Abstract
Background.
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival in abdominal cancer patients with metastatic disease limited to the peritoneal cavity. Patients are increasingly being offered repeat CRS-HIPECs for peritoneal recurrence. However, in this rare clinical scenario, the survival benefit of performing repeat CRS-HIPEC operations remains unclear.
Methods.
A retrospective review of the CRS-HIPEC database at Wake Forest Baptist Medical Center was performed over a 30-year timespan. From 1547 patients with appendix cancers, colorectal cancers, mesotheliomas, and other miscellaneous cancers, 156 received more than one CRS-HIPEC. Kaplan-Meier survival analysis was performed using overall survival (OS) from the time of surgery as the primary endpoint. Multi-variable Cox proportional hazards regression modelling was performed on pertinent clinical variables.
Results.
Patients who received multiple CRS-HIPECs had significantly better median OS (10.7 years) versus those who received one CRS-HIPEC (2.5 years), with appendix cancers faring best (12.9 years). Resection status R2a or better was achieved in 76.4% of repeat CRS-HIPECs. There were no significant changes in complication rates after repeat CRS-HIPEC. On multivariate analysis of repeat CRS-HIPEC, patients with appendix and colorectal cancers, heart disease, and poor functional status were independently associated with poor OS. Factors not independently associated with OS were age, sex, body mass index, race, diabetes, lung disease, smoking history, and systemic chemotherapy between CRS-HIPECs.
Conclusions.
Performing multiple CRS-HIPEC operations on appropriate surgical candidates may significantly prolong survival. Appendix cancers derived the greatest benefit. Satisfactory resection margins and complication rates are comparable to first cases and achievable in repeat CRS-HIPEC procedures.
Keywords: Cytoreductive surgery, Repeat cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy, HIPEC, Repeat HIPEC, Peritoneal surface malignancy
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is known to improve survival in patients with primary abdominal malignancies and metastases limited to the peritoneal cavity.1-5 Completeness of cytoreduction is key to HIPEC effectiveness.6 Some patients with recurrence may be in a position for complete cytoreduction more than once. Thus, postoperative patients with disease recurrence confined to the peritoneal cavity are increasingly being offered repeat CRS-HIPEC procedures. Appendiceal and colorectal cancers are most commonly offered repeat CRS-HIPECs, but there is potential benefit for other tumor types as well.7-12 Younger patients may derive the greatest benefit, due to equivalent progression-free survival after repeat HIPECs compared to the index cases.13 However, the exact value of performing repeat CRS-HIPEC operations is yet undefined.
Tumor rodent models exist for HIPEC14-16 but would likely be highly morbid to the animal if attempted repeatedly. Controlled clinical trials also would be impractical to address this question because: (1) the extreme rarity of peritoneal surface malignancies is magnified when considering peritoneal recurrences, (2) individualized patient treatment is usually required, and (3) the ethical quandary of withholding a potentially life-prolonging procedure when there is no comparable systemic alternative (i.e., lack of therapeutic equipoise). Due to these limitations, retrospective analyses are currently the best method to study the potential benefit of performing repeat CRS-HIPEC procedures. Preliminary evidence is promising but has only been reported in small numbers.13,17,18 A multi-institutional, collaborative database has been established and has reported promising data on repeat CRS-HIPEC in large numbers19; however, this database was retrospectively compiled and prone to data-variability between participating centers.
The Surgical Oncology Division at Wake Forest University is uniquely positioned to address these limitations, being one of the highest-volume HIPEC centers in the world and having one of the oldest legacies in this field. We established our HIPEC program in 1991 and began a prospectively maintained database of all HIPEC cases at that time. Our institutional database includes all cancer types for which HIPECs have been performed, as well as long-term survival data. We have previously published findings about our repeat CRS-HIPEC cases,20,21 but now having reached the 30-year mark, our cohort of repeat CRS-HIPEC patients has grown large enough provide more granular analyses of patient risk factors and outcomes, and inform treatment decisions.
We report our single-center, longitudinal experience and outcomes between years 1991–2021 in a set of 156 patients who received more than one CRS-HIPEC procedure. This subset is part of our total 1721 CRS-HIPEC procedures performed on 1547 patients over 30 years. In these patients, a total of 330 CRS-HIPEC operations (including first-time cases) were performed. A total of 156 patients received second-time repeat CRS-HIPECs. Of these, 17 patients then received a third CRS-HIPEC, and 1 patient received a fourth CRS-HIPEC.
METHODS
Patients who have undergone CRS-HIPEC at Wake Forest Baptist Medical Center between December 1991 and December 2021 were recorded in a prospectively-maintained database and were selected in keeping with previously reported criteria.5 Data recorded included demographics, operative, clinical, chemotherapy, radiotherapy, pathologic, complications (Clavien-Dindo22), survival, recurrence, and follow-up data were recorded. When a patient underwent a repeat CRS-HIPEC procedure, it was recorded in the database prospectively as well, and used for the current study cohort. The institutional review board at Wake Forest Baptist Comprehensive Cancer Center approved this database from its inception until current time and has approved this study.
Resection statuses are defined as: R0-1 is a complete cytoreduction in which there is no microscopic residual disease (R0) or no macroscopic residual disease (R1); R2a is residual disease ≤5 mm; R2b is residual disease >5 mm and up to 20 mm; and R2c is residual disease >20 mm.
We used a closed-abdomen HIPEC protocol with mitomycin C or oxaliplatin for 120 minutes and a target outflow temperature of 40 °C for colorectal and appendiceal primaries. The perfusion protocol doses were: oxaliplatin at 200 mg/m2 or mitomycin C 30 mg with an additional 10 mg given at 60 minutes. For mesothelioma, cisplatin at 200–250 mg/m2 for 90 minutes was used.
The primary outcome measured in this study is overall survival (OS), which was recorded prospectively for each patient. Generally, our patients are followed on a regular basis (every 3–6 months) for 5 years, and then pro re nata. If a patient receives a repeat CRS-HIPEC, they are followed for at least 5 years following the last CRS-HIPEC procedure. Patients who are lost to follow-up are censored at the time of last contact.
Kaplan-Meier survival analysis was performed using overall survival data. The log-rank (Mantel Cox) test was performed to compare features, including resection status and tumor type. For univariate and multivariate analyses, the stratified Cox proportional hazards regression model was used. Hazard ratios (HR) with confidence intervals (CI) (5–95%) were calculated, and the model was stratified by repeat CRS-HIPEC number. For some analyses, when this would not affect the overall result, appendix cancers and colorectal cancers were combined. The Chi-square test was performed for categorical variables. Statistical significance was set at p values < 0.05 for all tests.
Database entry and management was performed with Excel software version 2016 and earlier (Microsoft, Redmond, WA). Statistical analyses were performed with SPSS software version 26 (International Business Machines, Armonk, NY).
RESULTS
The demographic, clinical, and perioperative characteristics for patients who underwent multiple CRS-HIPECs at our institution are outlined in Table 1. A total of 156 of 1547 patients (10.1%) received multiple CRS-HIPEC procedures. Of these, 41.0% were male and 59.0% were female. Excluding ovarian cancers, this ratio becomes 43.2% male and 56.8% female. The 6 patients of other/unknown races included (2) American-Indian, (2) Hispanic, (1) Asian, and (1) unknown/undeclared. The vast majority of patients (92.3%) had a high performance score (0 or 1) on the ECOG (Eastern Cooperative Oncology Group) scale.
TABLE 1.
Patient Demographics
| Characteristic | Appendix and Colorectal Cancers |
Mesothelioma and Miscellaneous Cancers |
All Cancers |
|---|---|---|---|
| Number of Patients, n= | |||
| Received a Single CRS-HIPEC | 1193 | 354 | 1547 |
| Received a Second CRS-HIPEC | 118 | 38 | 156 |
| Received a Third CRS-HIPEC | 13 | 4 | 17 |
| Received a Fourth CRS-HIPEC | 1 | 0 | 1 |
| Sex, n= (%) | |||
| Male | 47 (39.8%) | 17 (44.7%) | 64 (41.0%) |
| Female | 71 (60.2%) | 21 (55.3%) | 64 (41.0%) |
| Race, n= | |||
| White | 98 (85.2%) | 32 (91.4%) | 130 (83.3%) |
| African-American | 17 (14.8%) | 3 (8.6%) | 20 (12.8%) |
| Other/Unknown | 0 (0.0%) | 0 (0.0%) | 6 (3.8%) |
| ECOG Performance Status at First CRS-HIPEC | |||
| ECOG 0 | 75 (63.6%) | 14 (36.8%) | 89 (57.1%) |
| ECOG 1 | 37 (31.4%) | 18 (47.4%) | 55 (35.3%) |
| ECOG 2 | 3 (2.5%) | 5 (13.2%) | 8 (5.1%) |
| ECOG 3 | 3 (2.5%) | 1 (2.6%) | 4 (2.6%) |
| Primary Tumor, n= (% of Repeat Patients) | |||
| Appendix | 102 (65.4%) | 102 (65.4%) | |
| Colorectal | 16 (10.3%) | 16 (10.3%) | |
| Mesothelioma | 17 (10.9%) | 17 (10.9%) | |
| Miscellaneous | 21 (13.5%) | 21 (13.5%) | |
| Age at Operation, mean years ± SD | |||
| 1st CRS-HIPEC | 49.5 ± 11.6 | 45.3 ± 13.1 | 48.5 ± 12.1 |
| 2nd CRS-HIPEC | 53.1 ± 11.8 | 46.8 ± 12.7 | 51.6 ± 12.3 |
| 3rd CRS-HIPEC | 55.6 ± 14.2 | 53.8 ± 14.5 | 55.2 ± 13.9 |
| 4rd CRS-HIPEC | 51.8 | 51.8 | |
| Time Interval Between Operations, mean months ± SD | |||
| 1st and 2nd CRS-HIPEC | 42.2 ± 42.1 | 38.9 ± 15.8 | 37.0 ± 38.5 |
| 2nd and 3rd CRS-HIPEC | 49.2 ± 43.9 | 1.8 ± 13.4 | 50.0 ± 38.5 |
| 3nd and 4th CRS-HIPEC | 42.1 | 42.1 | |
| Mean PCI Score ± SD | |||
| 1st CRS-HIPEC | 15.4 ± 8.2 | 14.0 ± 8.1 | 15.1 ± 8.2 |
| 2nd CRS-HIPEC | 13.5 ± 8.4 | 9.5 ± 6.9 | 12.5 ± 8.2 |
| 3rd CRS-HIPEC | 13.5 ± 5.2 | 9.7 ± 8.1 | 12.7 ± 5.8 |
| 4th CRS-HIPEC | 18.0 | 18.0 |
CRS-HIPEC Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy, ECOG Eastern Cooperative Oncology Group, SD Standard Deviation, PCI PeritonealCarcinomatosis Index.
Appendix cancers were the predominant tumor type among patients who underwent repeat CRS-HIPEC (65.4%), followed by mesotheliomas (10.9%), colorectal (10.3%), and miscellaneous (13.5%), which included ovarian (8), small bowel (3), sarcoma (3), gastrointestinal stromal tumors (GIST) (2), gastric (2), peritoneal serous carcinoma (1), gallbladder (1), and urachal (1).
Mean age was 48.5 and 51.6 years at first and second CRS-HIPEC, respectively. There was wide variability in the interval of time between repeat CRS-HIPEC procedures, with a median of 25.3 months between CRS-HIPEC procedures (range 4.1–261 months). The average peritoneal cancer index (PCI) scores were not significantly different when comparing first to repeat CRS-HIPEC procedures.
The adequacy of cytoreduction is generally good after repeat CRS-HIPEC, with at least R2a status achieved for the majority of repeat cases overall, regardless of primary tumor etiology (Fig. 1; Supplemental Fig. S-1). R2a or better was achieved in 71.6% of appendix cancers at a second CRS-HIPEC, and 100% of colorectal cancers at second CRS-HIPEC (Fig. 1). R2b or better was achieved for the vast majority of second appendix CRS-HIPECs (93.1%). For the one patient with appendiceal cancer who underwent four CRS-HIPECs, an R0-1 cytoreduction achieved at the fourth CRS-HIPEC.
FIG. 1.
Resection status after repeat CRS-HIPEC by case category: appendix and colorectal cancers
On Kaplan-Meier analysis of resection status for appendix and colon cancers, overall survival is comparable between R0-1 and R2a resections, after first CRS-HIPEC (log-rank χ2 = 0.023; p = 0.881; Fig. 2A), and after second CRS-HIPEC (log-rank χ2 = 0.369; p = 0.543; Fig. 2B). Survival is significantly decreased if R2c is achieved compared with R0-1, regardless of CRS-HIPEC number (p ≤ 0.005). Pairwise comparisons between each resection status, organized by tumor type and stratified by CRS-HIPEC number, are provided in Supplemental Table S-1. The colorectal cancer group did not include any resections worse than R2a (Supplemental Table S-1). On Kaplan-Meier analysis for appendix cancers, there was significantly worse survival of R2b resections compared with R0-1 resections (Supplemental Fig. S-2). On univariate Cox regression analysis, the risk of overall mortality for R2c resections was significantly greater compared with R0-1 resections (p < 0.0001), and there was no significant difference in OS when comparing R0-1 to R2a and R0-1 to R2b resections (Supplemental Table S-2), which was consistent with our Kaplan-Meier analysis (Supplemental Figs. S-3A and S-3B). When tumor types are analyzed individually, significant associations between survival and resection status were found for appendix and mesothelial cancers (Supplemental Table S-1).
FIG. 2.
A. OS from time of first CRS-HIPEC for patients receiving multiple CRS-HIPECs, by resection status at first CRS-HIPEC. B. OS from time of second CRS-HIPEC for patients receiving multiple CRS-HIPECs, by resection status
Complication rates, as measured by the Clavien-Dindo scale Grade I or greater, were 51.9% after first CRS-HIPEC for all cancer types combined and 57.7% after second CRS-HIPEC (Table 2). Appendix cancer cases had Clavien-Dindo Grade I or greater complications in 52% after first CRS-HIPEC and 59.8% after second CRS-HIPEC. Colon cancer cases had Clavien-Dindo Grade I or greater complications in 43.8% after first CRS-HIPEC and 64.7% after second CRS-HIPEC. Serious complications (Grade IIIa or greater) occurred in 16% of patients after first CRS-HIPEC for all combined cancer types, 25% after second CRS-HIPEC, and 41.2% after third CRS-HIPEC. The one appendix cancer patient who underwent a fourth CRS-HIPEC in our cohort had minor postoperative complications; he survived for an additional 57 months after his last operation. Postoperative 90-day mortality (i.e., Clavien-Dindo Grade V) remained low for all cancer types, regardless of CRS-HIPEC number. On Chi-square analysis, there were no significant differences from expected between tumor types for overall complications and serious complications, comparing first CRS-HIPEC to groups second through fourth CRS-HIPEC (Table 2). Fisher’s exact test for each tumor class also did not show significant differences from expected for overall complications and serious complications, comparing first CRS-HIPEC to groups second through fourth CRS-HIPEC (p > 0.05 for all, data not shown).
TABLE 2.
Complications after Repeat CRS-HIPEC
| Characteristic | Appendix | Colorectal | Mesothelioma | Miscellaneous | All Cancer Types |
|---|---|---|---|---|---|
| Number of Patients, n= | 102 | 16 | 17 | 21 | 156 |
| Complication Rate, Clavien-Dindo Grades I-V, % (Proportion); χ2 | χ2 1.09, p=0.78 | ||||
| 1st CRS-HIPEC | 52.0% (53/102) | 43.8% (7/16) | 52.9% (9/17) | 57.1% (12/21) | 51.9% (81/156) |
| 2nd CRS-HIPEC | 59.8% (61/102) | 56.3% (9/16) | 64.7% (11/17) | 42.9% (9/21) | 57.7% (90/156) |
| 3rd CRS-HIPEC | 66.7% (8/12) | 100.0% (1/1) | 50.0% (1/2) | 50.0% (1/2) | 64.7% (11/17) |
| 4th CRS-HIPEC | 100.0% (1/1) | − (0/0) | − (0/0) | − (0/0) | 100.0% (1/1) |
| Serious Complication Rate: Clavien-Dindo Grades IIIa-V, % (Proportion); χ2 | χ2 1.55, p=0.67 | ||||
| 1st CRS-HIPEC | 19.6% (20/102) | 6.3% (1/16) | 11.8% (2/17) | 9.5% (2/21) | 16.0% (25/156) |
| 2nd CRS-HIPEC | 26.5% (27/102) | 37.5% (6/16) | 17.6% (3/17) | 14.3% (3/21) | 25.0% (39/156) |
| 3rd CRS-HIPEC | 50.0% (6/12) | 0.0% (0/1) | 50.0% (1/2) | 0.0% (0/2) | 41.2% (7/17) |
| 4th CRS-HIPEC | 0.0% (0/1) | − (0/0) | −(0/0) | − (0/0) | 0.0% (0/1) |
| 90-Day Mortality Rate, Clavien-Dindo Grade V, % (Proportion); χ2 | |||||
| 1st CRS-HIPEC | 0.0% (0/102) | 0.0% (0/16) | 0.0% (0/17) | 0.0% (0/21) | 0.0% (0/156) |
| 2nd CRS-HIPEC | 2.9% (3/102) | 0.0% (0/16) | 0.0% (0/17) | 0.0% (0/21) | 1.9% (3/156) |
| 3rd CRS-HIPEC | 8.3% (1/12) | 0.0% (0/1) | 0.0% (0/2) | 0.0% (0/2) | 5.9% (1/17) |
| 4th CRS-HIPEC | 0.0% (0/1) | − (0/0) | − (0/0) | − (0/0) | 0.0% (0/1) |
CRS-HIPEC Cytoreductive Surgery-Hyperthermic Interperitoneal Chemotherapy, χ2, Chi-Square
To confirm our Chi-square analyses, we performed univariate Cox regression analysis by using Clavien-Dindo complication grades after first HIPEC as a predictor variable, stratified by first and second CRS-HIPEC for all tumor types combined. We found no increased risk of long-term mortality for all Clavien-Dindo grades I-IV compared with patients who had no complications (Supplemental Table S-3). These findings suggest that patients’ overall prognoses are unaffected, even if serious complications Grades III and IV occur after first or second CRS-HIPEC.
On Kaplan-Meier analysis, we found substantial long-term survival for patients undergoing repeat CRS-HIPEC procedures for all cancer types. For all tumor types combined, the median OS for patients undergoing repeat CRS-HIPEC procedures was 127.8 months (10.7 years) measured from the time of first CRS-HIPEC, whereas for patients who received a single CRS-HIPEC and subsequently developed tumor recurrence, the median overall survival was 29.9 months (p < 0.001) (Supplemental Table S-4). Kaplan-Meier analyses for cancer types again found significantly better median OS for patients who underwent repeat CRS-HIPEC procedures: appendix and colorectal (p < 0.001; Fig. 3A), as well as mesotheliomas and miscellaneous cancers (p < 0.001) (Supplemental Fig. S-4A). On Kaplan-Meier analysis (Fig. 3B), overall survival was better for Appendix cancers compared with colorectal cancers CRS-HIPEC (log-rank; p < 0.035). Peritoneal mesotheliomas and miscellaneous cancers had median OS of 67.7 months and 46.8 months, respectively (Supplemental Fig. S-4B).
FIG. 3.
A. Overall survival of appendix and colorectal cancer patients with recurrences who received single or iterative CRS-HIPEC operations. B. Overall survival after iterative CRS-HIPECs, from time of first operation, in appendix cancers versus colorectal cancers
There is variability in survival rates when comparing different cancers to each other. When measuring OS after first CRS-HIPEC, appendix cancers had the best prognosis among the cancer types, with a median overall survival of 154.9 months (12.9 years) after initial CRS-HIPEC (Supplemental Table S-4). This was followed by mesothelial cancers (median OS 67.7 months, 5.6 years), colorectal cancers (median OS 59.1 months, 4.9 years), and miscellaneous tumors (median OS 46.8 months, 3.9 years). When measuring OS from the time of second CRS-HIPEC (Supplemental Fig. S-5), appendix cancers continued to have the best prognosis (median OS 84 months), followed by colorectal cancers (median OS 40.1 months, mesotheliomas (median OS 32.2 months), and miscellaneous (median OS 24.2 months). For all tumor types combined, the median OS was 68.4 months.
We found significant variability in the use of systemic chemotherapy before a second CRS-HIPEC operation. In our cohort of repeat CRS-HIPEC patients, we found that 30.4% of appendix cancers, 75% of colorectal cancers, 17.6% of mesotheliomas, and 85.7% of miscellaneous cancers received some form of systemic chemotherapy between their first and second CRS-HIPEC operations (Table 3). The most commonly chosen treatments were FOLFOX for appendix cancers, 5-fluorouracil or capecitabine for colorectal cancers, and cisplatin/pemetrexed for mesotheliomas.
TABLE 3.
Chemotherapy regimens utilized in patients receiving repeat CRS-HIPECs, administered between operations.
| Characteristic | Appendix | Colorectal | Mesothelioma | Miscellaneous |
|---|---|---|---|---|
| Number of Patients, n = | 102 | 16 | 17 | 21 |
| Chemotherapy Between 1st and 2nd CRS-HIPEC (%, n) | 30.4% (31/102) | 75.0% (12/16) | 17.6% (03/17) | 85.7% (18/21) |
| None Given | 69.6% (71/102) | 25.0% (04/16) | 82.4% (14/17) | 14.3% (03/21) |
| 5-Fluorouracil or Capecitabine | 7.8% (08/102) | 25.0% (04/16) | – | – |
| FOLFOX | 13.7% (14/102) | 12.5% (02/16) | – | 9.5 % (02/21) |
| FOLFIRI | 3.9% (04/102) | 12.5% (02/16) | – | 4.8 % (01/21) |
| Carboplatin/Paclitaxel | – | – | – | 23.8 % (05/21) |
| Cisplatin/Pemetrexed | – | – | 17.6 % (03/17) | 4 .8 % (01/21) |
| FOLFOXIRI | – | 12.5 % (02/16) | – | – |
| XELOX | – | 6.3 % (01/16) | – | – |
| XELIRI | – | 6.3 % (01/16) | – | – |
| Cisplatin | 1.0 % (01/102) | – | – | |
| Gemcitabine | – | – | – | 4.8% (01/21) |
| Clinical Trial Agent/Other | 3.9% (04/102) | – | – | 38.1% (08/21) |
CRS-HIPEC Cytoreductive Surgery-Hyperthermic Interperitoneal Chemotherapy, FOLFOX leucovorin 5-fluorouracil oxaliplatin, FOLFIRI leucovorin 5-fluorouracil irinotecan, FOLFOXIRI leucovorin 5-fluorouracil oxaliplatin irinotecan, XELOX capecitabine oxaliplatin, XELIRI capecitabine irinotecan.
We used a multivariate Cox regression model, stratified by CRS-HIPEC number for appendix and colorectal tumor types combined, to examine risk factors in relation to overall survival (Table 4). Factors not independently associated with overall survival were age, sex, race, BMI, diabetes, lung disease, smoking history, PCI score, resection status, and receipt of chemotherapy between first and second CRS-HIPEC operations. Functional status measured by the ECOG (Eastern Cooperative Oncology Group) scale was significantly associated with a significantly worse OS for scores of 2-3 (HR 5.070; 95% CI 1.363-18.857; p = 0.015). The presence of heart disease was independently associated with worse OS (HR 1.217, 95% CI 1.139-10.016; p = 0.028).
TABLE 4.
Multivariate Cox regression analysis of patient and tumor factors for appendix and colorectal cancers receiving multiple CRS-HIPEC operations
| Coefficient (B) | Standard Error (SE) | (p =) Significance | Hazard Ratio [Exp(B)] | 95% CI for HR Exp(B) |
||
|---|---|---|---|---|---|---|
| Lower | Upper | |||||
| Age (yr) | 0.027 | 0.016 | 0.093 | 1.027 | 0.996 | 1.059 |
| Sex | −0.023 | 0.330 | 0.945 | 0.977 | 0.512 | 1.867 |
| Race (white) (Reference) | ||||||
| Race (black) | −0.818 | 0.509 | 0.108 | 0.441 | 0.163 | 1.197 |
| Race (other/unknown) | −12.082 | >10 | 0.980 | <0.0001 | <0.0001 | >10 |
| BMI | 0.017 | 0.034 | 0.629 | 1.017 | 0.951 | 1.087 |
| Diabetes | −0.252 | 0.760 | 0.740 | 0.777 | 0.175 | 3.448 |
| Heart disease (CAD, MI, CHF) | 1.217 | 0.555 | 0.028 | 3.378 | 1.139 | 10.016 |
| Lung disease (asthma, COPD) | −0.248 | 0.820 | 0.762 | 0.780 | 0.156 | 3.891 |
| Smoking (none vs. past or current) | 0.287 | 0.437 | 0.511 | 1.333 | 0.566 | 3.140 |
| ECOG (0) (Reference) | ||||||
| ECOG (1) | 0.401 | 0.404 | 0.322 | 1.493 | 0.676 | 3.296 |
| ECOG (2, 3) | 1.623 | 0.670 | 0.015 | 5.070 | 1.363 | 18.857 |
| PCI score | −0.009 | 0.026 | 0.725 | 0.991 | 0.941 | 1.043 |
| R-status (R0-1) (Reference) | ||||||
| R-status (R2a) | −0.197 | 0.435 | 0.650 | 0.821 | 0.350 | 1.924 |
| R-status (R2b-R2c) | 0.822 | 0.548 | 0.133 | 2.275 | 0.778 | 6.655 |
| Chemotherapy between CRS-HIPECs | 0.571 | 0.369 | 0.121 | 1.770 | 0.859 | 3.645 |
DISCUSSION
Our demographics and morbidity data are in keeping with previously published work from our cohort.21 We report a longer overall survival (68.4 months, i.e., 5.7 years) from the time of second CRS-HIPEC compared with our previous report in 2017 (4.3 years).21 This may be related to improvements in selection of regional chemotherapy agents,23 as well as improved rates of long-term follow-up with an updated health system app that allows to easily book and manage follow-up appointments on their mobile phones.
Appendix neoplasms, the most common tumor type for which we performed repeat CRS-HIPECs, had the best long-term survival compared with other tumor types. In comparison, the benefit of repeat CRS-HIPEC for colorectal cancer was less pronounced on Kaplan-Meier analysis. Yet on multivariate analysis, the survival for colorectal cancers became comparable to that of appendix cancers. This suggests that patient factors linked to the development of colorectal cancers may be responsible some of the apparent decreased survival in this scenario.
Adequacy of resection (R-status) was generally good after repeat CRS-HIPEC for the majority of patients, for all tumor etiologies. Of note, during fourth CRS-HIPEC for appendix cancer, and third CRS-HIPEC for colorectal cancers and mesotheliomas, R0-1 resections were uniformly achieved, likely because these patients are a highly selected group, having arrived at that situation and chosen to proceed given favorable imaging characteristics. Regardless of CRS-HIPEC number, our univariate analysis confirmed that it is better to achieve at least an R2a resection when performing a repeat CRS-HIPEC, in terms of OS.
Overall complications and serious complications occurred at expected frequencies for all tumor types, regardless of repeat CRS-HIPEC status. This may reflect patient selection, overall young age, and general good health of patients in this cohort. However, this finding also suggests the risks of a third, or even fourth, CRS-HIPEC operation are acceptable in the properly selected patient population.
Despite a recently published, randomized trial on HIPEC for colorectal cancers with peritoneal surface disease (PRODIGE7), which concluded that HIPEC combined with CRS had no effect on overall survival compared with CRS alone, our outcomes for CRS-HIPEC in colorectal cancers demonstrated survival of 59.1 months in the iterative CRS-HIPEC groups compared with 41-month median survival in that trial.24 Our findings may be attributable to significant differences in our intraperitoneal chemotherapy administration protocols, as well as consideration of iterative CRS-HIPEC. In this European study, oxaliplatin was used with a relatively short perfusion time (30 minutes), and combined with a dose of systemic chemotherapy (fluorouracil and folinic acid) at the time of surgery. By contrast, HIPEC protocols in the United States, including our own, differ significantly by using longer perfusion times (120 minutes) and no intraoperative systemic chemotherapy. Because of these differences in methods, we believe additional prospective studies are needed before discarding HIPEC as a potential treatment option for colorectal cancers with peritoneal surface disease. However, because our study is not prospective and does not have a CRS-only arm, other factors affecting clinical outcomes must be considered. We acknowledge that the specific added benefit of HIPEC to CRS is unknown in this subset of patients with colorectal cancers but that consideration of iterative CRS-HIPEC may be beneficial in the properly selected patient with colorectal cancer limited to the peritoneum.
A known challenge in the field of peritoneal surface disease is how to determine which patients are good candidates for repeat CRS-HIPEC operations when peritoneal recurrence is found and how to select such patients. For now, there are no accepted algorithms or guidelines for selecting patients for repeat procedures, nor for deciding when to proceed: i.e., immediate versus delayed intervention. In our experience, this decision is an integration of many factors, including tumor category and histologic characteristics, patient comorbidities, patient preferences, imaging findings, response to systemic chemotherapy (if applicable), and tumor marker trends. The decision of reoperation is then made in partnership with the patient, after a frank discussion about prognosis, potential benefit, and operative risk.
At our institution, the one basic guideline for repeat CRS-HIPEC are avoidance of iterative procedure less than 1 year after initial operation, given the magnitude of these surgeries and extended time needed for complete recover. In addition, our group reviewed outcomes of repeat CRS-HIPEC looking at optimal time interval between procedures as a marker of tumor biology. Complete repeat cytoreduction more than 2 years from the initial surgery was associated with the most favorable outcome.21 However, the ultimate decision to proceed with iterative CRS-HIPEC is a personalized decision with each patient, and there are significant differences in the rationales and indications between appendix cancers and colorectal cancers. For appendix cancers, particularly for low-grade appendiceal mucinous neoplasms (LAMN) in which there is an extremely low risk of extraperitoneal metastasis, the triggers for taking the patient to an iterative CRS-HIPEC are typically symptom-driven: increased abdominal girth from mucinous ascites, pain, and gastrointestinal symptoms. Systemic therapy is rarely recommended. Patient preferences may play a significant role in this decision for low-grade appendix tumors (e.g., delaying intervention due to significant family events is common), even in the young patient. In contrast, when colorectal cancers with disease limited to the peritoneum presents with recurrence after initial CRS-HIPEC, the threshold to reoperate is lower. In our experience, reoperation is typically triggered by a combination of rising tumor markers and radiographic findings rather than patient symptoms. The majority of these patients receive systemic chemotherapy between CRS-HIPECs, which is a reflection of the higher likelihood of systemic spread of colorectal cancers versus, for example, low-grade appendix cancers and peritoneal mesotheliomas. For the older patient with major comorbidities, the decision to perform a second CRS-HIPEC is not taken lightly, and often is accepted only after failure of systemic chemotherapy. For the young and healthy patient with colorectal peritoneal recurrence, in which an aggressive strategy is warranted, the decision to perform an iterative CRS-HIPEC is usually made early at first signs of disease on surveillance. Adjuvant systemic chemotherapy often is given even after complete cytoreduction is achieved.
In the future, individualized treatment decisions will be informed by patient-derived tumor organoids derived from the initial cytoreduction operation.25 For now, the decision to reoperate must rest upon the known factors, along with the surgeon’s experience and judgement. What this report provides is some historic context and prognostic information from our longitudinal experience, which may guide some in making this decision.
The main limitation in our study is this is a retrospective analysis in a single cohort group, although it is from a large and prospectively maintained database. Survivorship bias may potentially be at play, because a patient is more likely to receive a second CRS-HIPEC if that patient happens to live longer, but this would be a limitation of any retrospective study on iterative treatments. Additionally, our high-volume, single-institutional experience may not be easily applied to other settings. Despite these limitations, our study provides updated long-term outcome data in a relatively large group of patients in a rare clinical scenario and may serve to inform clinical decision-making and risk-assessment when considering repeat CRS-HIPECs.
CONCLUSIONS
Performing repeat CRS-HIPEC procedures for peritoneal surface disease is beneficial for survival in a variety of primary tumor types, and appendix cancers are associated with the best prognoses. Adequate resection margins (R0, R1, R2a) are achievable even after repeat CRS-HIPECs and are associated with improved outcomes compared to R2b and R2c resections. Overall complication rates and serious complication rates are no worse after repeat CRS-HIPECs compared with initial CRS-HIPECs.
Supplementary Material
FUNDING
The Smith Family Fund, Wake Forest University Comprehensive Cancer Center Biostatistics shared resource funded via the NCI grant award P30CA012197.
Footnotes
This work was presented at the 2021 Society of Surgical Oncology International Conference on Surgical Cancer Care.
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1245/s10434-022-11441-3.
DISCLOSURE The authors declare there are no relationships/conditions/circumstances that present a potential conflict of interest.
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