Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case-control study

Uppsala University

This is an accepted version of a paper published in Annals of Oncology. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.

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Cashin, P., Graf, W., Nygren, P., Mahteme, H. (2012)

"Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case-control study"

Annals of Oncology, 23(3): 647-652

URL: http://dx.doi.org/10.1093/annonc/mdr301

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Original Article

Intraoperative Hyperthermic versus Postoperative Normothermic Intraperitoneal Chemotherapy for Colonic

Peritoneal Carcinomatosis: a Case-Control Study

P. H. Cashin

, W. Graf

, P. Nygren

, H. Mahteme

Department of Surgical Sciences, Section of Surgery

Department of Oncology, Radiology and Clinical Immunology, Section of Oncology

, Uppsala University, Uppsala, Sweden

Abstract count: 198 Word count: 2604 Tables: 4

Figures: 1

Corresponding Author:

Dr. Peter H Cashin Inst. of Surgical Sciences Uppsala University Akademiska Sjukhuset 75185 Uppsala

peter.cashin@surgsci.uu.se Work phone: +46 18 6110000 Fax: +46 18 556808

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Summary

Background:

Cytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer.

Patients and methods:

A matched case-control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis: matching was according to the peritoneal cancer index score.

Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival;

disease-free survival; morbidity; mortality; and clinicopathological parameters were compared.

Results:

Median overall survival was 36 . 5 months in the HIPEC group and 23 . 9 months in the SPIC group (p=0 . 01). Median disease-free survival for these groups were 22 . 8 (HIPEC) and 13 . 0 months (SPIC: p=0 . 02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group.

Conclusions:

HIPEC was associated with improved overall survival and disease-free survival compared to SPIC at similar morbidity and mortality; suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.

Keywords: colon cancer, cytoreductive surgery, HIPEC, intraperitoneal chemotherapy, peritoneal carcinomatosis, SPIC

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INTRODUCTION

Intraperitoneal chemotherapy together with cytoreductive surgery has been used for treating peritoneal carcinomatosis from colorectal cancer since the 1980’s

. Intraperitoneal chemotherapy has developed since then, and there are currently three main types of intraperitoneal chemotherapy treatments: hyperthermic intraperitoneal chemotherapy (HIPEC)

, sequential post-operative intraperitoneal chemotherapy (SPIC)

, and early post- operative intraperitoneal chemotherapy (EPIC)

. HIPEC is the commonly used modality and a combination of HIPEC and EPIC has also been used

. Of these three modalities, HIPEC is the only hyperthermic treatment that is administered during surgery; both EPIC and SPIC are post-operative normothermic treatments. EPIC is an intraperitoneal chemotherapy treatment given in the immediate postoperative period, usually 4-6 days after surgery, whereas SPIC is a repetitive (adjuvant) treatment administered over six months.

Cytoreductive surgery and intraperitoneal chemotherapy (HIPEC, SPIC, and EPIC) have been compared with systemic treatments. HIPEC is evaluated in one randomized control trial

, two case control trials

, and numerous observational non-comparative

studies

. SPIC is evaluated in one case control study

and one randomized adjuvant chemotherapy study

. EPIC has been evaluated in a randomized control trial that had to be terminated prematurely due to recruitment problems

, and as part of observational studies

. Despite contention concerning whether peritoneal carcinomatosis from colorectal cancer should be treated with cytoreductive surgery and intraperitoneal chemotherapy instead of systemic treatment, many surgical and medical oncologists now consider cytoreductive surgery and intraperitoneal chemotherapy as the standard of care for limited peritoneal carcinomatosis

.

Although several studies conducted compare intraperitoneal chemotherapy and systemic treatment, there is only one comparison between two intraperitoneal chemotherapy treatments (EPIC and HIPEC)

, which indicated better results with HIPEC. HIPEC and SPIC have not been compared and the type of intraperitoneal chemotherapy providing the best benefit/risk ratio needs to be defined. The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality.

METHODS

Methods and patient selection

The patient material for this study was taken from the intraperitoneal

chemotherapy database at Uppsala University Hospital, Uppsala, Sweden, where all patients who’ve received intraperitoneal chemotherapy treatment, regardless of tumour type, since 1993 are logged. In order to be accepted for cytoreductive surgery and intraperitoneal chemotherapy, all patients had to be in good general health (WHO status 1-2); have normal liver, kidney, and haematological function; and, to be free of distant metastases. To allow for comparison of HIPEC and SPIC, patients in these groups had to have had similar surgery and baseline tumour distribution, according to the peritoneal cancer index. The peritoneal cancer index is a semi-quantitative score that combines tumour nodule size with distribution according to 13 abdominal regions and is determined during the opening phase of surgery

. Each region can have a score from zero to three, depending on nodule size; thus, the top score with maximal tumour size and distribution is 39. A HIPEC/SPIC pair was considered matched if the scores were within 3 points of each other and a one to one matching was performed.

Patient data were collected from the patient charts. The parameters collected were gender; age; histopathology; prior surgical score (extent of surgical trauma prior to cytoreductive surgery)

; synchronous or metachronous disease; peroperative bleeding volume; operating time; haematological status; tumour markers; overall survival; disease- free survival; 90-day morbidity; 90-day mortality; and systemic chemotherapy administered

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pre- or post-operatively. The 90-day treatment-related morbidity was reported according to Common Terminology Criteria for Adverse Events v3.0 and only grades III to V adverse events were registered. Informed consent was obtained from each subject in this study and the study was approved by the Uppsala Regional Ethics board.

SPIC method

The SPIC patients received a PORT A CATH (No. 21-2000-04, SIMS Deltec, Inc., St Paul, MN, USA) placed subcutaneously above the periost of the lower ribs with the catheter was tunnelled through the abdominal wall and directed towards the principal tumour site

. A SPIC treatment consisted of 5-fluorouracil 500-600mg/m

administered intraperitoneally and leucovorin 20-30mg/m

administered intravenously once a day for six days. In six patients (37%), the first day of treatment was altered to oxaliplatin 460mg/m

intraperitoneally and 5-fluorouracil 500mg/m

intravenously with leucovorin as above and then 5-fluorouracil intraperitoneally with leucovorin for the remaining five days. Eight cycles of SPIC were planned.

HIPEC method

The HIPEC patients received intraoperative treatment according to the coliseum method, as previously described

. Briefly, a Tenchoff inflow catheter was centrally placed in the abdomen and four outflow catheters were inserted through separate stab incisions through the abdominal wall. Both the inflow and outflow catheters were connected to a perfusion pump and a heat exchanger. The skin of the abdomen was attached to a retractor ring and covered with a plastic film. In 15 patients, the HIPEC treatment consisted of oxaliplatin 460mg/m

for 30 min intraperitoneally combined with 5-FU 450-500mg/m

and Leucovorin 25-30mg/ m

intravenously; and in one patient it consisted of mitomycin C 30mg/m

for 90 min with no intravenous chemotherapy. The intra-abdominal temperature measured with three thermal probes was maintained at 41-42

C with a flow rate of 1-2L/min. Electrolyte-free glucose (50 mg/ml) was used for oxaliplatin perfusion and a low calcium peritoneal dialysis solution PD4 (Dianeal 13.6 mg/ml, Baxter, Deerfield, IL, USA) was used for mitomycin C.

Before perfusion, the body temperature was lowered to 35

C with a cooling blanket (Allon 2001 Thermowrap, MTRE Advanced Technology Ltd. Yavne, Island). Nine patients (56%) received additional EPIC for between 1 and 5 days; the mean was 2.5 days of EPIC consisting of 5-FU 500mg/m

given IP daily together with leucovorin IV.

Statistics

Comparisons of categorical variables between SPIC and HIPEC were evaluated with Pearson’s X

test and continuous variables with Student’s t-test. Survival data were represented by a Kaplan-Meier curve and differences were calculated with Cox’s F test.

Patients were considered censored if they died of causes other than cancer (which included postoperative mortality), or if they were still alive at the last check up. Statistical significance was set at p<0.05.

A univariate Cox regression analysis for overall survival was used to assess the prognostic value of independent variables through hazard ratios. The limit for statistical significance was set at p<0.1 due to the smaller number of observations. A multivariate Cox regression analysis was not done due to the small number of events (21 death events), as events per statistically significant variable (3 variables, Table 4) did not reach ten (21/3=7)

. Calculations were made with STATISTICA 9.1 software.

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RESULTS Participants

From the intraperitoneal chemotherapy database, there were 98 patients treated for peritoneal carcinomatosis from colon cancer between 1993 and 2008 (no rectal cancers were included). Only patients with R1 surgery (macroscopically complete surgery) were selected and this resulted in 60 patients – 33 HIPEC and 27 SPIC. Matching according to the peritoneal cancer index was performed starting from the lowest score and working towards the higher scores. This resulted in a total of 16 possible matched pairs. All 16 were included in the study, which resulted in 32 patients.

Demographics and clinical data

Baseline characteristics, surgery and systemic treatment are presented in Tables 1-3. Despite matching, a few statistical differences between the HIPEC and SPIC groups were found: date of treatment, preoperative systemic treatment, and exposure to systemic oxaliplatin.

The median number of SPIC treatments received was four out of the eight planned: only three patients received six or more. The most common causes for discontinuing the SPIC were tumour progression (31%), catheter problems (20%; clogged catheter or fluid leak through abdominal wound), toxicity (12%; hepatic or neurotoxicity), or abdominal pain during treatment (12%): there was one catheter-induced perforation of the bowel (6%). All HIPEC treatments were completed as planned.

Overall survival and prognostic factors

The median follow-up time was 38 months for the HIPEC group and 66 months for the SPIC group. The HIPEC group survived longer than the SPIC group, median overall survival 36.5 vs. 23.9 months (p=0.01; Figure 1). The median disease-free survival was also longer for the HIPEC group, 22.8 vs. 13.0 months (p=0.02).

The univariate Cox regression analysis of the overall survival included

preoperative systemic treatment and exposure to systemic oxaliplatin and three other factors that were numerically but not statistically different: gender, lymph node status, and prior surgical score (Table 4). Three variables were significant (p<0.1): treatment with systemic oxaliplatin, prior surgical score, and choice of intraperitoneal chemotherapy treatment.

A subgroup analysis revealed better overall survival (p=0.002) for patients treated with HIPEC without EPIC (n=7; median survival not reached, but > 32 months) than HIPEC with EPIC (n=9; median overall survival 17 months).

Morbidity and mortality

In the SPIC group, the grade III-IV 90-day morbidity was 19% and mortality was 6% (1 patient). For the HIPEC group, the grade III-IV 90-day morbidity was 37%

and mortality was 6%. Although morbidity was numerically higher for HIPEC, it was not statistically significant (p=0.2). In the SPIC group there was one reoperation (6%) due to a wound rupture and the mortality was due to haemolytic uremic syndrome. In the HIPEC group there were two reoperations (12%), one for postoperative bleeding and one for anastomotic leak, and one treatment-associated death due to post-operative thrombotic cerebral vascular lesion.

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DISCUSSION

This study compared HIPEC and SPIC in peritoneal carcinomatosis from colon cancer and found a disease-free survival and an overall survival benefit associated with the HIPEC method. These results suggest that HIPEC is superior to both SPIC and EPIC

. This improved outcome seems to come with no significant increase in mortality or morbidity.

There are several limitations of this trial that could influence the conclusions;

these include the retrospective and non-randomized design and low number of patients. For a matched case-control study, there should ideally be a sufficient number of patients to allow rigorous matching of all established and hypothetical prognostic factors to render the groups as comparable as possible. However, colon cancer with isolated peritoneal carcinomatosis treated with cytoreductive surgery and intraperitoneal chemotherapy is rare, which leaves limited patient data for analysis and allows matching for only two key prognostic factors:

the surgical result (R1 resection) and tumour burden. In order to be accepted into the

cytoreductive surgery and intraperitoneal chemotherapy program, all patients were rigorously selected in the same way, which made the patient groups’ general health fairly homogenous.

The matching of patients according to peritoneal cancer index and only R1 surgical resections rendered the two groups similar prognostically. Although, there are reasons to believe that the outcome differences are true, several differences are difficult to completely account for.

During the studied time period, a shift in treatment over time towards HIPEC has occurred, which was reflected in the SPIC and HIPEC groups (Table 1). The difference in time may have affected the results in ways that are difficult to account for in the analysis.

An improvement in skills and technical refinements over time, reflecting the learning curve, would favour the HIPEC group, irrespective of type of intraperitoneal chemotherapy.

Furthermore, the cytoreductive surgery tended to be more extensive in the HIPEC group (Table 2), although not statistically significantly so. Conversely, the bleeding volume and operating times were similar (Table 2). Furthermore, in a recent study of the learning curve of cytoreductive surgery and HIPEC over 10.5 years (323 patients: 184 with peritoneal

carcinomatosis from colorectal cancer)

, no firm association between time and survival could be demonstrated, when comparing R1 resections. The morbidity and mortality rates, though, improved over time, as did the proportion of R1 resections

.

Six variables were analysed in a univariate Cox regression (Table 4) and three had statistical impact on overall survival. The prior surgical score of 0 was a strong negative factor. Yet only two patients with a score of 0 were included in the study, one in each group (Table 1). The other two factors, systemic oxaliplatin treatment and choice of intraperitoneal chemotherapy treatment, had similar hazard ratios. HIPEC, as intraperitoneal chemotherapy treatment, was associated with 60% lower risk of death as was oxaliplatin treatment (Table 4). To determine which factor had greater influence, a multivariate analysis would be needed; however, there were too few cases in order to do the analysis

. Thus, it was not possible to draw any definite conclusions about which variable had greater prognostic weight. The main difference in oxaliplatin treatment was in the neoadjuvant setting. This is because of the increased use of neoadjuvant treatment during the last few years, which is, partly, due to its success in livermetastases surgery

. This randomized control trial on colorectal liver metastases determined a 7% absolute increase in progression-free survival at 36 months in a neoadjuvant treated group (with oxaliplatin – FOLFOX4) compared to those who went directly to surgery

. HIPEC has a 23% absolute increase in overall survival over SPIC at 36 months (Figure 1), and it appears, therefore, unlikely that neoadjuvant oxaliplatin treatment could alone explain the difference in overall survival.

It should be noted that both groups are somewhat heterogenous concerning the chemotherapy regimens. This is partly due to the evolution of both treatments over time.

HIPEC treatment switched from mitomycin C to oxaliplatin and the SPIC treatments were

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augmented with oxaliplatin on the first day of each cycle. However, the increased use of oxaliplatin in the treatment of PC benefited both groups and is in line with the evolution of CRC treatment in general.

The question of whether HIPEC or SPIC is more effective is difficult to categorically answer without a randomized control trial. However, this study’s conclusion is supported by several practical and theoretical differences in the treatments. Firstly, it is noteworthy that so few of the SPIC patients managed to complete their treatment (median number of treatments was 4 out of 8). This is a major problem, which is also the case with SPIC treatment in ovarian cancer (86 out of 170 received all assigned treatments)

. However, despite this deficiency, SPIC in advanced ovarian cancer has been shown to be superior to systemic therapy. As of yet, no trial between HIPEC and SPIC in ovarian cancer has been performed; and considering this article, it may be important to execute such a trial. Secondly, there is the theoretical problem of tumor cell entrapment due to postoperative adhesions and poor drug distribution. Thirdly, hyperthermia is not available to augment the SPIC treatment.

These differences may all contribute to the inferior survival outcome of SPIC.

Morbidity presented a numerical but not statistically significant difference and there was no difference in mortality. Yet HIPEC may result in substantial morbidity, particularly when using drug combinations

. Thus, cytoreductive surgery with HIPEC should only be used in patients with good performance status without major comorbidity and with the capability to combat adverse events.

HIPEC and EPIC have been used in combination before, and a few patients in this study had this combination. However, the combination rendered no benefit in this study and hasn’t shown benefit in other studies either

. HIPEC and SPIC have not been reported in combination yet. Yanemura and colleagues repeated intraperitoneal chemotherapy treatments (in the same manner as SPIC) together with systemic therapy in a neoadjuvant setting, NIPS (neoadjuvant intraperitoneal and systemic chemotherapy), and found a significant down- staging in gastric cancer prior to cytoreductive surgery and HIPEC

. Similarly, it could be beneficial to test HIPEC in combination with SPIC and systemic chemotherapy for trying to optimize intraperitoneal chemotherapy and improve survival. Furthermore, as SPIC may have a benefit over systemic chemotherapy, it could be of use where resources for HIPEC are not available.

In conclusion, this small retrospective study indicates that HIPEC is associated with better overall survival and disease-free survival than SPIC at similar morbidity and mortality. Until further enhancement in the SPIC technique, HIPEC is suggested as the first- line treatment strategy in peritoneal carcinomatosis from colon cancer.

CONFLICTS OF INTEREST

The authors have declared no conflicts of interest.

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Table 1. Clinical characteristics at diagnosis of peritoneal carcinomatosis for HIPEC and SPIC

Characteristic HIPEC SPIC p-value

Date of treatment (month/year) First treatment

Last treatment

Median treatment for the group

1/2004 4/2008 1/2007

4/1996 11/2007

3/2004 <0.01 Gender ( Nr. of patients )

Male Female

4 12

9 7

0.07

Mean age, years 53.3 56.3 0.6

Lymph node status ( Nr. of patients ) Positive

Negative Not reported

13 1 2

9 5 2

0.07

Tumour grade ( Nr. of patients ) Well

Moderate Poor

Not reported

5 8 2 1

5 8 3 0

0.9

Initial pT stage ( Nr. of patients ) 1

2 3 4

Not reported

0 0 5 11 0

0 1 4 11 0

0.6

Peritoneal cancer index

Mean value 14.4 13.2

0.6 Prior surgical score ( Nr. of patients )

0 1 2 3

Not reported

1 1 5 9 0

1 4 9 2 0

0.06

Synchronous peritoneal carcinomatosis ( Nr. of patients ) Yes

No

13 3

11 5

0.4

Abbreviations: HIPEC – hyperthermic intraperitoneal chemotherapy, SPIC – sequential postoperative intraperitoneal chemotherapy.

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Table 2: Surgical characteristics for HIPEC and SPIC.

Characteristics HIPEC SPIC p-value

Mean bleeding volume (ml) 1231 1246 1.0 Adjusted median operating time (min)

excluding the HIPEC phase.

385 384 1.0

Operating procedures Gastrointestinal resection

Mean/patient

Urogenital resection

Mean/patient Peritonectomy

Mean/patient

1-3 resections (Nr of patients) 4-5 resections (Nr of patients) 6-7 resections (Nr of patients) Greater omentectomy

Splenectomy Cholecystectomy Small liver resections Miscellaneous

27 1.7 13 0.8 4.1 6 8 2 13 2 3 4 0

29 1.8 11 0.7 3.1 8 7 1 10 1 1 1 2

0.3 0.4 0.9 0.7 0.1

0.2 0.5 0.3 0.1 0.3

a

Gastric, small bowel, or large bowel resections.

Nephrectomy, ureter/bladder resection, hysterectomy, salpingoophorectomy, or orchidectomy.

Right iliac fossa, right diaphragm, left diaphragm, left iliac fossa, pelvic, visceral and parietal peritonectomy.

Vena cava resection and removal of the 12

rib.

Abbreviations: HIPEC – hyperthermic intraperitoneal chemotherapy, SPIC – sequential postoperative intraperitoneal chemotherapy.

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Table 3: Systemic chemotherapy comparison between HIPEC and SPIC groups (Nr of patients).

Characteristics HIPEC SPIC p-value

Chemotherapy prior to surgery One line

Two lines Missing data

13 12 1 0

7 7 0 0

0.07 0.03 0.3 1.0 Chemotherapy after surgery

One line Two lines Three lines

6 4 1 1

6 4 2 0

1.0 1.0 0.5 0.3 No postoperative chemotherapy

Postoperative missing data

7 4

6 5

0.7 0.3 Drugs

5-fluorouracil Oxaliplatin Irinotecan Bevacizumab Capecitabin Cetuximab

13 13 3 3 2 1

11 6 1 0 2 0

0.4 0.01 0.1 0.07 1.0 0.3

Abbreviations: HIPEC – hyperthermic intraperitoneal chemotherapy, SPIC – sequential postoperative intraperitoneal chemotherapy.

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Table 4 –Univariate Cox proportional hazards analysis on overall survival for all

32 patients.

Parameters Hazard Ratio

95%

lower

95%

higher p value 1. 1 preoperative

chemo-treatment 2. Systemic oxaliplatin 3. Female gender 4. Positive lymph node 5. Prior surgical score 0

1 2 3

6. Choice of intraperitoneal chemotherapy HIPEC treatment SPIC treatment

0.9 0.4 0.8 0.6 18

0.4 1.3 0.8

0.4 2.5

0.5 0.2 0.3 0.2 2.5

0.1 0.5 0.3

0.1 0.9

2.2 1.0 2.0 1.8 134

1.8 3.3 2.4

1.1 6.7

0.7 0.06 0.7 0.4 0.01 0.2 0.6 0.7

0.06 0.06

a

Only two patients in this category, thus the wide range in hazard ratio.

Abbreviations: HIPEC – hyperthermic intraperitoneal chemotherapy, SPIC – sequential postoperative intraperitoneal chemotherapy.

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Figure 1: Overall survival between SPIC and HIPEC. p=0.01

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