|Year : 2014 | Volume
| Issue : 2 | Page : 189-192
Initial experience with hyperthermic intra peritoneal chemotherapy and cytoreductivesurgery
N Dharmadhikari, R Shah, P Jagannath
Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
|Date of Web Publication||7-Aug-2014|
Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Promising results were reported with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis. Experiences in India are not published. This is a preliminary report. Materials and Methods: From eight patients with peritoneal metastasis, six patients (5 M, 1 F), aged (40-62 years) were treated with CRS and HIPEC between May 2010 and August 2011 from a single institution. Three had Mucinous Adenocarcinoma of Appendix and one each with Mesothelioma, Ovarian Cancer and Colonic Cancer. Four were earlier treated with systemic chemotherapy and recurred. Pre-operative peritoneal cancer index (PCI) was calculated based on recent computerized tomography or positron emission tomography scans. Surgical completeness cytoreduction score (CCS) was classified as macroscopically complete (CCS-0); optimal residual disease ≤2.5 mm in any region (CCS-1); or grossly incomplete: Residual disease >2.5 mm (CCS-2) or >25 mm (CCS-3). They were treated by closed perfusion technique with mitomycin-C (MCC) and cisplatin at 41-42°C, for 60 min. Results: Optimal cytoreduction (residual tumor nodules <2.5 mm i.e. CC0 and CC1) was performed in four patients (66.67%). There was no operative mortality or Grade 3 and 4 toxicity. Patients with PCI <11 are alive without recurrence with overall survival of 26-31 months. Those with PCI >11 had recurrence with overall survival of 3-19 months. Two patients died at 3 and 9 months. Conclusion: CRS and HIPEC is a promising therapeutic option in selected patients with peritoneal carcinomatosis. These results in six patients are preliminary but encouraging. Patient with low PCI had better disease free survival.
Keywords: Cytoreduction, hyperthermic intra peritoneal chemotherapy, hyperthermic chemotherapy, peritoneal carcinomatosis
|How to cite this article:|
Dharmadhikari N, Shah R, Jagannath P. Initial experience with hyperthermic intra peritoneal chemotherapy and cytoreductivesurgery. Indian J Cancer 2014;51:189-92
|How to cite this URL:|
Dharmadhikari N, Shah R, Jagannath P. Initial experience with hyperthermic intra peritoneal chemotherapy and cytoreductivesurgery. Indian J Cancer [serial online] 2014 [cited 2019 Dec 16];51:189-92. Available from: http://www.indianjcancer.com/text.asp?2014/51/2/189/138304
| » Introduction|| |
Peritoneal carcinomatosis either primary or by spread from gastrointestinal or gynaecologic cancers is a difficult challenge. Cytoreductive surgery (CRS) combined with intraoperative intraperitoneal chemotherapy is a choice option in selected patients. The procedure is referred as hyperthermic intraperitoneal chemotherapy (HIPEC) and was originally described for peritoneal carcinomatosis following colon and appendiceal cancers.  It involves extensive surgical resection of malignant tissue, followed in the same intraoperative session with intraperitoneal chemotherapy with hyperthermia. Detailed guide lines are given by Sugarbaker in his book.  This paper reports experience of this procedure in the Indian context in a few cases as there are no previous published reports from India.
| » Materials and Methods|| |
Selection and evaluation of patients for the procedure
Patients with metastasis in peritoneum, but without metastasis outside the abdomen (lung, bone, brain); patients with up to three liver metastasis; those with good physical status without major comorbid conditions (like heart, kidney, liver or lung failure) were selected.
Tumor histology (differentiation and type), summary of chemotherapy and radiotherapy treatments received earlier, previous surgeries and pathology reports were noted. Four patients underwent prior chemotherapy and recurred.
Disease volume, extent and location were assessed with recent computerized tomography scans or positron emission tomography (PET) scans to arrive at peritoneal cancer index (PCI) in 13 areas of the peritoneal cavity necessary for CRS [Figure 1].  It is difficult to evaluate preoperatively the extent of peritoneal carcinomatosis and precise evaluation is possible only during surgical exploration.  Initially, eight patients (May 2010 to August 2011) were considered for this procedure after assessing feasibility and tolerance to HIPEC. During operation two patients who had extensive spread of disease, not revealed on preoperative PET scan was excluded. Finally, six patients underwent the complete procedure. An informed consent form was signed by all patients.
Procedure of CRS
Briefly, with the patient in a supine position, a xiphoid-pubic midline incision was made. The peritoneal cavity was explored to determine the extent of disease and feasibility of a complete cytoreduction for removal of all visible disease along with peritonectomy. The technique was described by Sugarbaker.  Bowel resection wherever required was done before the HIPEC with linear staplers, but anastomosis was done after HIPEC procedure was completed.
Completeness and degree of cytoreduction was scored at the end of the surgical phase following Sugarbaker criteria:  It is scored as macroscopically complete (CCS-0); "optimal" with residual disease ≤2.5 mm in any region as (CCS-1); or grossly incomplete: Residual disease >2.5 mm as (CCS-2); or >25 mm as (CCS-3).
Open drains two 28 Fr for inflow and two 32 Fr for out flow (sub-diaphragmatic, pelvis) were placed in to the abdomen. The abdomen was then closed with Polydioxanone (PDS) no.1 interrupted, ethilon no. 1 continuous. Some interrupted stitches were kept long, to help lift the abdominal wall later. Two Thompson's retractors were attached to the operation table. The long stitches were hung over the retractors to lift the abdominal wall. The inflow and out flow tubes were connected to heart lung perfusion machine with in-line warmer. A thermostat was inserted into abdominal cavity for temperature monitoring.
Drug solutions of MMC at 15 mg/m sq. and Cisplatin at 80 mg/m sq. were prepared separately in 3 L of normal saline (NS) each.
The drains were connected to inflow and outflow channel of cardiac bypass machine. Initially, 1 L NS was used to wash abdominal cavity and discarded. MMC solution was first circulated at 300 mL/min, at 41-42°C temperature, for 60 min and drained off. During infusion the table was tilted in various positions to ensure adequate exposure of the peritoneal cavity to drug. Next cisplatin solution was similarly circulated for 60 min.
| » Results|| |
From May 2010 to August 2011, Cytoreduction with HIPEC at a single session were performed in six patients (5 males and 1 female) aged 40-62 years. Primary cancer was in appendix in three patients and one each in peritoneum, ovary and colon.
The duration of surgery ranged from 5 to 9 h with mean 7 h. The patients were shifted to intensive care unit (ICU) post-operatively. Median ICU stay was 3.66 days (2-5 days).
Hemoglobin, complete blood count, renal profile were done daily to assess chemotoxicity. Among the six patients, two had Grade 1 toxicity and four Grade 2 toxicity. No Grade 3 or Grade 4 toxicity of chemotherapy was observed in any.
The particulars of the six patients and their progress followed-up to March 2013, arranged in terms of their survival benefit in descending order are given in [Table 1] and [Table 2].
|Table 1: Details of patients and chemotherapy received before and after HIPEC|
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|Table 2: Factors influencing outcome of surgery in 6 operated cases as on march 2013|
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It is observed that patients with low PCI 5-12 responded better and are still alive, but with higher PCI passed away. No recurrence occurred with PCI 5-11, but with PCI 12 disease recurred after 8 months. With PCI 16 it recurred in 7 months and with PCI 19 in 1 month.
Systemic chemotherapy was given after HIPEC in two patients with carcinoma arising from ovary and colon and with high PCI [Table 1]. One patient with origin from appendix and with a PCI of 19 had recurrence in 1 month and no further chemotherapy was given as his general condition was poor.
The completeness cytoreduction score (CCS) was CCS-1 in four patients all with PCI <12 are alive. Two patients with CCS-2 and PCI Score 16 and 19 died [Table 2].
Differentiation of the tumor did not appear to influence significantly the outcome of the procedure.
The primary organ of origin from which cancer spread to peritoneum seemed to influence the outcome depending mainly on the extent of its spread i.e. PCI. 1 patient with appendiceal cancer and another from ovary both with high PCI were not benefited. It appears that more than the primary organ of origin, its extent of spread seems to be important.
Extent of survival and the benefit of HIPEC (19-31 months) observed in six patients seem promising in cases with low PCI (<12)
| » Discussion|| |
This initial report of six cases with CRS and HIPEC with four surviving at 31 months is a positive indicator of usefulness of technique. Though there are established centers in the west for treating selected patients by HIPEC, only isolated trials are made in India. Reasons could be shortage of experienced surgical teams, time-taking surgery requiring extensive technical support and cost thereof. Furthermore, late referral of patients and their acceptance are limiting factors. Present report from a single institution with a small number of patients is one of the first from India.
The procedure of CRS and HIPEC in treating PC arising from different organs is gaining momentum with more institutions acquiring technical support and expertise in various parts of world. Reports from single institutions are published for example in 11 patients from Arizona;  12 patients with irinotecan and mitomycin - Phase I study from France;  20 patients from 2001 to 2008 with follow-up of 8-28 months from Spain;  21 patients followed for 43 months from China;  22 patients from 2007 to 2010 followed for 35 months from Croatia;  26 patients from 2007 to 2011 from Mexico. 
Peritoneal carcinomatosis is often fatal. It is sequel to spread from intra-abdominal malignant lesions, sometimes at the time of resection of the primary. Though new drugs are introduced, chemotherapy alone was disappointing.
CRS in peritoneal carcinomatosis was advocated aiming at complete removal of visible tumor tissue from peritoneum and visceral resections.  CRS also provides maximum surface for intra-operative heated peritoneal chemotherapy to sterilize residual tumor nodules and avoid entrapment of tumor cells at operative sites.  Intraperitoneal chemotherapy enables large quantity of the anticancer drug at greater concentration applied to the tumor tissue. These drugs given intraperitoneally do not readily pass into systemic circulation due to poor plasma clearance.  Small peritoneal tumor nodules (<1 mm) cannot be reached by intravenous route due to hypoxia and poor circulation, but better by intra-peritoneal application.  Hyperthermia has synergistic effect with chemotherapy. 
The anticancer drugs used for HIPEC in several studies are MCC, cisplatin, oxaliplatin, doxorubicin, paclitaxel, 5-fluorouracil and irinotecan.  Oxaliplatin is often used in France. ,
Peritoneal carcinomatosis from the following cancers are treated with HIPEC
Appendiceal, colorectal carcinoma, pseudomyxoma peritonei, peritoneal mesothelioma, gastric carcinoma  and ovarian. 
We found from our six cases, that success of CRS and HIPEC is influenced by prognostic factors such as low PCI, effective CRS scores, primary malignancy. Optimal CRS scores are possible with low PCI. The role of PCI as a prognostic factor is reported in 24 patients of colonic cancer with PCI varying from 4 to 35, recurrence occurred with PCI > 24. At the end of follow-up of 3 years the overall survival was 65% and disease free survival 50%. 
In our study, primary cancer was in appendix in three patients and one each in peritoneum, ovary and colon. We observed maximum survival with peritoneal cancer, appendix, colon, ovary in that order. Thus, the survival rates after CRS and HIPEC may also vary from the organ of origin as can be seen from following reports.
Our patient with PC of peritoneal origin with PCI 5 and CCS-1 is alive on follow-up for 31 months without recurrence. In a report on 405 patients of peritoneal mesothelioma pooled from eight institutions the overall median survival was 53 months, the 3 year survival rate 60% and 5-year was 47%.  Of three patients studied with primary cancer in appendix two with low PCI 9, 11 survived but 1 with 19 died. In a retrospective study from 25 institutions from 1989 to 2007 with CRS and HIPEC in 1154 patients the overall median survival for appendiceal adenocarcinoma (N = 50) was 77 months. 
Patient with PC from Colon in our study with PCI 12 is alive at 19 months. In 48 patients of PC arising from colorectal adenocarcinoma treated with HIPEC, the overall 2 years survival rate was 81% and for 5 years 51%.  In a pooled study of PC from colorectal cancers in 523 patients from 23 French centers between 1990 and 2007 with CRS and perioperative intraperitoneal chemotherapy with or without hyperthermia, 5 years overall survival was 27% and disease-free survival was 10%. 
Patient with PC following ovarian malignancy in our cases with PCI of 16 had recurrence in 7 months and passed away. In a review of data on PC following ovarian cancer in 51 patients from 1996 to 2009 treated with HIPEC, it was observed that those who had maximum cytoreduction had longer survival of 47 versus 12 months. 
With emergence of new centers with trained surgical teams for CRS and HIPEC, it is becoming necessary to review data from many institutions pooled together to analyze the results. For example: Eight institutions with 405 patients of peritoneal mesothelioma;  25 institutions studied 1290 patients of PC non-ovarian origin from 1989 to 2007;  two Belgian centres with 48 patients from PC of colorectal origin a multicentre prospective phase II clinical study. 
CRS with HIPEC has emerged as a feasible alternative for PC, though it is a complex procedure involving extensive surgery, operative time beyond 6 h and high-dose chemotherapy with hyperthermia. It offers a reasonable solution in selected patients and prolongs survival.
| » Conclusion|| |
CRS and HIPEC is a promising therapeutic option in highly selected patients with peritoneal carcinomatosis. These results in only 6 patients are preliminary but encouraging. Patient with low PCI had better disease free survival. The completeness of cytoreduction plays a pivotal role for long-term survival. This procedure can be performed with low mortality and acceptable morbidity in specialized centres.
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[Table 1], [Table 2]
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