Research Article
Outcomes of HIPEC and Cytoreductive Surgery Following Radiotherapy and Excision of Rectal Carcinoma
Singh KT1, Traiki TAB1*, Alzharani N1, Liauw W2 and Morris DL1
1Department of Surgery, University of New South Wales, Australia
2Department of Medical Oncology, University of New South Wales, Australia
*Corresponding author: Thamer Abdullah Bin Traiki, Department of Surgery, St George Hospital, University of New South Wales, Sydney, Australia
Published: 19 Sep, 2016
Cite this article as: Singh KT, Traiki TAB, Alzharani N,
Liauw W, Morris DL. Outcomes of
HIPEC and Cytoreductive Surgery
Following Radiotherapy and Excision
of Rectal Carcinoma. Clin Surg. 2016;
1: 1126.
Abstract
Introduction: Rectal and rectosigmoidal carcinoma is traditionally treated with a combinationof surgery and either adjuvant or neoadjuvant radiotherapy. Local peritoneal recurrence may be treated with cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). Given the toxicity of radiotherapy and HIPEC on the bowel, we aim to determine post-operative outcomes of patients with combined treatment.
Method: Our prospective database from 1996 to 2014 was searched for patients with radiotherapy and primary excision, followed by CRS and HIPEC. 5 patients were identified and analysed for postoperative complication and survival.
Results: Survival post-CRS range from 11 to 45 months with 2 of the 5 patients still living. In the 3 patients that died, 2 had metastatic recurrence while 1 had recurrent post-HIPEC fistulae causing death.
Conclusion: CRS and HIPEC after adjuvant or neoadjuvant radiotherapy for rectal carcinoma
are associated with considerable morbidity but can also achieve relatively longer term survival
compared to no CRS or HIPEC.
Keywords: HIPEC; Cytoreductive surgery; Radiotherapy; Rectal carcinoma; Outcomes
Introduction
Colorectal carcinoma (CRC) continues to prove a significant burden with both the second highest incidence and mortality rate amongst neoplasms [1]. Localised peritoneal spread, termed peritoneal carcinomatosis (PC) has traditionally had a poor prognosis [2]. Sugarbaker’s relatively recent pioneering of cytoreductive surgery (CRS) with perioperative intraperitoneal chemotherapy has increased survival in appropriately selected patients [2-4]. The incidence of PC has been estimated between 4-7% in patients presenting at primary surgery and 4-19% in patients with recurrence [5-6]. However these techniques do come at the risk of significant post-operative complication. Bowel complications including fistulae formation and anastamotic leak are all relatively common and attributed to the combination of cytotoxic effects of heated intraperitoneal chemotherapy (HIPEC) and extensive surgery [7]. Adjuvant or neoadjuvant radiotherapy, used especially in rectal and rectosigmoidal carcinoma, also predispose to significant gastrointestinal complications; the extent of which is proportional to the radiation dose [8]. Poor wound healing and gastrointestinal complaints have been described in rectal cancer irradiation [8-10]. The cumulative toxicity of intraperitoneal chemotherapy and radiotherapy may result in poorer post-operative outcomes, the true extent of which has not been studied. We report a 5 patient series of patients with primary rectal or rectosigmoidal carcinoma who received adjuvant/neo-adjuvant radiotherapy prior to peritoneal recurrence and treatment with CRS and HIPEC.
Materials and Methods
Cytoreductive surgery criteria
Our unit receives a high volume of patients with peritoneal and liver metastatic disease.
Our selection criteria for patients with peritoneal carcinomatosis of colorectal origin include an
intraoperative peritoneal cancer index (PCI) less than 15, or less than 10 if liver metastases are
present. Typically patients of a reasonable performance status undergo thorough radiological
workup with computerised tomography (CT) scan of the chest, abdomen and pelvic, PET scan
and hepatic arteriography and portography. Scans are reviewed in
a multidisciplinary meeting attended by radiologists, surgeons and
oncologists to determine if the patient is suitable for intervention
with CRS and HIPEC.
Patients with operable disease undergo cytoreductive surgery
involving anterior parietal peritoneum resection, diaphragm stripping,
pelvic stripping, omentectomy, splenectomy, cholecystectomy and
abdominal visceral resection if macroscopic disease is visible in these
areas. Additionally they receive HIPEC at 41.5 degrees centigrade,
with either mitomycin C or oxaliplatin. Post-surgical treatment with
Early Post-operative Intraperitoneal Chemotherapy (EPIC) may be
delivered via an abdominal port typically with 5-fluorouracil (5-FU).
Patients are given ongoing follow-up with frequent re-imaging
and following tumour marker status.
Data collection
Retrospective study of our prospective database searching for
patients with primary rectal or rectosigmoidal carcinoma, who
received adjuvant or neoadjuvant chemoradiotherapy for their
primary tumour. Of the 250 patients with colorectal disease, 43
had rectal/rectosigmoidal primary and only five had received
radiotherapy at the time of primary resection. These five patients all
suffered recurrence necessitating HIPEC and CRS, and their notes
were reviewed. Details of their disease, treatment, post-operative
morbidity and long-term follow up were recorded. In all patients
complete cytoreduction was possible. The results are included.
Table 1
Table 2
Results
Patient 1 presented with stage IIIb rectal adenocarcinoma, treated
with neoadjuvant chemoradiation, followed by low anterior resection
in 2009. Represented 3 years later with shoulder pain and loose stools
and rising tumour markers suggestive of recurrence. Intraoperative
examination showed PCI of 3 with no hepatic abnormalities on
ultrasound. CRS with cholecystectomy, retroperitoneal lymph node
dissection of para-aortic nodes and omentectomy was performed.
HIPEC with mitomycin C for 90 minutes. A small bowel oversews
and placement of a peritoneal port was performed. His post-operative
recovery was relatively rapid at 6 days, without complications. This
was followed by 24 weeks of adjuvant chemotherapy with 5-FU
and folinic acid (FOL). Unfortunately scans showed multiple lung
metastases, 18 months post-surgery. Lesions were not amenable to
radiofrequency ablation. The patient was commenced on cetuximab.
The lesions are slow growing and the patient is still alive, 36 months
after CRS.
Patient 2: presented initially with stage IIc rectal adenocarcinoma
treated with neoadjuvant chemoradiation, followed by a low
anterior resection in November 2009. Represented 3 years later
with a palpable pelvic mass and rising tumour markers suggestive
of recurrence. Intraoperative examination showed PCI of 5 with no
hepatic abnormalities on ultrasound. CRS with cholecystectomy,
appendicectomy, resection of small bowel adherent to the pelvic
mass, Hartmann’s resection and bilateral ureteric re-implantation.
Both small bowel and ureters were adherent to the mass requiring
removal and resection. 30 minutes of HIPEC with oxaliplatin. Postoperative
stay of 23 days complicated by development of pneumonia
with lung atelectasis which was managed with antibiotics. No
detected urine or bowel leaks. Adjuvant chemotherapy with FOL,
5-FU, and oxaliplatin. Patient is presently disease free with normal
tumour markers and imaging.
Patient 3: presented initially with an 11 cm rectal tumour
diagnosed on colonoscopy. Treated with a low anterior resection
with mesorectal excision followed by adjuvant chemoradiation
in February 2005. On excision there was visible mesorectal tissue
involvement and tethering of a loop of ileum to the peritoneal
reflection near the tumour. Represented 3 years later with lung lesions
and a pelvic wall mass. She had an intraoperative PCI of 6, with no
hepatic abnormalities seen on ultrasound. CRS with hysterectomy,
Hartmann’s procedure, small bowel resection and re-implantation
of the left ureter which was fixed in the pelvic mass. 90 minutes of
HIPEC with mitomycin C and insertion of a peritoneal port for 5
days of early postoperative intraperitoneal chemotherapy (EPIC)
Post-operative stay of 21 days was complicated by the development
of ileus, fevers and urinary tract infection. Readmission 4 days postdischarge
for management of a pelvic collection which was drained
percutaneously. Adjuvant post-operative FOLFOX-4 regiment
with bevacizumab. A right lung lesion was ablated a year after CRS.
Unfortunately there was local recurrence on the bladder roof, with
rising CEA treated with palliative chemotherapy. She died 45 months
post-CRS.
Patient 4: presented initially with stage IIIc rectosigmoidal
tumour initially treated with anterior resection in January 2004.
Lymphatic spread was noted in all 9 of the 9 biopsied nodes. Resection
was followed by adjuvant chemoradiation. Represented 2 years
later with recurrence of a 6cm segment 4 hepatic recurrence, which
was resected, and then 8 months later with pelvic wall recurrence.
CRS with small bowel resection and omentectomy was performed
followed by 90 minutes of HIPEC with mitomycin C. Post-operative
stay of 24 days with 5 days of EPIC was complicated by small bowel
obstruction managed conservatively. Recurrence with multiple
hepatic metastases occurred 5 months later which was managed with
FOLFOX-6 systemic chemotherapy and then treatment with Sirtex
sphere implantation but continued to decline and died 12 months
post-CRS (Table 1).
Patient 5: presented initially with stage IIc rectosigmoidal
tumour in December 2002. Interestingly the mass caused obstruction
and perforation producing a retroperitoneal abscess in the psoas
muscle. This was treated with a Hartmann’s procedure and left hemicolectomy
due to extensive sigmoid involvement. An unfortunate false
negative on frozen section biopsy of the abscess meant incomplete
resection. Thus, the patient was planned for adjuvant chemotherapy
with FOL and 5-FU and radiotherapy.
The patient represented 6 months after for CRS as his tumour
was progressing while he was on chemotherapy. Intraoperative
examination showed a PCI of 2, and no abnormality on intraoperative
liver ultrasound. CRS with small bowel resection, omentectomy and
splenectomy was performed with complete excision of the abscess
cavity with part of the psoas and iliacus muscles. 2 hours HIPEC with
mitomycin C complete and insertion of peritoneal port for 5 days
of EPIC Extremely difficult post-operative recovery complicated by
pancreatic leak, multiple collections and enteric fistulae and small
bowel perforation requiring re-operation. Post-operative stay of 206
days with multiple nosocomial infections during this duration. The
patient died 16 months after CRS due to a fistula communicating
with a large retroperitoneal sinus. This was complicated by longterm
anorexia requiring TPN and respiratory failure from morphine
sedation.
As evident from Table 2, post-operative recovery varied from a
6 day LOS with morbidity grade 0 to a 206 day LOS with morbidity
grade 4. The survival times post-surgery were 12, 17, 31, 35 and
45 months. 4 of the 5 patients experienced some post-operative
complication with a morbidity grade >2. Of these patients 3, 4 and 5,
the 3 patients who received EPIC, experienced bowel complications.
Patient 3 experienced post-operative ileus, patient 4 experienced
small bowel obstructions and patient 5’s recovery was complicated by
multiple bowel fistulae, pancreatic leaks and perforation.
Discussion
Overall survival outcomes in our 5 patient series are comparable to the overall median survival of 28 months seen in other patients with CRC who underwent CRS and HIPEC at our institution [4]. All 5 patients received complete cytoreduction of their peritoneal recurrence following their CRS. Patients 1-4 have/had been able to enjoy a significant period of remission as a result of their therapy and did not experience any long-term sequelae. From a quality of life perspective, this suggests significant utility in the procedure. Patient 5’s presentation with bowel perforation and abscess formation on the psoas muscle was undoubtedly complex. Colorectal cancer leading to perforated bowel is associated with greater risks of recurrence and operative complication [11-12]. However, it should be noted that the patient remained disease-free with negative tumour markers for their life and that death was a result of recurrent fistula, which histopathology showed communicated with the retroperitoneal space. We believe that the man’s initial abscess combined with the radiotherapy and HIPEC regime was risk factors for his postoperative fistula. Interestingly the 3 patients who experienced bowel related complications were also the only 3 to have bowel related complications. It has been suggested that combination of EPIC and HIPEC produces a greater rate of complication post-surgery, and the need to avoid combinations when possible. We are unable to find any studies focused on the cumulative effect of preoperative radiotherapy with intraperitoneal chemotherapy and CRS. Klaver et al. [13] demonstrated the efficacy of combined intraoperative radiotherapy with intraperitoneal chemotherapy. In their series of 5 patients with locally advanced rectal carcinoma there were no reports of anastamotic leaks or collections increasing the post-operative stay. The disease free survival of 4 patients at follow-ups of 12, 22, 25, and 34 months suggested an excellent outcome in selected patients [13]. However, their series also showed a patient with recurrent abscess formation following a perforated rectal carcinoma, reinforcing the possibility of HIPEC and radiotherapy to promote complication in some patients.
Comparing HIPEC and CRS with traditional treatments
Peritoneal carcinomatosis of CRC origin treated with systemic
chemotherapy alone shows poor tumour response with several
studies showing a median survival of approximately 6 months
[5,14-16]. Survival may be boosted by additional palliative surgery
to 12.6 months [16]. In comparison, a systematic review by Cao et
al. [2] demonstrated that combination HIPEC and CRS increases
median survival to over 18 months. Results from our institution are
encouraging with a median survival of 28 months, with a significant
proportion of long-term survivors [4]. This suggests an additional
22 month of life over chemotherapy alone [4]. Despite this, toxicity
and complication associated with CRS and HIPEC are both common
and severe. Grade III/IV morbidity range from 14-55%, [6,7,17,18]
although our institution has shown a steady decline in patients with
grade IV morbidity and overall mortality [4]. Peri-pancreatitis (6%),
fistula (4.5%), post-operative bleeding (4.5%), haematological toxicity
(4.5%) and anastamotic leak (3%) are the most commonly reported
complications. A 60 patient series by Jacquet et al. [19] suggested
serious complication in 35% of patients most commonly due to
bowel-related anastomotic leakage or perforation.
Multiple trials have proven the efficacy of adjuvant and
neoadjuvant rectal radiotherapy at reducing local recurrence and
death compared to excision alone [20-22]. However, post-operative
complication with radiotherapy and surgery is common, with
48% of patients suffering immediate complications [10] Common
complications in these patients, and within the first 6 months of
surgery include localised wound infection, abscess, cardiopulmonary
complications, bowel obstruction, constipation and non-specific
abdominal pains [8 and 10] This compares with 41% of patients with
complications who had surgery alone [10].
Gastrointestinal disorders, including risk of bowel obstruction,
abdominal pain, nausea and constipation are the most common longterm
adverse effects, 6 months after radiotherapy treatment [22]. Due
to these adverse effects, patients who underwent radiotherapy were
more likely to express dissatisfaction than those with surgical excision
alone [23].
In summary both adjuvant/neoadjuvant radiotherapy and
HIPEC with CRS are associated with increased survival at the expense
of likely adverse effects. In our patient series, the extent of these
adverse outcomes did not deviate from the typical CRS an HIPEC
patient. Although patient 5 did experience a difficult recovery, it
has been established that a perforated bowel with abscess formation
accounts for a higher risk of complication. Thus we believe that
previous radiotherapy would benefit from HIPEC and CRS, which is
in accordance with our current management practice.
Of course the power of our case series and the conclusions we
can draw is restricted by limited patient numbers. Additionally it
is gathered from retrospective data which is prone to experimental
bias and inability to compare with a standardised control group.
However, patients who are diagnosed with rectal/rectosigmoidal
carcinoma treated with both radiotherapy and CRS with HIPEC are
exceedingly rare and unfeasibly large populations would be required
for prospective studies. This necessitates further study to obtain
more data in regards to efficacy and complication of CRS and HIPEC
following radiotherapy.
Conclusion
Overall complication rates in our series did not extend beyond what is reported in the literature for either radiotherapy or HIPEC alone. Median survival of patients receiving radiotherapy is comparable to those who did not require radiotherapy. There may be an increased risk of complication in radiotherapy and HIPEC in patients with pre-existing abscess, but this should not be an absolute contra-indication to surgery. Further studies to investigate mortality and morbidity in these patients are required.
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