Abstract
Background.
Patient age is a significant factor in preoperative selection for major abdominal surgery. The association of age, tumor biology, and postoperative outcomes in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains ill-defined.
Methods.
Retrospective analysis was performed for patients who underwent a CCR0/1 CRS/HIPEC from the US HIPEC Collaborative Database (2000–2017). Age was categorized into < 65 or ≥ 65 years. Primary outcome was postoperative major complications. Secondary outcomes were non-home discharge (NHD) and readmission. Analysis was stratified by disease histology: non-invasive (appendiceal LAMN/HAMN), and invasive (appendiceal/colorectal adenocarcinoma).
Results.
Of 1090 patients identified, 22% were ≥ 65 (n = 240), 59% were female (n = 646), 25% had non-invasive (n = 276) and 51% had invasive (n = 555) histology. Median PCI was 13 (IQR 7–20). Patients ≥ 65 had a higher rate of major complications (37 vs 26%, p = 0.02), NHD (12 vs 5%, p < 0.01), and readmission (28 vs 22%, p = 0.05), compared to those < 65. For non-invasive histology, age ≥ 65 was not associated with major complications or NHD on multivariable analysis. For invasive histology, when accounting for PCI and CCR, age ≥ 65 was associated with major complications (OR 2.04, 95% CI 1.16–3.59, p = 0.01). When accounting for major complications, age ≥ 65 was associated with NHD (OR 2.54, 95% CI 1.08–5.98, p = 0.03). Age ≥ 65 was not predictive of readmission for any histology when accounting for major complications.
Conclusions.
Age ≥ 65 years is an independent predictor for postoperative major complications and non-home discharge for invasive histology, but not non-invasive histology. These data inform preoperative counseling, risk stratification, and early discharge planning.
BACKGROUND
In the United States, over 60,000 patients are diagnosed yearly with peritoneal metastases.1 Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has emerged as a potentially curative treatment for patients with peritoneal carcinomatosis, with a notable survival benefit seen in patients with appendiceal, colorectal, ovarian, and peritoneal mesothelioma histologies.2–5
Despite recent advances, CRS/HIPEC harbors morbidity and mortality rates of 12–24% and 1–5%, respectively.6–9 These rates are comparable to other major oncologic intra-abdominal surgeries, including pancreaticoduodenectomy, hepatectomy, and esophagectomy.10–12 In elderly patients over the age of 65, however, the morbidity and mortality rates are higher, with ranges of 19–40% and 3–9%, respectively.13–16
Given longer life expectancies, the number of adults age 65 or greater is expected to exceed 55% by 2050, making up 21–25% of the population.17 The number of patients in this population requiring surgical intervention and CRS/HIPEC is projected to increase.18 It has been previously established that advanced age is independently associated with an increased risk of postoperative complications and death.19 However, there is an emerging body of literature that supports the utility of frailty scores to better predict adverse outcomes, especially given the heterogeneous phenotypes of elderly patients.20 Such scoring systems often include age in addition to other physiologic markers to stratify patients. Unfortunately, there is little standardization, which stems from no universally accepted definition of frailty, which results in variable component criteria. In addition, with the incidence of frailty reported to be only approximately 11% in the general population, frailty assessment tools are not germane to the majority of patients who are candidates for elective surgery.21 Consequently, age may prove a more readily applicable surrogate for evaluating the majority of elderly patients who are deemed “medically fit” for surgery.
Current data for postoperative outcomes of CRS/HIPEC of elderly and frail patients is inconclusive. Using a multi-institutional collaborative database, our primary aim was to determine if an age category serves as a clinically useful proxy for frailty in patients undergoing CRS/HIPEC to predict postoperative outcomes, discharge destination, and readmission, considering histologic subtype.
METHODS
Data Source and Cohort Selection
Patients were retrospectively identified from the US HIPEC Collaborative Database, a multi-institutional collaboration of 12 academic tertiary and quaternary referral centers in the US, including Emory University, The Ohio State University, City of Hope, Johns Hopkins University, Mayo Clinic, University of Wisconsin, Medical College of Wisconsin, Moffitt Cancer Center, University of California San Diego, University of Cincinnati, University of Massachusetts, and MD Anderson Cancer Center. Patients 18 years or older who underwent a complete cytroreduction with no visible residual macroscopic disease (CCR0) or with residual disease < 2.5 mm (CCR1) between 2000 and 2017 were included. Tumor histology was categorized into two groups: non-invasive and invasive. Non-invasive histology included low-grade appendiceal mucinous neoplasm (LAMN) and high-grade appendiceal mucinous neoplasm (HAMN) while invasive histology included appendiceal and colorectal adenocarcinoma. Patients who received an operation with palliative intent, early postoperative intraperitoneal chemotherapy (EPIC), no intraperitoneal chemotherapy, a previous CRS/HIPEC, or had chemotherapy perfusion terminated were excluded. The Institutional Review Board (IRB) at each study site independently provided approval prior to data collection.
Study Variables and Outcomes
Clinicopathologic data was obtained via retrospective review of patient electronic medical records. Pathologic diagnoses were determined by expert gastrointestinal pathologists at each institution. The peritoneal cancer index (PCI) was determined preoperatively by radiologists using cross-sectional imaging or intraoperatively by surgeons using established guidelines.22,23 The median PCI was determined to be 13, which was then categorized as a dichotomous variable less than 13 or greater than or equal to 13.
Age was categorized as a dichotomous variable less than 65 years or greater than or equal to 65 years. Sequential data analysis for varying age cut-points yielded 65 years to be appropriate for providing adequate statistical power. Complications were classified as either minor (Clavien-Dindo I and II) or major complications (Clavien-Dindo III, IV, or V). Discharge destination was defined as either home (home or home with home-health) or non-home discharge (acute rehabilitation, skilled nursing facility, or hospice).
The primary outcome was major complications. Secondary outcomes were non-home discharge (NHD), and 30-day hospital readmission.
Statistical Analysis
Statistical analysis was performed using SPSS 26.0 software (IMB Inc., Armonk, NY). Descriptive statistics were determined using frequencies for categorical data and medians and interquartile ranges for continuous data. Chi squared tests or Fisher’s exact test were used for the comparison of categorical variables. Student’s t test or Mann–Whitney tests were used for the comparison of medians of continuous variables. Univariate binary logistic regression analysis was used to determine the association of demographic, histopathologic, and perioperative data with primary and secondary outcomes. Analysis was performed for all histologies then stratified by non-invasive and invasive histology, as previously reported.24 Clinically relevant covariates with weighted odds ratios (ORs) with statistically significant p values (< 0.05) were selected for our multivariable logistic regression models. All analyses were performed with a significance level (alpha) of 0.05.
RESULTS
Demographic and Clinicopathologic Characteristics
Of the 2372 patients who underwent CRS/HIPEC in the US HIPEC Collaborative Database, 1090 met the inclusion criteria. The demographic, operative, pathologic, and postoperative characteristics of the entire study cohort are presented in Table 1. Seventy-eight percent (n = 850) were < 65 years and 22% (n = 240) were ≥ 65 years. The median age of all patients was 54 years (interquartile range [IQR] 46–63). Median ages for the < 65 years and ≥ 65 years cohorts were 53 years (IQR 46–61) and 68 years (IQR 66–72), respectively. Twenty-five percent (n = 276) were determined to have non-invasive histology while 51% (n = 551) had invasive histology. The remaining 24% (n = 259) were comprised of other histologies, including other appendiceal, small bowel, gastric, sarcoma, and peritoneal mesothelioma. The mean modified frailty index (mFI) score for all patients was 2. Median follow-up was 27 months (IQR 9–40). A higher proportion of patients < 65 were female (62 vs 50%, p < 0.01), and had a PCI < 13 (49 vs 40%, p = 0.03) compared to those in the ≥ 65 cohort, but were otherwise well-matched (Table 1). For patients who underwent multivisceral resection, specifically concomitant solid organ resection, patients < 65 and ≥ 65 years had similar rates of undergoing gastrectomy (6.5 vs 6.4%), formal liver resection (10.1 vs 12.3%), distal pancreatectomy (5.0 vs 3.2%), splenectomy (31.2 vs 35.8%), partial colectomy (50.9 vs 52.3%), and low anterior resection (16.3 vs16.6%) (all p values > 0.05).
TABLE 1.
Demographic and clinicopathologic features of patients undergoing CRS/HIPEC based on age group
| Variable | All patients n = 1090 | < 65 years n = 850 | ≥ 65 years n = 240 | p value |
|---|---|---|---|---|
| All histologies | ||||
| Age (median, IQR) | 54 (46–63) | 53 (46–61) | 68 (66–72) | < 0.01 |
| Sex | ||||
| Female | 646 (59) | 527 (62) | 119 (50) | < 0.01 |
| Male | 444 (41) | 323 (38) | 121 (50) | |
| Race | ||||
| White | 881 (82) | 685 (82) | 196 (83) | 0.68 |
| Black | 73 (7) | 60 (7) | 13 (6) | |
| Other | 120 (11) | 94 (11) | 26 (11) | |
| BMI | ||||
| ≤ 18.5 | 27 (2) | 23 (3) | 4(2) | < 0.01 |
| 18.5–24.9 | 358 (33) | 288 (34) | 70 (30) | |
| 25–29.9 | 338 (32) | 240 (29) | 98 (41) | |
| 30–34.9 | 193 (18) | 155 (19) | 38 (16) | |
| 35–39.9 | 96 (9) | 75 (9) | 21 (9) | |
| ≥ 40 | 59 (6) | 53 (6) | 6 (2) | |
| ASA | ||||
| 1 | 4(1) | 4(1) | 0 (0) | 0.64 |
| 2 | 174 (17) | 139 (17) | 35 (15) | |
| 3 | 808 (77) | 626 (77) | 182 (79) | |
| 4 | 59 (5) | 45 (5) | 14 (6) | |
| Functional status | ||||
| Independent | 1021 (98) | 799 (98) | 222 (97) | 0.81 |
| Partially dependent/totally dependent | 23 (2) | 17 (2) | 6 (3) | |
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | 692 (64) | 532 (63) | 160 (67) | 0.25 |
| Received neoadjuvant chemotherapy | 392 (36) | 314 (37) | 78 (33) | |
| Histology | ||||
| Non-invasive appendiceal | 276 (25) | 207 (24) | 69 (29) | 0.28 |
| Invasive appendiceal | 555 (51) | 434 (51) | 121 (50) | |
| Other | 259 (24) | 209 (25) | 50 (21) | |
| PCI (median, IQR) | ||||
| PCI < 13 | 489 (47) | 398 (49) | 91 (40) | 0.03 |
| PCI ≥ 13 | 554 (53) | 419 (51) | 135 (60) | |
| CCR | ||||
| CCR0 | 622 (57) | 487 (57) | 135 (56) | 0.83 |
| CCR1 | 468 (43) | 363 (43) | 105 (44) | |
| Complication(s) | ||||
| No complication(s) | 424 (57) | 348 (58) | 76 (50) | 0.02 |
| Minor complication(s) | 115 (15) | 96 (16) | 19 (13) | |
| Major complication(s) | 207 (28) | 152 (26) | 55 (37) | |
| Readmission | ||||
| No readmission | 825 (76) | 656 (78) | 169 (72) | 0.05 |
| Readmission | 255 (24) | 188 (22) | 67 (28) | |
| Discharge destination | ||||
| Home (home and home-health) | 877 (93) | 695 (95) | 182 (88) | < 0.01 |
| Non-home (acute rehab, SNF, hospice) | 64 (7) | 39 (5) | 25 (12) | |
| 30-day mortality | ||||
| No | 1078 (99) | 844 (99) | 234 (98) | 0.05 |
| Yes | 12(1) | 6(1) | 6(3) | |
| Median follow-up (months, IQR) | 27 (9–40) | 22 (10–41) | 18 (7–36) | 0.01 |
| n = 276 | n = 162 | n = 114 | ||
| Non-invasive histology | ||||
| Age (median, IQR) | 55 (48–65) | 51 (45–57) | 68 (66–72) | < 0.01 |
| Sex | ||||
| Female | 162 (59) | 126 (61) | 36 (52) | 0.21 |
| Male | 114 (41) | 81 (39) | 33 (48) | |
| Race | ||||
| White | 224 (82) | 168 (82) | 56 (82) | 0.58 |
| Black | 14(5) | 12(6) | 2 (3) | |
| Other | 35 (13) | 25 (12) | 10 (15) | |
| BMI | ||||
| ≤ 18.5 | 4(1) | 3 (2) | 1 (1) | 0.23 |
| 18.5–24.9 | 84 (31) | 63 (31) | 21 (30) | |
| 25–29.9 | 90 (33) | 61 (30) | 29 (42) | |
| 30–34.9 | 46 (17) | 38 (18) | 8(12) | |
| 35–39.9 | 34 (12) | 25 (12) | 9 (13) | |
| ≥ 40 | 16 (6) | 15 (7) | 1 (1) | |
| ASA | ||||
| 1 | 1 (1) | 1 (1) | 0 (0) | 0.75 |
| 2 | 57 (22) | 40 (20) | 17 (26) | |
| 3 | 186 (71) | 142 (73) | 44 (68) | |
| 4 | 16 (6) | 12(6) | 4 (6) | |
| Functional status | ||||
| Independent | 251 (97) | 192 (98) | 59 (94) | 0.61 |
| Partially dependent/totally dependent | 7 (3) | 3 (2) | 4 (6) | |
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | 225 (93) | 192 (94) | 61 (90) | 0.29 |
| Received neoadjuvant chemotherapy | 20 (7) | 13 (6) | 7 (10) | |
| PCI (median, IQR) | ||||
| PCI < 13 | 109 (41) | 91 (46) | 18 (28) | 0.02 |
| PCI ≥ 13 | 154 (59) | 108 (54) | 46 (72) | |
| CCR | ||||
| CCR0 | 139 (50) | 108 (52) | 31 (45) | 0.29 |
| CCR1 | 137 (50) | 99 (48) | 38 (55) | |
| Complication(s) | ||||
| No complication(s) | 110 (60) | 89 (63) | 21 (52) | 0.40 |
| Minor complication(s) | 31 (17) | 24 (17) | 7(18) | |
| Major complication(s) | 41 (23) | 29 (20) | 12 (30) | |
| Readmission | ||||
| No readmission | 213 (78) | 160 (77) | 53 (78) | 0.91 |
| n = 276 | n = 162 | n = 114 | ||
| Readmission | 62 (22) | 47 (23) | 15 (22) | |
| Discharge destination | ||||
| Home (home and home-health) | 207 (93) | 160 (95) | 47 (87) | 0.051 |
| Non-home (acute rehab, SNF, hospice) | 15 (7) | 8 (5) | 7(13) | |
| 30-day mortality | ||||
| No | 276 (100) | 207 (100) | 69 (100) | - |
| Yes | - | - | - | |
| Median follow-up (months, IQR) | 23 (9–45) | 23 (9–43) | 22 (9–49) | 0.88 |
| n = 555 | n = 434 | n = 121 | ||
| Invasive histology | ||||
| Age (median, IQR) | 55 (47–63) | 52 (45–57) | 69 (67–72) | < 0.01 |
| Sex | ||||
| Female | 320 (58) | 261 (60) | 59 (49) | 0.03 |
| Male | 235 (42) | 174 (40) | 62 (51) | |
| Race | ||||
| White | 439 (80) | 343 (80) | 96 (82) | 0.84 |
| Black | 43 (8) | 34 (8) | 9 (8) | |
| Other | 64 (12) | 52 (12) | 12 (10) | |
| BMI | ||||
| ≤ 18.5 | 8(2) | 7(2) | 1 (1) | 0.16 |
| 18.5–24.9 | 187 (35) | 153 (36) | 34 (29) | |
| 25–29.9 | 180 (33) | 129 (31) | 51 (43) | |
| 30–34.9 | 100 (19) | 81 (19) | 19 (16) | |
| 35–39.9 | 41 (7) | 31 (7) | 10 (8) | |
| ≥ 40 | 23 (4) | 20 (5) | 3 (3) | |
| ASA | ||||
| 1 | 3 (1) | 3 (1) | 0 (0) | 0.12 |
| 2 | 68 (13) | 60 (15) | 9 (7) | |
| 3 | 424 (80) | 325 (79) | 99 (85) | |
| 4 | 34 (6) | 25 (5) | 9 (8) | |
| Functional status | ||||
| Independent | 523 (98) | 408 (98) | 115 (99) | 0.26 |
| Partially dependent, totally dependent | 11 (2) | 10(2) | 1 (1) | |
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | 294 (53) | 224 (52) | 70 (58) | 0.22 |
| Received neoadjuvant chemotherapy | 257 (47) | 207 (48) | 50 (42) | |
| PCI (median, IQR) | ||||
| PCI < 13 | 255 (48) | 198 (48) | 57 (48) | 0.94 |
| PCI ≥ 13 | 281 (52) | 219 (52) | 62 (52) | |
| CCR | ||||
| CCR0 | 334 (60) | 253 (58) | 81 (67) | 0.08 |
| CCR1 | 221 (40) | 181 (42) | 40 (33) | |
| Complication(s) | ||||
| No complication(s) | 203 (53) | 169 (55) | 34 (43) | 0.09 |
| n = 555 | n = 434 | n = 121 | ||
| Minor complication(s) | 49 (13) | 39 (13) | 10 (13) | |
| Major complication(s) | 132 (34) | 97 (32) | 35(44) | |
| Readmission | ||||
| No readmission | 412 (75) | 331 (77) | 81 (69) | 0.08 |
| Readmission | 138 (25) | 101 (23) | 37 (31) | |
| Discharge destination | ||||
| Home (home and home-health) | 454 (93) | 362 (95) | 92 (85) | < 0.01 |
| Non-home (acute rehab, SNF, hospice) | 37 (7) | 21 (5) | 16 (15) | |
| 30-day mortality | ||||
| No | 554 (98) | 428 (99) | 116 (96) | 0.08 |
| Yes | 11 (2) | 6(1) | 5 (4) | |
| Median follow-up (months, IQR) | 20 (10–39) | 21 (11–41) | 15 (7–32) | 0.03 |
Bold values indicate statistical significance with a p value of < 0.05
For patients with non-invasive histology, 59% (n = 162) were < 65 years and 41% (114) were ≥ 65 years. Median age was 55 years (IQR 48–65) and 59% (n = 162) were female. Median follow-up was 23 months (IQR 9–45). More patients < 65 years had a PCI < 13 compared to patients ≥ 65 (46 vs 28%, p = 0.02).
Among patients with invasive histology, 78% (n = 434) were < 65 years and 22% (n = 121) were ≥ 65 years. Median age was 55 (IQR 47–63) and median follow-up was 20 months (IQR 10–39). Patients in the < 65 cohort were more likely to be female, compared to the ≥ 65 years cohort (60 vs 49%, p = 0.03).
Age Category and Major Complication Rates
Among all patients, 28% (n = 207) had a major complication. Patients ≥ 65 were more likely to have a major complication (37 vs 26%, p = 0.02) (Fig. 1, panel A). On univariate analysis, age ≥ 65, invasive histology, PCI ≥ 13, and a CCR1 resection were associated with a higher major complication rate (Table 2). When accounting for histology and PCI, age ≥ 65 remained associated with a higher rate of major complications (odds ratio [OR] 1.72, 95% CI 1.08–2.75, p = 0.02).
FIG. 1.
Major complication rates based on disease histology (panel A); non-home discharge rates based on disease histology (panel B)
TABLE 2.
Univariate and multivariable regression analysis for major complications
| Variable | Univariate logistic regression | Multivariable logistic regression | ||
|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |
| All histologies | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 1.66 (1.12–2.46) | 0.01 | 1.72 (1.08–2.75) | 0.02 |
| Gender | ||||
| Female | Reference | |||
| Male | 1.01 (0.73–1.42) | 0.94 | ||
| Race | ||||
| White | Reference | |||
| Black | 1.44 (0.75–2.79) | 0.27 | ||
| Other | 1.18 (0.69–2.01) | 0.54 | ||
| BMI | ||||
| ≤ 18.5 | Reference | |||
| 18.5–24.9 | 1.04 (0.34–3.15) | 0.95 | ||
| 25–29.9 | 0.91 (0.29–2/76) | 0.87 | ||
| 30–34.9 | 1.06 (0.34–3.31) | 0.93 | ||
| 35–39.9 | 1.11 (0.33–3.71) | 0.86 | ||
| ≥ 40 | 0.67 (0.17–2.63) | 0.56 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | 2.03 (0.58–7.09) | 0.27 | ||
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | Reference | |||
| Received neoadjuvant chemotherapy | 1.18 (0.84–1.66) | 0.35 | ||
| Histology | ||||
| Non-invasive appendiceal | Reference | Reference | ||
| Invasive appendiceal | 1.75 (1.15–2.66) | 0.01 | 2.15 (1.36–3.37) | < 0.01 |
| PCI (median, IQR) | ||||
| PCI < 13 | Reference | Reference | ||
| PCI ≥ 13 | 2.65 (1.86–3.77) | < 0.01 | 2.13 (1.38–3.29) | < 0.01 |
| CCR | ||||
| CCR0 | Reference | Reference | ||
| CCR1 | 2.01 (1.43–2.81) | < 0.01 | 1.58 (0.64–3.92) | 0.32 |
| Non-invasive histology | ||||
| Age | ||||
| < 65 years | Reference | |||
| ≥ 65 years | 1.75 (0.77–3.99) | 0.18 | ||
| Gender | ||||
| Female | Reference | |||
| Male | 0.58 (0.27–1.22) | 0.15 | ||
| Race | ||||
| White | Reference | |||
| Black | 1.50 (0.35–6.36) | 0.65 | ||
| Other | 1.80 (0.61–5.36) | 0.31 | ||
| BMI | ||||
| ≤ 18.5 | Reference | |||
| 18.5–24.9 | 0.84 (0.35–2.03) | 0.49 | ||
| 25–29.9 | 0.95 (0.29–3.10) | 0.90 | ||
| 30–34.9 | 1.69 (0.56–5.19) | 0.25 | ||
| 35–39.9 | 1.07 (0.19–6.10) | 0.95 | ||
| ≥ 40 | 0 (0) | 0.83 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | - | - | ||
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | Reference | |||
| Received neoadjuvant chemotherapy | 0.51 (0.11–2.44) | 0.40 | ||
| PCI (median, IQR) | ||||
| PCI < 13 | Reference | |||
| PCI C 13 | 1.44 (0.67–3.09) | 0.35 | ||
| CCR | ||||
| CCR0 | Reference | |||
| CCR1 | 1.46 (0.71–3.00) | 0.30 | ||
| Invasive histology | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 1.79 (1.05–3.06) | 0.03 | 2.04 (1.16–3.59) | 0.01 |
| Gender | ||||
| Female | Reference | |||
| Male | 1.10 (0.71–1.71) | 0.67 | ||
| Race | ||||
| White | Reference | |||
| Black | 1.25 (0.54–2.89) | 0.60 | ||
| Other | 0.49 (0.23–1.05) | 0.07 | ||
| BMI | ||||
| ≤ 18.5 | Reference | |||
| 18.5–24.9 | 0.91 (0.19–4.3) | 0.91 | ||
| 25–29.9 | 0.79 (0.17–3.68) | 0.76 | ||
| 30–34.9 | 0.94 (0.19–4.54) | 0.94 | ||
| 35–39.9 | 0.74 (0.14–3.99) | 0.73 | ||
| ≥ 40 | 1.67 (0.23–12.22) | 0.52 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | 0.38 (0.04–3.39) | 0.38 | ||
| Neoadjuvant chemotherapy | ||||
| No neoadjuvant chemotherapy | Reference | |||
| Received neoadjuvant chemotherapy | 1.15 (0.74–1.79) | 0.54 | ||
| PCI (median, IQR) | ||||
| PCI < 13 | Reference | Reference | ||
| PCI ≥ 13 | 2.90 (1.93–4.61) | < 0.01 | 2.66 (1.62–4.37) | < 0.01 |
| CCR | ||||
| CCR0 | Reference | Reference | ||
| CCR1 | 1.94 (1.24–3.04) | < 0.01 | 1.50 (0.91–2.48) | 0.11 |
Bold values indicate statistical significance with a p value of < 0.05
For patients with non-invasive histology, age was not associated with an increased major complication rate on univariate analysis (OR 1.75, 95% CI 0.77–3.99, p = 0.18). In contrast, patients with invasive histology, age ≥ 65, PCI ≥ 13, and CCR1 resections were associated with increased major complication rates while other race (non-black and non-white) was associated with decreased major complication rates on univariate analysis. Considering race, PCI, and CCR, age ≥ 65 remained associated with higher major complication rates on multivariable analysis (OR 2.04, 95% CI 1.16–3.59, p = 0.01).
Non-home Discharge Analysis
For all histologies, patients ≥ 65 years were more likely to be discharged to a non-home destination (12 vs 5%, p < 0.01) (Fig. 1, panel B). On univariate analysis, age ≥ 65 was associated with non-home discharge (OR 2.45, 95% CI 1.44–4.15, p < 0.01) in addition to major complications, PCI ≥ 13, and CCR1 (Table 3). On multivariable analysis, accounting for major complications, PCI, and CCR, age ≥ 65 remained associated with NHD (OR 2.88, 95% CI 1.19–6.93, p < 0.01).
TABLE 3.
Univariate and multivariable regression analysis for non-home discharge
| Variable | Univariate logistic regression | Multivariable logistic regression | ||
|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |
| All histologies | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 2.45 (1.44–4.15) | < 0.01 | 2.88 (1.19–6.93) | < 0.01 |
| Gender | ||||
| Female | Reference | |||
| Male | 0.67 (0.39–1.16) | 0.16 | ||
| Race | ||||
| White | Reference | |||
| Black | 0.21 (0.29–1.54) | 0.13 | ||
| Other | 1.37 (0.63–2.98) | 0.43 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | 1.38 (0.31–6.02) | 0.67 | ||
| Histology | ||||
| Non-invasive appendiceal | Reference | |||
| Invasive appendiceal | 1.14 (0.60–2.09) | 0.71 | ||
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | 1.10 (0.30–4.02) | 0.89 | 2.28 (0.39–13.17) | 0.36 |
| Major complication(s) | 7.67 (3.78–15.53) | < 0.01 | 8.40 (2.71–26.05) | < 0.01 |
| PCI | ||||
| PCI < 13 | Reference | Reference | ||
| PCI ≥ 13 | 1.80 (1.05–3.09) | 0.03 | 1.05 (0.41–2.67) | 0.92 |
| CCR | ||||
| CCR0 | Reference | Reference | ||
| CCR1 | 1.65 (0.99–2.75) | 0.05 | 1.58 (0.64–3.92) | 0.32 |
| Non-invasive histology | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 2.98 (1.03–8.65) | 0.06 | 3.32 (0.81–13.59) | 0.09 |
| Gender | ||||
| Female | Reference | |||
| Male | 0.57 (0.17–1.84) | 0.34 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | 2.89 (0.32–26.42) | 0.35 | ||
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | - | - | - | - |
| Major complication(s) | 12.83 (2.58–63.83) | < 0.01 | 12.19 (2.41–61.69) | < 0.01 |
| PCI | ||||
| PCI < 13 | Reference | |||
| PCI ≥ 13 | 3.56 (0.96–13.14) | 0.06 | ||
| CCR | ||||
| CCR0 | Reference | |||
| CCR1 | 1.31 (0.46–3.74) | 0.62 | ||
| Invasive histology | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 2.98 (1.50–5.97) | < 0.02 | 2.54 (1.08–5.98) | 0.03 |
| Gender | ||||
| Female | Reference | |||
| Male | 0.70 (0.35–1.41) | 032 | ||
| Functional status | ||||
| Independent | Reference | |||
| Partially dependent/totally dependent | 1.22 (0.15–9.82) | 0.85 | ||
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | 2.29 (0.41–12.98) | 0.35 | 2.19 (0.38–12.48) | 0.38 |
| Major complication(s) | 10.70 (3.58–31.98) | < 0.01 | 10.23 (3.41–30.74) | < 0.01 |
| PCI | ||||
| PCI < 13 | Reference | |||
| PCI ≥ 13 | 1.92 (0.94–3.94) | 0.8 | ||
| CCR | ||||
| CCR0 | Reference | |||
| CCR1 | 1.90 (0.98–3.73) | 0.06 | ||
Bold values indicate statistical significance with a p value of < 0.05
Among patients with non-invasive histology, on univariate analysis, major complications associated with NHD, while age ≥ 65 did not. On multivariable regression, accounting for major complications, age ≥ 65 was not an independent predictor for NHD (OR 3.32, 95% CI 0.81–13.59, p = 0.09). For patients with invasive histology, patients ≥ 65 were 3 times more likely to be discharged to a non-home destination (15 vs 5%, p < 0.01). However, unlike patients with non-invasive histology, both age ≥ 65 and major complications were independent predictors of NHD on univariate analysis for those with invasive histology. On multivariable regression, considering major complications, age ≥ 65 was a predictor for NHD (OR 2.54, 95% CI 1.08–5.98, p = 0.03).
Hospital Readmission Analysis
Among all patients, patients ≥ 65 were more likely to be readmitted (28 vs 22%, p = 0.05). On univariate analysis, age ≥ 65 and major complications were associated with readmission (Table 4). Accounting for major complications, age ≥ 65 was not associated with readmission on multivariable analysis. For both non-invasive and invasive histology, major complications alone were associated with readmission while age ≥ 65 was not on univariate or multivariable analysis.
TABLE 4.
Univariate and multivariable regression analysis for readmission Bold values indicate statistical significance with a p value of < 0.05
| Variable | Univariate logistic regression | Multivariable logistic regression | ||
|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |
| All histologies | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 1.38 (0.99–1.92) | 0.05 | 1.30 (0.82–2.06) | 0.26 |
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | 4.07 (2.36–7.01) | < 0.01 | 4.09 (2.37–7.05) | < 0.01 |
| Major complication(s) | 9.45 (0.05–14.76) | < 0.01 | 9.38 (5.99–14.66) | < 0.01 |
| Non-invasive histology | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 0.96 (0.49–1.86) | 0.91 | 0.81 (0.29–2.29) | 0.69 |
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | 14.59 (3.65–58.28) | < 0.01 | 14.71 (3.68–58.86) | < 0.01 |
| Major complication(s) | 37.45 (10.2–137.49) | < 0.01 | 38.36 (10.37–141.89) | < 0.01 |
| Invasive histology | ||||
| Age | ||||
| < 65 years | Reference | Reference | ||
| ≥ 65 years | 1.49 (0.96–2.34) | 0.08 | 1.24 (0.67–2.31) | 0.49 |
| Complication(s) | ||||
| No complication(s) | Reference | Reference | ||
| Minor complication(s) | 3.25 (1.41–7.51) | < 0.01 | 3.33 (1.39–7.45) | < 0.01 |
| Major complication(s) | 8.81 (4.81–16.14) | < 0.01 | 8.67 (4.72–15.91) | < 0.01 |
DISCUSSION
For clinicians, the decision to pursue CRS/HIPEC for an elderly patient can be difficult. Preoperative assessment for advanced age patients with peritoneal carcinomatosis provides critical information for risk stratification, patient and family counseling, and discharge planning. Our multi-institutional study demonstrates that patients ≥ 65 years had a higher rate of major complications and non-home discharge, compared to those < 65 years. In addition to age, consideration of tumor biology is essential. In non-invasive histology, advanced age was not associated with increased major complications, but it was for elderly patients with invasive histology. Further, age ≥ 65 years was an independent predictor of NHD only for patients with invasive histology. As complications are associated with a longer length of hospitalization, health care resource utilization, and NHD, an age category also offers a reliable framework to evaluate patients at increased risk for postoperative morbidity.25–30
While advanced age may be an independent predictor for adverse outcomes, prior studies have shown the feasibility of extensive intra-abdominal surgeries in elderly patients.31–33 This illustrates the fact that elderly patients can achieve acceptable morbidity and mortality rates with careful selection. While frailty indices aim to capture physiologic status, comorbidities, and level of baseline cognition, the widespread application of these tools is not possible given the fact that many elderly patients selected for morbid operations tend to be more “fit,” with lower composite frailty scores. Historically, an mFI score greater than 3.6 is indicative of frailty.34 A retrospective review of 1171 patients who underwent CRS/HIPEC found an increasing mFI score correlated with increased Clavien-Dindo morbidity (mFI 0: 6.7%; mFI 1 or 2: 10.9%; mFI ≥ 3: 33.3%, p = 0.004).35 In this study, it is worth noting that < 1% of patients (n = 6) had an mFI of ≥ 3. This trend was also seen in our study population, which was comprised of predominantly non-frail patients, as the average composite mFI was 2. This is indicative of surgeons at participating institutions selecting patients who are “fit for surgery.” Therefore, for CRS/HIPEC, age may serve as a useful surrogate for physiologic reserve.
Though the defined age for elderly patients ranges from 65 to 85 years, the majority of studies consider 65 or 70 years an appropriate cut-point.28 For CRS/HIPEC, the data regarding the association of advanced age and complication rates is mixed, largely due to varying age cut-points, disease biology, and PCI evaluation. A German retrospective review reported increased overall complication rates in patients ≥ 70 years compared to younger patients who underwent CRS/HIPEC for mixed histology (76 vs 46%, p = 0.048).9 Similarly, Alyami et al. demonstrated an increased rate of postoperative cardiovascular complications in elderly patients (14 vs 9%, p = 0.04).36 Advanced age was also associated with major adverse events. Increased grade IV and V complication rates was seen in patients ≥ 70 years (56 vs 8%, p = 0.02) in a subsequent study by Kitai and colleagues.37 A recent 2018 meta-analysis of 2544 patients including all disease histologies also corroborated these findings.38 In contrast, other institutions using 65- and 70-year cut-points failed to show a statistically significant difference in complication rates between the older and younger patients.13,16 It is worth noting these studies were conducted at single institutions and incorporated mixed tumor histologies.
Subgroup analysis in our collaborative dataset by histology revealed that age ≥ 65 years was associated with major complication rates only for invasive histology. A possible explanation for this observation is the potential need for neoadjuvant chemotherapy and for more extensive resection for aggressive tumor biology. Interestingly, however, a greater proportion of patients ≥ 65 years with non-invasive histology had more extensive disease, as measured by PCI, compared to those ≥ 65 with invasive histology. For patients with invasive histology, tumor burden and extent of surgery was similar but, despite this, a higher rate of major complications was evident, suggesting that organ involvement and resection are not adequate to explain the observed complication rates. It seems complications are not merely a function of disease burden, but likely due to the intersection of advanced age and tumor biology. Elderly patients with decreased physiologic reserve with invasive histology are more prone to major complications and NHD. With histopathologic differences and postoperative complications impacting survival, it is critical to pay particular attention to at-risk patients who may require additional counseling, intervention, or early discharge planning.39,40
Complications after CRS/HIPEC also have a substantial financial impact. Efforts to minimize complications ultimately contributes to improved patient outcomes, higher quality care, and cost reduction. A 2015 retrospective review by Squires et al. highlights the fact that complications were associated with a 128% increase in total hospital costs at a single institution in the US.41 In addition, as advanced age is associated with NHD, efforts to identify, counsel, and prepare patients ≥ 65 will streamline care and lead to further cost reduction.27
Limitations of this study include its retrospective nature. In addition, there is a high degree of surgeon selection bias in identifying operative candidates for major abdominal surgery. Specifically, more “medically fit” patients underwent CRS/HIPEC, which may impact generalizability. Additionally, multi-visceral resection was not included in multivariable models. However, PCI and CCR scores are indicators for the extensiveness of cytoreduction. Lastly, while additional age cut-points would have been ideal for sub-group analysis, there was insufficient data to provide the statistical power to investigate these outcomes of interest, and age 65 represents an accepted stratification for defining an ‘elderly’ patient.
CONCLUSIONS
In summary, age serves as a quantifiable measure and predictor for major complications, but it is crucial disease histology is considered. Specifically, age ≥ 65 was an independent predictor for major complications for invasive histology. For CRS/HIPEC, advanced age is not a contraindication to surgery and should be offered with appropriate preoperative counseling to guide expectations for postoperative outcomes, recovery, and discharge destination. Providers should also maintain vigilance for patients at increased risk for major complications to deliver efficient and cost-effective care. Age should not be considered in isolation but within each patient’s unique context of medical comorbidities and tumor biology. Future prospective, histology-specific studies of homogeneous patients are needed.
ACKNOWLEDGEMENTS
This study was supported in part by the Katz Foundation and the National Center for Advancing Translational Science, Grant/Award Number: UL1TR002378/TL1TR002382.
Footnotes
DISCLOSURES The authors do not have relevant commercial or financial conflicts of interest and no additional funding sources.
ETHICAL STATEMENT The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
REFERENCES
- 1.Foster JM, Sleightholm R, Patel A, et al. Morbidity and mortality rates following cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy compared with other high-risk surgical oncology procedures. JAMA Netw Open. 2019;2(1):e186847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Cao C, Yan TD, Black D, Morris DL. A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol. 2009;16(8):2152–65. [DOI] [PubMed] [Google Scholar]
- 3.Omohwo C, Nieroda CA, Studeman KD, et al. Complete cytoreduction offers longterm survival in patients with peritoneal carcinomatosis from appendiceal tumors of unfavorable histology. J Am Coll Surg. 2009;209(3):308–12. [DOI] [PubMed] [Google Scholar]
- 4.Alexander HR, Hanna N, Pingpank JF. Clinical results of cytoreduction and HIPEC for malignant peritoneal mesothelioma. Cancer Treat Res. 2007;134:343–55. [DOI] [PubMed] [Google Scholar]
- 5.Spiliotis J, Halkia E, Lianos E, et al. Cytoreductive surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study. Ann Surg Oncol. 2015;22(5):1570–5. [DOI] [PubMed] [Google Scholar]
- 6.Desantis M, Bernard JL, Casanova V, et al. Morbidity, mortality, and oncological outcomes of 401 consecutive cytoreductive procedures with hyperthermic intraperitoneal chemotherapy (HIPEC). Langenbecks Arch Surg. 2015;400(1):37–48. [DOI] [PubMed] [Google Scholar]
- 7.Ceelen WP, Peeters M, Houtmeyers P, Breusegem C, De Somer F, Pattyn P. Safety and efficacy of hyperthermic intraperitoneal chemoperfusion with high-dose oxaliplatin in patients with peritoneal carcinomatosis. Ann Surg Oncol. 2008;15(2):535–41. [DOI] [PubMed] [Google Scholar]
- 8.Kusamura S, Younan R, Baratti D, et al. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique. Cancer. 2006;106(5):1144–53. [DOI] [PubMed] [Google Scholar]
- 9.Beckert S, Struller F, Horvath P, Falcke A, Konigsrainer A, Konigsrainer I. Overall morbidity but not mortality is increased in elderly patients following cytoreductive surgery and HIPEC. Langenbecks Arch Surg. 2015;400(6):693–8. [DOI] [PubMed] [Google Scholar]
- 10.Melis M, Marcon F, Masi A, et al. The safety of a pancreaticoduodenectomy in patients older than 80 years: risk vs. benefits. HPB (Oxford). 2012;14(9):583–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ide T, Miyoshi A, Kitahara K, Noshiro H. Prediction of postoperative complications in elderly patients with hepatocellular carcinoma. J Surg Res. 2013;185(2):614–9. [DOI] [PubMed] [Google Scholar]
- 12.D’Amico TA. Outcomes after surgery for esophageal cancer. Gastrointest Cancer Res. 2007;1(5):188–96. [PMC free article] [PubMed] [Google Scholar]
- 13.Huang Y, Alzahrani NA, Alzahrani SE, Zhao J, Liauw W, Morris DL. Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis in the elderly. World J Surg Oncol. 2015;13:262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Spiliotis JD, Halkia E, Boumis VA, Vassiliadou DT, Pagoulatou A, Efstathiou E. Cytoreductive surgery and HIPEC for peritoneal carcinomatosis in the elderly. Int J Surg Oncol. 2014;2014:987475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Votanopoulos KI, Newman NA, Russell G, et al. Outcomes of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients older than 70 years; survival benefit at considerable morbidity and mortality. Ann Surg Oncol. 2013;20(11):3497–503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tabrizian P, Jibara G, Shrager B, et al. Outcomes for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the elderly. Surg Oncol. 2013;22(3):184–9. [DOI] [PubMed] [Google Scholar]
- 17.H. WLCSGDW. 65? in the United States: 2010. US Government Printing Office. 2014:23–212. [Google Scholar]
- 18.Yang R, Wolfson M, Lewis MC. Unique aspects of the elderly surgical population: an anesthesiologist’s perspective. Geriatr Orthop Surg Rehabil. 2011;2(2):56–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Al-Refaie WB, Parsons HM, Henderson WG, et al. Major cancer surgery in the elderly: results from the American College of Surgeons National Surgical Quality Improvement Program. Ann Surg. 2010;251(2):311–8. [DOI] [PubMed] [Google Scholar]
- 20.Lin HS, Watts JN, Peel NM, Hubbard RE. Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr. 2016;16(1):157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Buigues C, Juarros-Folgado P, Fernández-Garrido J, Navarro-Martínez R, Cauli O. Frailty syndrome and pre-operative risk evaluation: a systematic review. Arch Gerontol Geriatr. 2015;61(3):309–21. [DOI] [PubMed] [Google Scholar]
- 22.Govaerts K, Chandrakumaran K, Carr NJ, et al. Single centre guidelines for radiological follow-up based on 775 patients treated by cytoreductive surgery and HIPEC for appendiceal pseudomyxoma peritonei. Eur J Surg Oncol. 2018;44(9):1371–7. [DOI] [PubMed] [Google Scholar]
- 23.Lee RM, Zaidi MY, Gamboa AC, et al. What is the optimal preoperative imaging modality for assessing peritoneal cancer index? An analysis from the United States HIPEC Collaborative. Clin Colorectal Cancer. 2019;19:e1–7. [DOI] [PubMed] [Google Scholar]
- 24.Gamboa AC, Zaidi MY, Lee RM, et al. Optimal surveillance frequency after CRS/HIPEC for appendiceal and colorectal neoplasms: a multi-institutional analysis of the US HIPEC Collaborative. Ann Surg Oncol. 2020;27(1):134–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Chiu H-C, Lin Y-C, Hsieh H-M, Chen H-P, Wang H-L, Wang J-Y. The impact of complications on prolonged length of hospital stay after resection in colorectal cancer: a retrospective study of Taiwanese patients. J Int Med Res. 2017;45(2):691–705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Khan NA, Quan H, Bugar JM, Lemaire JB, Brant R, Ghali WA. Association of postoperative complications with hospital costs and length of stay in a tertiary care center. J Gen Intern Med. 2006;21(2):177–180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Burguete D, Mokdad AA, Augustine MM, et al. Non-home discharge and prolonged length of stay after cytoreductive surgery and HIPEC. J Surg Res. 2019;233:360–7. [DOI] [PubMed] [Google Scholar]
- 28.Wong EYT, Tan GHC, Chia CSL, Kumar M, Soo KC, Teo MCC. Morbidity and mortality of elderly patients following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Asia Pac J Clin Oncol. 2018;14(2):e193–202. [DOI] [PubMed] [Google Scholar]
- 29.Lee TC, Wima K, Sussman JJ, et al. Readmissions after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a US HIPEC Collaborative Study. J Gastrointest Surg. 2020;24(1):165–76. [DOI] [PubMed] [Google Scholar]
- 30.Paredes AZ, Abdel-Misih S, Schmidt C, Dillhoff ME, Pawlik TM, Cloyd JM. Predictors of readmission after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Surg Res. 2019;234:103–9. [DOI] [PubMed] [Google Scholar]
- 31.Turrentine FE, Wang H, Simpson VB, Jones RS. Surgical risk factors, morbidity, and mortality in elderly patients. J Am Coll Surg. 2006;203(6):865–77. [DOI] [PubMed] [Google Scholar]
- 32.Saltzstein SL, Behling CA. 5- and 10-year survival in cancer patients aged 90 and older: a study of 37,318 patients from SEER. J Surg Oncol. 2002;81(3):113–6 (discussion 117). [DOI] [PubMed] [Google Scholar]
- 33.Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. 1999;134(1):36–42. [DOI] [PubMed] [Google Scholar]
- 34.Ethun CG, Bilen MA, Jani AB, Maithel SK, Ogan K, Master VA. Frailty and cancer: implications for oncology surgery, medical oncology, and radiation oncology. CA Cancer J Clin. 2017;67(5):362–77. [DOI] [PubMed] [Google Scholar]
- 35.Konstantinidis IT, Chouliaras K, Levine EA, Lee B, Votanopoulos KI. Frailty correlates with postoperative mortality and major morbidity after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2017;24(13):3825–30. [DOI] [PubMed] [Google Scholar]
- 36.Alyami M, Lundberg P, Kepenekian V, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in the elderly: a case-controlled, multicenter study. Ann Surg Oncol. 2016;23(Suppl 5):737–45. [DOI] [PubMed] [Google Scholar]
- 37.Kitai T, Yamanaka K, Miyauchi Y, Kawashima M. Indications for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in elderly patients with peritoneal malignancy. Int J Clin Oncol. 2017;22(3):519–25. [DOI] [PubMed] [Google Scholar]
- 38.Gagniere J, Veziant J, Pereira B, Pezet D, Le Roy B, Slim K. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the elderly: is it reasonable? A Meta-Analysis. Ann Surg Oncol. 2018;25(3):709–19. [DOI] [PubMed] [Google Scholar]
- 39.Schneider MA, Eshmuminov D, Lehmann K. Major postoperative complications are a risk factor for impaired survival after CRS/HIPEC. Ann Surg Oncol. 2017;24(8):2224–32. [DOI] [PubMed] [Google Scholar]
- 40.Ihemelandu C, Mavros MN, Sugarbaker P. Adverse events postoperatively had no impact on long-term survival of patients treated with cytoreductive surgery with heated intraperitoneal chemotherapy for appendiceal cancer with peritoneal metastases. Ann Surg Oncol. 2016;23(13):4231–7. [DOI] [PubMed] [Google Scholar]
- 41.Squires MH 3rd, Staley CA, Knechtle W, et al. Association between hospital finances, payer mix, and complications after hyperthermic intraperitoneal chemotherapy: deficiencies in the current healthcare reimbursement system and future implications. Ann Surg Oncol. 2015;22(5):1739–45. [DOI] [PubMed] [Google Scholar]