensive bilobar disease, or in patients who are poor surgical candidates. When resection is not possible, liver ablation or chemoembolization are alternative techniques to decrease tumor burden and prolong survival.3 Treatment with aggressive multimodality therapy has led to 5-year survival rates exceeding 50% for select patients.4
There is a paucity of data on the current management and outcomes in older patients presenting with colorectal cancer liver metastases. In the setting of metastatic disease at presentation, the management of liver metastases is especially challenging and the benefit of liver directed therapy in the setting of modern chemotherapy is not as clear. While single institution retrospective studies from specialized centers have demonstrated low mortality rates in carefully selected older patients undergoing liver resection,5–12 these reports have included both synchronous and metachronous disease. In addition, the effects of ablative therapies such as radiofrequency ablation and chemoembolization on survival have not been well studied.
We used population-based data to evaluate the use of liver resection, ablation, and chemoembolization (liver directed therapy) in older patients presenting with metastatic colorectal cancer (CRC) in the era of more effective oxaliplatin- and irinotecan-containing chemotherapeutic regimens. 13–15 We specifically evaluated time trends in the use of these modalities and, when employed, the timing of liver directed therapy in relation to treatment of the primary tumor and receipt of systemic therapy. Finally, we evaluated the effects of these therapies on long-term survival.
METHODS
This study was deemed to be exempt from review by the Institutional Review Board at the University of Texas Medical Branch.
Data Source
We used Texas Cancer Registry (TCR)- and Surveillance Epidemiology and End Results (SEER)-linked Medicare data from 2000–2009. SEER and TCR collect data on all cancer cases covered by the respective registries. Data collected include patient demographics, primary tumor site, stage, first course of treatment, tumor morphology, cause of death, and survival.16, 17 All cancer-related variables included in the analysis were identical between the two registries. The Center for Medicare and Medicaid Services performed the Medicare linkage for both datasets. Approximately 98% of all people aged 65 and older in TCR and 93% in SEER can be linked with Medicare enrollment and claims files.18, 19 The Medicare claims data include billing information on hospital stays, physician services, and hospital outpatient visits.20 For this study, data were extracted from the Medicare Denominator file (demographics and eligibility), the Medicare Provider Analysis and Review file (MEDPAR, inpatient claims), the Carrier claim file (claims from non-institutional service providers), and the Outpatient Standard Analytical File (OutSAF, claims from institutional outpatient providers).20
Cohort Selection
We selected patients diagnosed with stage IV colon and rectal cancers and ICD-O-3 histology codes (Table 1) consistent with adenocarcinoma diagnosed between 2001 and 2007. We excluded patients who did not have Medicare Parts A and B coverage without HMO for one-year prior and two years following diagnosis to allow for evaluation of comorbidity in the year prior to diagnosis and to follow all patients for at least two years. Follow-up was complete in both datasets through the end of 2009. Finally, we excluded patients who did not undergo resection of the primary tumor and did not receive chemotherapy at any point after diagnosis, as liver resection is generally not indicated if the primary tumor is not optimally treated. Resection of the primary tumor and chemotherapy were included if they occurred before or after liver directed therapy. 5,500 patients met our inclusion criteria (Figure 1).
Table 1.
ICD-9 diagnosis codes used to identify colorectal cancer, treatment, and sites of metastatic disease in patients presenting with stage IV colorectal cancer
| Cancer | ICD-O-3 histology codes |
|---|---|
| Adenocarcinoma | 8000, 8050, 8051, 8052, 8010, 8021, 8022, 8140, 8141, 8143, 8145, 8147, 8210, 8211, 8220, 8221, 8230, 8260, 8261, 8262, 8263, 8430, 8440, 8470, 8471, 8480, 8481, 8490, 8550, 8551, 8570, 8571, 8572, 8573, 8574, and 8575 |
| Treatment | Procedure codes |
| Colorectal resections | ICD-9-CM: 45.71–45.76, 45.79, 45.81- 45.83, 17.31–17.36, 17.39, 48.42–48.43, 48.49–48.52, 48.59–48.64, 48.69 CPT: 44140–44141, 44143–44147, 44150- 44153, 44160, 44204–44208, 44210, 44155–44158, 45110–45114, 45116, 45119- 45121, 45123, 45126, 45160, 45170, 45171, 45172, 44120–44212, 45395, 45397 |
| Chemotherapy | ICD-9 procedure code: 99.25 ICD-9 diagnosis codes: v58.1, v66.2, and v67.2 HCPCS and CPT codes: Q0083-Q0085, 51720, J0640, 964XX, 96400–96549, J9000-J9999, G0355-G0363, G9021- G9032 |
| Modern chemotherapy (oxaliplatin, irinotecan, or bevacizumab containing regimens) | J9263, J9206, and J9035 |
| Standard chemotherapy (5FU/LV only) | J9190 and J0640 |
| Liver resections | CPT: 47100, 47120, 47122, 47125, 47130 ICD-9 codes: 50.12, 50.2, 50.22, 50.3 |
| Ablation/embolization liver procedures | CPT: 47370 (RFA), 47371 (cryosurgical), 47380 (open RFA), 47381 (open cryosurgical), 47382 (percutaneous RFA) ICD-9: 50.2, 50.23–50.26, 50.29 |
| Liver chemoembolization | CPT: 37204 and 75894 ICD-9: 50.93–50.94 |
Figure 1.
Cohort selection. TCR- and SEER-Medicare linked data for patients presenting with stage IV colorectal cancer. Patients who did not have Medicare Parts A and B coverage without HMO for one-year prior and two years following diagnosis were excluded. Only patients undergoing resection of the primary tumor and chemotherapy were included. The final cohort included 5,500 patients.
Resection of Primary Tumor, Chemotherapy, and Liver-Directed Therapy
Treatment of the primary tumor was defined as the receipt of chemotherapy and resection of the primary tumor after a diagnosis of stage IV colorectal cancer. Definitive resection of the primary tumor was identified from the Medicare claims (MEDPAR, carrier, outpatient SAF) using International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM) procedure codes and Current Procedural Terminology, Fourth Edition (CPT-4) codes for colorectal resection (Table 1), including open and laparoscopic colon and rectal resections, with or without colostomy.
As defined on the SEER-Medicare website, we used MEDPAR, carrier, and outpatient claims to identify ICD-9, CPT/Healthcare Common Procedure Coding System (HCPCS) codes, J codes, and revenue center codes for administration of chemotherapy.21 Specific regimens were identified by J codes for specific agents (Table 1). “Standard” chemotherapy was defined as 5-fluorouracil ± leucovorin. “Modern” chemotherapy was defined as any regimen containing oxaliplatin or irinotecan. Use of bevacizumab was analyzed independently. Patients were considered to have received chemotherapy if they had any of the codes listed in Table 1 at any point before or after surgical resection of the primary tumor.
Medicare claims in inpatient, outpatient, and carrier files were examined for ICD-9 or CPT procedure codes indicating receipt of liver directed therapy. Liver directed therapy was defined as liver resection, liver ablation, or chemoembolization (Table 1). Few patients underwent ablation or chemoembolization; therefore, these categories were combined as “ablation/embolization” for all analyses.
Covariates
Patient characteristics included age, sex, race (white, black, Hispanic, other), and the Klabunde modification of the Charlson comorbidity index (0, 1, 2, ≥3).22 Median income and percent of residents with <12 years education were determined at the zip code level. Tumor characteristics included type (colon vs. rectum), site (right, left, transverse, and rectum), nodal status, and tumor differentiation. All patients had stage IV disease at the time of diagnosis.
Statistical Analysis
We calculated summary statistics for the overall cohort and determined the percentage of patients receiving liver directed therapy. Chi square tests were used to evaluate the unadjusted associations between liver directed therapy and patient, tumor, and primary treatment characteristics.
We used a Cochran-Armitage test for trend to evaluate trends in use of liver resection and liver ablation/embolization procedures. Multivariable logistic regression was used to determine factors independently associated with the receipt of liver directed therapy. Kaplan-Meier disease-specific 5-year survival curves were generated from date of diagnosis for patients in the following treatment groups: overall cohort, patients undergoing liver directed therapy, and those not treated with liver directed therapy. Log rank tests were performed to compare survival in patients treated with liver directed therapy vs. those not treated with liver directed therapy. This analysis was also stratified by time period (early = 2001–2004 and late = 2005–2007). A Cox proportional hazards model was used to evaluate the independent association between liver directed therapy and survival, as well as the interaction between time period of diagnosis and liver directed therapy.
All p-values were from two-sided tests. All analyses were performed with SAS version 9.2 (SAS Inc., Cary, NC, USA). Statistical significance was accepted at the p<0.05 level.
RESULTS
Patient and tumor characteristics (Table 2)
Table 2.
Summary of overall cohort and bivariate analysis of factors associated with receipt of any liver directed therapy and liver resection in older adults with stage IV colorectal cancer
| Factor (p-value) | Overall cohort N=5,500 (% of overall cohort) | Liver directed therapy N=1,918 (% Receiving LDT) | Liver resection N= 1,686 (% Receiving liver resection) |
|---|---|---|---|
| Gender | |||
| Female | 2,758 (50.2%) | 909 (33.0%) | 797 (28.9%) |
| Age (mean)*§ | 74.3 ± 5.7 | 73.8 ± 5.5 | 73.7 ± 5.5 |
| 66–69 yrs | 1,339 (24.4%) | 516 (38.5%) | 452 (33.8%) |
| 70–74 yrs | 1,653 (30.1%) | 611 (37.0%) | 547 (33.1%) |
| 75–79 yrs | 1,430 (26.0%) | 489 (34.2%) | 425 (29.7%) |
| 80–84 yrs | 789 (14.3%) | 229 (29.0%) | 202 (25.6%) |
| 85+ yrs | 289 (5.2%) | 73 (25.3%) | 60 (20.8%) |
| Race | |||
| White | 4,666 (84.9%) | 1,648 (35.3%) | 1,449 (31.1%) |
| Black | 479 (8.7%) | 163 (34.0%) | 144 (30.1%) |
| Other | 350 (6.4%) | 107 (30.6%) | 93 (26.5%) |
| Charlson comorbidity Index | |||
| 0 | 3,522 (64.0%) | 1,220 (34.6%) | 1,071 (30.4%) |
| 1 | 1,309 (23.8%) | 457 (34.9%) | 400 (30.6%) |
| 2 | 428 (7.8%) | 156 (36.4%) | 141 (32.9%) |
| ≥3 | 241 (4.4%) | 85 (35.3%) | 74 (30.7%) |
| Cancer type | |||
| Colon | 4,532 (82.4%) | 1,561 (34.4%) | 1,386 (30.6%) |
| Rectum | 968 (17.6%) | 357 (36.9%) | 300 (31.0%) |
| Poorly differentiated tumors | 1,611 (29.3%) | 488 (30.3%) | 433 (26.9%) |
| Emergency surgery | |||
| Yes | 1,109 (20.2%) | 368 (33.2%) | 335 (30.2%) |
| No | 4,391 (79.8%) | 1,550 (35.3%) | 1,351 (30.8%) |
| Chemotherapy*§ | |||
| Standard | 1,599 (29.1%) | 478 (29.9%) | 427 (26.7%) |
| Modern | 3,123 (56.8%) | 1,197 (38.3%) | 1,050 (33.6%) |
| Other | 778 (14.2%) | 243 (31.2%) | 209 (26.9%) |
| Bevacizumab*§ | |||
| Yes | 1,535 (27.9%) | 602 (39.2%) | 514 (33.5%) |
| Liver directed therapy | |||
| Resection | 1,686 (30.7%) | NA | NA |
| Ablation/embolization | 554 (10.1%) | NA | NA |
| Time period§ | |||
| 2001–2004 | 3,313 (60.2%) | 1,173 (35.4%) | 1,052 (31.8%) |
| 2005–2007 | 2,187 (39.8%) | 745 (34.1%) | 634 (29.0%) |
denotes P<0.0001 for liver directed therapy
denotes P≤0.030 for liver resection
P values for χ 2 analysis representing any difference within categories
We identified 5,500 patients who received chemotherapy and underwent resection of the primary tumor (Figure 1). The mean age of the cohort was 74.3 ± 5.7 years. Women comprised 50.2% of the study sample. The majority of patients were white and had a Charlson comorbidity score of zero. The primary tumor was of colonic origin in 82.4% of patients.
Treatment (Table 2)
Per the selection criteria, all patients underwent surgical resection of the primary tumor and received chemotherapy. Surgical resection was performed in an emergent setting in 20.2% of patients. Modern oxaliplatin- or irinotecan-containing chemotherapy regimens were used in 56.8% of patients. Standard chemotherapy (5-FU and leucovorin) was administered to 29.0% of patients. The remaining 14.2% of patients received other agents. Bevacizumab was used in 27.9% of patients (Table 2).
Liver directed therapy, defined as liver resection or ablation/embolization, was performed in 1,918 (34.9%) patients. Liver resection was performed in 1,686 patients (30.7%). Liver resection was performed in 1,686 patients over the course of the study period. Of these, 1,289 had one or more biopsy/wedge resection, 174 had one or more lobectomies, 108 had one or more partial hepatectomies, and 115 had a combination of any of the procedures. Of the 115 patients having more than one type of resection, 96 had a biopsy/wedge and either a lobectomy or partial hepatectomy. The remaining 19 patients had lobectomy and partial hepatectomy. Ablation/embolization was performed in 554 patients (10.1%). Of these patients, 322 were treated with both resection and some form of ablation/embolization. Liver resection rates were stable over time (31.0% in 2001 to 27.8% in 2007, P=NS, Figure 2) as were rates of ablation/embolization (7.6% in 2001 to 10.9% in 2007, P=NS, Figure 2), but the use of modern chemotherapy increased from 41.0% in 2001 to 77.3% in 2007, P<0.0001.
Figure 2.
Time trends in use of liver directed therapy. Rates of liver directed therapy remained stable over time (34.1% in 2001 vs. 33.4% in 2007, P=NS).
The mean time from diagnosis to liver directed therapy was 117 ± 217 days. Patients undergoing liver resection underwent liver resection a mean of 83 ± 168 days after diagnosis; whereas, patients undergoing ablation/embolization had a mean time of 390 ± 371 days between diagnosis and ablation or chemoembolization. Liver directed therapy was performed at the time of resection of the primary tumor in 74.4%, after resection in 21.2%, and before resection in 4.5%. In 76.0% of patients, liver directed therapy and resection of the primary tumor were performed prior to administration of systemic chemotherapy. Liver directed therapy and primary tumor resection were performed after chemotherapy in 7.4% and chemotherapy was administered between primary tumor resection and liver directed therapy in 16.6% of patients (Figure 3).
Figure 3.
Timing of liver directed therapy in relation to treatment of the primary tumor in patients undergoing treatment of liver metastases. A) Timing of liver directed therapy relative to resection of the primary tumor. 74.4% of patients underwent liver directed therapy at the time of primary tumor resection. B) Timing of chemotherapy relative to resection of the primary tumor and liver directed therapy. 76.0% of patients received chemotherapy as the initial treatment modality. 16.6% of patients received chemotherapy between resection of the primary tumor and liver directed therapy.
Factors associated with liver directed therapy
In a bivariate analysis (Table 2), younger age, receipt of modern chemotherapy, and use of bevacizumab were associated with a higher likelihood of receiving liver directed therapy. Patients treated with ablation/chemoembolization were more likely to be younger and have colon primary tumors. In a multivariable model (Table 3) controlling for comorbidity and socioeconomic status, there was a negative association between use of liver directed therapy and increasing year of diagnosis (OR=0.96, 95% CI 0.93–0.99), age >85 (OR=0.61, 95% CI 0.45–0.82), and poor tumor differentiation (OR=0.73, 95% CI 0.64–0.83). The administration of modern chemotherapy was more strongly associated with liver directed therapy use than treatment with standard chemotherapeutic regimens (OR=1.44, 95% CI 1.25–1.66).
Table 3.
Multivariate analysis of factors associated with liver directed therapy in patients with stage IV colorectal cancer
| Factor (REF) | Odds Ratio | Confidence Interval |
|---|---|---|
| Year of diagnosis | 0.96 | 0.93–0.99 |
| Age (66–69 yrs) | ||
| 70–74 yrs | 0.94 | 0.81–1.10 |
| 75–79 yrs | 0.87 | 0.74–1.02 |
| 80–84 yrs | 0.71 | 0.89–0.87 |
| ≥ 85 yrs | 0.61 | 0.45–0.82 |
| Sex (Female) | 1.13 | 1.00–1.26 |
| Race (White) | ||
| Black | 0.96 | 0.78–1.18 |
| Hispanic | 0.89 | 0.58–1.35 |
| Other | 0.74 | 0.56–0.99 |
| Cancer (Rectum) | 0.88 | 0.58–1.35 |
| Poorly differentiated (No) | 0.73 | 0.64–0.83 |
| Charlson Comorbidity (0) | ||
| 1 | 1.05 | 0.92–1.20 |
| 2 | 1.13 | 0.91–1.39 |
| ≥ 3 | 1.18 | 0.89–1.56 |
| Node status (Positive) | ||
| Negative | 1.02 | 0.88–1.18 |
| Unknown | 0.59 | 0.48–0.74 |
| Income (Q1) | ||
| Q2 | 1.03 | 0.87–1.22 |
| Q3 | 0.98 | 0.83–1.15 |
| Q4 | 1.14 | 0.97–1.35 |
| Surgery (Elective) | 0.94 | 0.82–1.09 |
| Chemotherapy (Standard) | ||
| Modern | 1.44 | 1.25–1.66 |
| Other | 1.11 | 0.92–1.35 |
Liver directed therapy and survival
The median disease-specific survival for the overall cohort was 23.4 months. When stratified by treatment of liver metastases, the median survival was 28.4 months for patients undergoing liver-directed therapy compared to 21.1 months in patients who did not receive treatment for liver metastases (P<0.0001, Figure 4). However, survival improved for both groups over time. When stratified by time period of diagnosis, there was an improvement in median survival from 25.4 months in the early time period (2001-2004) to 35.9 months in the late time period (2005–2007) in patients undergoing liver directed therapy (P<0.0001). Similarly, for patients not treated with liver directed therapy, median survival improved from 19.6 months to 23.4 months between the early and late time periods (P<0.0001, Figure 5).
Figure 4.
Kaplan-Meier analysis of the five-year disease specific survival for patients treated with resection of the primary tumor and chemotherapy stratified by receipt of liver directed therapy. Median survival was 28.4 months for patients undergoing liver-directed therapy compared to 21.1 months in patients who did not receive treatment for liver metastases (P<0.0001).
Figure 5.
Kaplan-Meier analysis of the five-year disease specific survival for patients treated with resection of the primary tumor and chemotherapy ± liver directed therapy, stratified by early and late time periods. Median survival improved over time, from 25.4 months to 35.9 months in patients undergoing liver directed therapy (P<0.0001). Median survival also improved for patients who did not receive liver directed therapy (19.6 months vs. 23.4 months, P<0.0001).
In a Cox proportional hazards model, there was a significant interaction between receipt of liver directed therapy and time period of diagnosis (P=0.04). Therefore, the analysis was stratified by time period of diagnosis. Receipt of liver directed therapy in the later time period was associated with a 25% decrease in the hazard of death compared to a 16% decrease in the early time period (Table 4).
Table 4.
Cox models for five-year disease specific survival for the overall cohort, in the early time period (2001–2004) and late time period (2005–2007).
| Factor (REF) | Overall cohort | 2001–2004 HR (95% CI) | 2005–2007 HR (95% CI) |
|---|---|---|---|
| Treatment (- LDT) | 0.82 (0.76–0.88) | 0.84 (0.77–0.91) | 0.75 (0.66–0.86) |
| Time period (2001–2004) | 0.68 (0.63–0.73) | NA | NA |
| Age (66–69 yrs) | |||
| 70–74 yrs | 1.13 (1.03–1.24) | 1.09 (0.97–1.22) | 1.20 (1.02–1.41) |
| 75–79 yrs | 1.23 (1.12–1.36) | 1.20 (1.07–1.35) | 1.28 (1.08–1.52) |
| 80–84 yrs | 1.40 (1.25–1.56) | 1.37 (1.20–1.57) | 1.46 (1.21–1.78) |
| ≥ 85 yrs | 1.66 (1.42–1.95) | 1.80 (1.48–2.18) | 1.35 (1.01–1.80) |
| Sex (Female) | 0.97 (0.91–1.03) | 0.93 (0.86–1.00) | 1.07 (0.95–1.20) |
| Race (White) | |||
| Black | 1.09 (0.97–1.23) | 1.07 (0.93–1.24) | 1.14 (0.92–1.41) |
| Hispanic | 0.88 (0.69–1.12) | 0.91 (0.69–1.20) | 0.79 (0.47–1.32) |
| Other | 0.94 (0.80–1.10) | 0.94 (0.77–1.15) | 0.94 (0.71–1.24) |
| Cancer (Rectum) | 1.21 (1.11–1.33) | 1.17 (1.05–1.30) | 1.35 (1.15–1.59) |
| Poorly differentiated (No) | 1.37 (1.27–1.47) | 1.33 (1.22–1.45) | 1.45 (1.28–1.65) |
| Charlson Comorbidity (0) | |||
| 1 | 1.01 (0.94–1.09) | 1.00 (0.91–1.10) | 1.00 (0.87–1.15) |
| 2 | 1.15 (1.02–1.30) | 1.14 (0.98–1.32) | 1.18 (0.96–1.47) |
| ≥ 3 | 1.10 (0.92–1.30) | 1.34 (1.08–1.66) | 0.81 (0.61–1.08) |
| Node status (Positive) | |||
| Negative | 0.52 (0.47–0.57) | 0.51 (0.46–0.57) | 0.55 (0.46–0.66) |
| Unknown | 0.99 (0.88–1.11) | 0.96 (0.84–1.11) | 1.05 (0.86–1.28) |
| Income (Q1) | |||
| Q2 | 1.08 (0.98–1.19) | 1.05 (0.93–1.18) | 1.11 (0.93–1.31) |
| Q3 | 1.02 (0.92–1.12) | 1.01 (0.90–1.14) | 1.02 (0.86–1.21) |
| Q4 | 0.93 (0.84–1.02) | 0.94 (0.83–1.05) | 0.90 (0.75–1.07) |
| Chemotherapy (Standard) | |||
| Modern | 1.13 (1.04–1.22) | 1.26 (1.15–1.37) | 0.81 (0.68–0.95) |
| Other | 1.27 (1.15–1.41) | 1.22 (0.07–1.38) | 1.23 (1.00–1.51) |
Interaction between time period and receipt of liver directed therapy P=0.04
DISCUSSION
Our data demonstrate that survival has significantly improved over time in older patients presenting with stage IV colorectal cancer. As expected, carefully selected patients treated with chemotherapy, resection of the primary tumor, and liver directed therapy experienced optimal 5-year disease-specific survival. However, our data suggest that many older patients deemed to be appropriate candidates for resection of the primary tumor and receipt of systemic chemotherapy did not receive liver directed therapy. All patients in this study underwent resection of the primary tumor, implying a reasonable performance status. In addition, the 40% five-year disease specific survival rate in the group not receiving liver directed therapy indicates that a large proportion of these patients may have been adequate candidates for liver directed therapy, both from the standpoint of operative risk and disease burden.
Liver directed therapy use was stable over time in this older cohort with stage IV colorectal cancer and resected primary tumors, with the majority of liver directed therapy in this age group being wedge resections or minor liver procedures rather than formal lobectomies or partial hepatectomies. In addition, survival improved over time, independent of receipt of liver-directed therapy or modern chemotherapy. Younger age was one of three factors independently associated with receipt of liver directed therapy, consistent with previous studies demonstrating lower use of liver directed therapy, particularly liver resection, with increasing age.23–25 In a population based study evaluating referral patterns in patients with isolated colorectal cancer liver metastases, Ksienski et al. found that age was the most common reason cited for non referral to a hepatobiliary surgeon.26 However, short-term and long-term outcomes following liver resection in carefully selected older patients are no different than in their younger counterparts.6–12, 27–29 Similarly, in patients ≥ 70 years old not eligible for hepatic resection, the use of arterial embolization with or without radiofrequency ablation has not been associated with worse short-term outcomes.30 With advances in chemotherapeutic regimens, our data suggest that early referral and optimal selection of patients for liver directed therapy has the potential to further improve survival in older patients presenting with advanced colorectal cancer.
Our data contribute to the existing literature illustrating a marked improvement in survival over the last two decades for patients with stage IV colorectal cancer. Even after we controlled for receipt of liver-directed therapy, time period of diagnosis was independently associated with improved survival. Improvements in cancer survival over time have been previously documented using SEER data by Sun et al.31 Likewise, using data from two high-volume cancer referral centers and SEER data from 1990–2005 to confirm the trends, Kopetz et al. observed a survival improvement for patients with metastatic colorectal cancer over time. Survival for those diagnosed after 2004 was temporally related to the adoption of newer chemotherapeutic agents.32 The value of newer chemotherapeutic agents has also been observed in a previous population-based study.33 The gains in survival over time are likely multi-factorial and attributable in part to the rapid adoption of modern chemotherapeutic regimens, improvements in patient selection for surgery, and advances in the management of tumor related complications.34 In addition, it is established that colorectal cancer patients have improved survival when metastatic disease is identified early in the course of illness. The use of computed tomography in the work up of patients with colorectal cancer has proven to lead to the earlier detection of metastases and improved survival and may also account for the improved survival seen over time.35–37
Our findings also support the concept that optimal selection for hepatic resection may improve outcomes, which has been previously introduced in other population-based studies. A retrospective review by Mala et al. validated a preoperative clinical risk score to select patients who are most likely to benefit from hepatic resection of colorectal cancer metastases.38 Patients undergoing hepatic resection for colorectal cancer liver metastases were stratified into one of five clinical risk scores as defined by Fong et al.39 Survival analysis of these patients demonstrated a statistically significant difference in survival for patients with a clinical risk score of 0–2 compared to patients with a clinical risk score of 3–4 (P=0.0006). Multiple subsequent studies have since validated the clinical risk score as a viable tool to reduce postoperative morbidity and mortality through better patient selection.40, 41 Another study further emphasized enhanced urgency in applying this selection process specifically to older patients.6
Our study has several limitations. Using observational data in cancer patients, there is a significant likelihood for selection bias in comparing patients undergoing different treatment regimens, especially when surgery is considered. Our cohort included only patients receiving combined treatment for colorectal cancer metastatic to the liver, making them a highly selected group of patients. These patients likely had a higher functional status, were fit enough to tolerate aggressive cancer treatment, and their extent of metastatic disease was likely limited when compared to other patients with stage IV colorectal cancer. As a result, the validity of our study is limited to these patients only, and care should be taken when extrapolating these results to all colorectal cancer patients with synchronous liver metastases. Although patients who underwent liver directed therapy likely had a lower burden of disease, we are unable to assess the extent of disease present using administrative data. Nonetheless, we observed a survival improvement over time for all patients independent of treatment of liver metastases.
Older patients with stage IV CRC are experiencing improved survival over time independent of age, comorbidity, and use of liver directed therapy. However, many older patients deemed to be appropriate candidates for resection of the primary tumor and receipt of systemic chemotherapy are not receiving liver directed therapy. Improved patient selection and earlier detection of metastatic disease may be positively impacting outcomes. Early referral and optimal selection of patients for liver directed therapy has the potential to further improve survival in older patients presenting with advanced colorectal cancer. Patients presenting with stage IV colorectal cancer should be treated by a multi-disciplinary team approach and practitioners should continue to incorporate patient and tumor factors in the selection criteria for treatment of liver metastases.
Acknowledgments
Funding: Supported by grants from the Cancer Prevention Research Institute of Texas Grant # #RP101207-P03, the UTMB Clinical and Translational Science Award #UL1TR000071, NIH T-32 Grant # 5T32DK007639, and AHRQ grant #1R24HS022134
Statement Regarding Texas Cancer Registry and SEER Data
The collection of cancer incident data used in this study was supported by the Texas Department of State Health Services and Cancer Prevention Research Institute of Texas, as part of the statewide cancer reporting program, and the Centers for Disease Control and Prevention’s National Program of Cancer Registries Cooperative Agreement #5U58/DP000824-05. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the DSHS, CPRIT, or CDC. The collection of the California cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries under agreement No. U55/CCR921930-02 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.
Footnotes
Author contributions:
Gabriela M. Vargas, MD, MS-Analysis and interpretation, writing the article, and critical revisions of the article.
Abhishek D. Parmar, MD, MS- Writing the article and critical revisions of the article.
Kristin M. Sheffield, PhD-Conseption, design, data interpretation, and writing the article.
Nina P. Tamirisa, MD- Writing the article and critical revisions of the article.
Kimberly M. Brown, M.D-Conception and design
Taylor S. Riall, MD, PhD-Conception, design, data analysis and interpretation, writing the article and critical revisions of the article.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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