Systemic chemotherapy for peritoneal disease in ovarian carcinoma is associated with a recurrence rate of more than 75%, and most of the cases are confined to the peritoneal cavity. The propensity of locoregional treatment failure has paved the way for the discovery of cytoreductive surgery with intra-cavitary chemotherapy. Cytoreductive surgery (CRS) is the present-day treatment modality for a variety of peritoneal carcinomatosis including ovarian cancer, and multi-visceral resection is critical for completion of CRS. In cases of diaphragmatic infiltration by tumor deposits, partial resection leads to a diaphragmatic rent, which can be used for the perfusion of chemotherapeutic drugs into the pleural cavity. Disease transmission from the peritoneal to pleural cavity is a poor prognostic factor however. Hence, intrathoracic hyperthermic chemotherapy may be a reasonable treatment option for ovarian carcinoma with malignant pleural effusion or pleural deposits. Hyperthermic intraperitoneal chemotherapy (HIPEC) is added to the treatment plan in cases of complete CRS but this is a technically demanding procedure. Therefore, performing hyperthermic intrathoracic chemotherapy on top of CRS and HIPEC may be even more complicated for such advanced cancers. The technique of combining HIPEC and hyperthermic intrathoracic chemotherapy is also commonly known as hyperthermic thoracoabdominal chemotherapy (HITAC). The perioperative morbidity and mortality may be remarkably high in such scenarios. We describe our CRS technique with HITAC, which was performed in three FIGO stage IVA ovarian carcinoma patients with metastatic pleural effusion after complete CRS. The patients were retrospectively identified from a prospectively maintained database. All had partial diaphragmatic resection followed by HITAC as part of CRS treatment. Surgical techniques are outlined along with accompanying intra-operative images. Patient demographics, clinical and follow-up details were also described briefly. No comparative analysis with control patients was done. Adjustments in chemotherapy dose are not mandatory for HITAC. Of three patients, one had intrathoracic recurrence on follow-up; no mortality was recorded HITAC is a complex and potentially harmful procedure whose toxicity profile is still poorly known. Morbidity was not life-threatening and survival was acceptable.
Previously, peritoneal disease was considered terminal and systemic chemotherapy was offered for palliative intent while palliative surgery only had a role in symptom relief. With the advent of cytoreductive surgery (CRS) in the early 1990’s, it is now the accepted treatment modality for a subset of patients with peritoneal carcinomatosis from pseudomyxoma peritonei, appendiceal adenocarcinoma and mesothelioma, and has also showed promising results in selected patients with ovarian, colorectal and gastric cancer[
This is a retrospective study of three prospectively selected patients with ovarian carcinoma and metastatic pleural effusion treated with CRS and HITAC after neoadjuvant chemotherapy. The aim was to describe the technical aspects of the surgery with brief descriptions of the postoperative outcomes and treatment-related morbidities on follow up.
For CRS, a midline laparotomy extending from the xiphoid process to symphysis pubis was performed to provide greater exposure of the abdomen. Bilateral pelvic and retroperitoneal lymph node dissection with total omentectomy were done routinely as a part of CRS in ovarian cancer apart from total hysterectomy and salpingo-oophorectomy. Regarding peritonectomy, we do not routinely practice total peritonectomy in all cases. Selective peritonectomy was performed in the region(s) macroscopically affected by the tumor. Total peritonectomy was performed in two cases in the present study, which had gross peritoneal disease. Total peritoneal stripping in continuity is a technically demanding procedure, hence in the current study, we followed the split technique, which involves stripping and removal of the entire peritoneum in five parts - right subdiaphragmatic peritoneum along with Glisson’s capsule, left sub-diaphragmatic peritoneum, right and left parietal wall/paracolic gutter peritoneum and pelvic peritoneum. Peritonectomy was performed by holding and lifting the peritoneal edges with multiple artery forceps
Peritonectomy using multiple artery forceps for retraction
Surgical dissection was performed using monopolar diathermy with a sharp tip and diathermy settings at 30 coagulation spray mode although many surgeons prefer ball tip diathermy in pure cut mode. Additional visceral organ resection (colectomy, colo-proctectomy, splenectomy, gastrectomy, appendicectomy, cholecystectomy, liver resection and small bowel resection) may be performed, depending upon involvement. Whenever bowel resection is required, we prefer resection-anastomosis before HIPEC. Bowel edema, erythema and other hyperthermic chemotherapy-induced changes due to HIPEC at the edges of the bowel wall may become a constant threat for anastomotic leaks. For diaphragmatic peritonectomy, access and exposure of the diaphragmatic peritoneum were of utmost importance. Adequate exposure was obtained with the Omni-Tract surgical retractor and the liver was completely mobilized, except at the area of the hepatic veins and the suprahepatic inferior vena cava. For full-thickness large solid deposits involving the diaphragm, we performed full thickness diaphragmatic resection in two cases of the present study. In another case, partial resection of the hemidiaphragm was created for HITAC. Full-thickness resection of the diaphragm and the subsequent diaphragmatic rent created are shown in
Diaphragmatic peritonectomy with full-thickness resection of diaphragmatic deposits
For diaphragmatic resection, one must be aware of the anatomy of the diaphragm in relation to the phrenic nerve. The phrenic nerve originates mainly from the 4th cervical nerve, but also receives contributions from the 5th and 3rd cervical nerves (C3-C5).
The right phrenic nerve enters the diaphragm through the central tendon or inferior vena cava opening. On the right side, it courses relatively more medially throughout its thoracic course to various structures like the right brachiocephalic vein, SVC and pericardium over the right atrium. The inferior vena cava lies medially and reaches under the surface of the diaphragm by passing through the inferior vena cava foramen in the central tendon.
The left phrenic nerve pierces the superior surface of the muscular part of the diaphragm, just to the left border of the heart.
Both nerves divide or trifurcate at, or just above the diaphragm. The branches travel together into the diaphragmatic musculature, while small sensory branches supply the peritoneum over the central part of the diaphragm. The larger motor branches separate within the diaphragm into four major nerves trunks - sternal, anterolateral, postero-lateral and crural. The nerve trunks travel partly within the diaphragmatic muscle and innervate the inferior surface covered by peritoneum. Therefore, the diaphragmatic incision has to be made circumferentially to avoid the main phrenic nerve trunks.
In the present study, we made an incision in the above-mentioned manner and excised the tumor deposits.
The patient’s head end was lowered during HITAC procedures, so that the chemotherapeutic fluid can gain easy access to the thoracic cavity by free flow from the abdominal cavity.
In two cases, we had to incise approximately one-fourth of the diaphragm
Diaphragmatic rent after partial diaphragmatic excision (black arrow)
HIPEC was performed using the open Coliseum technique
Demonstrating the creation of coliseum for performing hyperthermic intraperitoneal chemotherapy
An adhesive plastic sheet was incorporated to prevent spillage of the chemotherapy solution and heat loss
Showing the coliseum (semi-open technique) and hyperthermic intraperitoneal chemotherapy tubes with adhesive sheet
In cases of ovarian carcinoma, cisplatin was used as a chemotherapeutic drug in HITAC. Apart from routine drug dosage calculation using body surface area, another method of estimation uses the approximate volume of the peritoneal cavity in litres. Dosage was calculated at 50 mg of cisplatin per litre. The chemotherapeutic solution was prepared by a resident doctor/specialized staff nurse using aseptic technique and full body personal protective equipment in a separate room adjacent to the surgical suite. The desired temperature from the inflow tube was kept in the range between 42 °C to 44 °C and out-flow was maintained at 41 °C to 43 °C. Per the literature, microscopic as well as tumour deposits up to 2.5 mm are destroyed by the synergistic effects of hyperthermia (42 °C) and chemotherapy[
The role of the anesthesiologist is crucial during CRS with HITAC because of the extensive resection and long duration of procedures. The addition of hyperthermia in HITAC presents further challenges for the clinicians so a team approach is paramount. The main concern is related to the various physiological changes that can occur during CRS with HITACe, where hyperthermia and the use of chemotherapeutic agents concurrently may affect body systems. These concerns relate mainly to major fluid shifts, respiratory, hemodynamic, renal, hepatic, hematological and metabolic changes along with electrolyte, fluid and thermal imbalances. The maintenance of normal physiology remains the main goal. Ventilatory strategies are also of a major concern, not only because of abdominal surgery but also from exposure of the thorax to chemotherapy drugs and hence, the need for single lung ventilation.
Preoperative assessment and optimization are thus required for optimal outcomes. A thorough history and examination is key and includes routine assessment along with evaluation of prior drug therapy including chemotherapy, analgesics or drugs for associated comorbidities. Preoperative rehabilitation is also emerging as an important management tool because of its various beneficial aspects in enhanced recovery after surgery.
Appropriate monitoring is essential for patients undergoing CRS and HITAC. Apart from routine conventional intra-operative monitoring (electrocardiogram, non-invasive blood pressure monitoring, pulse oximeter, capnography, temperature), certain additional monitoring strategies are required for such interventions. For airway management, the conventional endotracheal tube is used routinely with oropharyngeal core body temperature probe monitoring. However, single lung ventilation is desirable in cases of pleural deposit excision. Anesthesia induction is usually done using propofol, fentanyl and atracurium and maintained with atracurium, fentanyl and inhalational agents like sevoflurane or desflurane in oxygen and air mixture. Based on the extent of the abdominal mass and the patient’s clinical condition, ventilator strategies may require further planning.
Goal-directed fluid therapy is desirable for fluid management. Monitoring for fluid management is routinely done using urine output measurement and non-invasive methods such as cardiac output monitors for assessing the fluid status to guide management. Multimodal analgesia is required for optimal outcomes. The use of thoracic epidural analgesia with local anesthetic and opioids appears to be acceptable in the current study. Coagulopathy needs to be identified and corrected as necessary. The use of point of care tools for assessing coagulopathy remains promising. Postoperative monitoring is crucial as these patients continue to have various physiological changes for days in the postoperative period. The patient should be monitored closely for fluid balance, hemodynamic fluctuations, renal impairment, coagulopathy and electrolyte imbalances. Such patients also need DVT prophylaxis in the postoperative period using pharmacological and/or mechanical measures.
CRS with HIPEC and HITAC were performed in three patients with ovarian carcinoma and peritoneal carcinomatosis after neoadjuvant chemotherapy.
Patients were 29-46 years with a mean age of 40 years. All patients resided in urban localities and were of middle class socioeconomic status.
Patient serial number “1” is a 45-year-old female with known hypothyroidism. She underwent staging laparotomy at another institution for ovarian malignancy in December 2015 and histopathology was FIGO stage IB. The patient did not undergo any adjuvant chemotherapy. Six months later, she self-referred to our tertiary centre in May 2016 with symptoms of cough, breathlessness and abdominal distension and was diagnosed as FIGO stage IVA, recurrent ovarian carcinoma. The patient underwent chemotherapy with 6 cycles of TP (Paclitaxel/Carboplatin), 6 cycles of Gem/CDDP (Gemcitabine/Cisplatin) and 1 cycle of TP (Paclitaxel/Carboplatin). Post-chemotherapy, the patient had partial response and she proceeded with secondary CRS and HITAC as mentioned in
Showing the demographic and clinical details with follow-up status
Patient Sl. No 1 | Patient Sl. No 2 | Patient Sl. No 3 | |
---|---|---|---|
Age (years) | 45 | 46 | 29 |
Date of registration | 08-05-2016 | 04-06-2018 | 27-06-2017 |
Prior surgery | Staging laparotomy | None | None |
FIGO stage | IVA | IVA | IVA |
NACT (cycles/regimen) | 6#TP, 6#Gem + CDDP, 1#TP | 12#TP | 3#TP |
Date of surgery | 20-05-2019 | 08-11-2018 | 12-03-2018 |
Types of CRS | Secondary CRS | Interval CRS | Interval CRS |
CRS procedure | Disease limited peritonectomy + omental cake excision + terminal ileum and limited right colon resection anastomosis | TAH + BSO + B/L PLND + RPLND + total omentectomy + pouch of douglas and liver deposit excision | TAH + BSO + B/L PLND + RPLND + total omentectomy + right diaphragmatic stripping + selective peritonectomy |
CRS duration (min) | 370 | 410 | 330 |
Blood loss (mL) | 1150 | 600 | 450 |
PCI | 23/39 | 2/39 | 15/39 |
HITAC drug | Mitomycin | Cisplatin | Cisplatin |
Drug dosage (mg) | 30 | 100 | 100 |
Duration (min) | 60 | 45 | 60 |
Temperature (°C) | 42 | 42 | 42 |
Perfusate | Normal saline | Normal saline | Normal saline |
Perfusate volume (L) | 2.5 | 3.0 | 2.5 |
CC score | 1 | 0 | 0 |
Comorbidity | Cl. Dindo II | Cl. Dindo III | Cl. Dindo II |
Adj chemotherapy | 3#TP | 6#TP + Bev | 3#TP |
Follow up status | Alive & disease-free | Alive with disease | Alive & disease-free |
Sl. No: serial number; FIGO: International Federation of Gynecology and Obstetrics; NACT: neoadjuvant chemotherapy; TP: Paclitaxel/Carboplatin; CDDP: Cisplatin; TAH: total abdominal hysterectomy; BSO: bilateral salpingo-oophrectomy; B/L PLND: bilateral pelvic lymph node dissection; PAND: paraaortic node dissection; CRS: cytoreduction surgery; PCI: peritoneal carcinomatous index; HITAC: hyperthermic thoracoabdominal chemotherapy; CC score: completeness of cytoreduction score; Cl. Dindo: Clavien Dindo score; Adj: adjuvant; Bev: Bevacizumab
Patient serial number “2” is a 46-year-old female with no known comorbidities nor significant family history. She initially presented to another institution with symptoms of abdominal pain, constipation, fever and weight loss. She was diagnosed with Koch’s abdomen and received tuberculosis treatment for 1 year. However, she had persistent and worsening of symptoms, so a right-sided intercostal drainage tube was placed for a right pleural effusion. Image-guided pleural biopsy was performed and histopathology was suggestive of poorly differentiated carcinoma which was immunopositive for CK7+, ER+ and focal CA125+. The patient then self-referred to our hospital. After thorough work-up, she was planned for weekly TP neoadjuvant chemotherapy followed by surgical reassessment before proceeding with interval CRS with HITAC. Details of the surgical procedure were mentioned earlier and are based on pre- and intra-operative clinical findings. Post-operative histopathology was consistent with FIGO stage IVA. In the early post-operative period, the patient developed a recurrent right pleural effusion which necessitated another right intercostal drainage tube. After delayed clinical recovery, six cycles of adjuvant TP and bevacizumab were administered to the patient. The patient is currently alive with persistent disease at the last follow-up on 13-03-2020 and is still on bevacizumab based chemotherapy.
Patient serial number “3” is a 29-year-old female with no known comorbidities, significant family history nor past medical or surgical history. She presented with a dry cough and shortness of breath for 10 months. The patient was worked-up and diagnosed with ovarian carcinoma with right sided malignant pleural effusion (FIGO IVA). Multidisciplinary tumor board discussion advised for TP based neoadjuvant chemotherapy followed by CRS and intraperitoneal/intrathoracic chemotherapy. Post 3 cycles TP, the patient underwent interval CRS with HITAC. The procedure details are mentioned in
CRS with HITAC is a complex and evolving procedure. These are viable treatment options for cases of ovarian carcinoma with peritoneal carcinomatosis and pleural disease in the post neoadjuvant chemotherapy setting. Macroscopic disease can be removed with CRS and the remaining microscopic disease can be dealt with through HITAC to reduce thoracic recurrences. In this study, there were no life-threatening surgical morbidities. No mortality was recorded till the last follow-up. Following the technique described in this study, CRS with HITAC can be safely performed and replicated easily without additional morbidity or need for extra resources for HITAC. However, multicenter studies with larger numbers of patients and longer follow-up is warranted to establish reproducibility and acceptance of the procedure.
We like to acknowledge our head of department Professor (Dr.) S V S Deo, DR BRA-IRCH, AIIMS, New Delhi for constant support and inspiration. The acknowledgment extends to all faculty and senior residents of the Department of Surgical Oncology and Department of Onco-anesthesia and Palliative Care for intraoperative and postoperative patient care.
Substantial contributions to the conception or design of the manuscript, writing manuscript, revising it critically for important intellectual content and to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the manuscript: Ray MD
Data collection, data analysis, data curation, drafting the work, manuscript writing, editing, conceptualisation, technical and material support, study supervision, revising it critically for important intellectual content and proofreading with final approval of the manuscript version to be published: Kumar N
Data collection, data analysis, drafting the work, manuscript writing, drawing pictorial depiction and formatting, editing, provided technical, and material support: Kuppusamy R
Manuscript writing and final approval of manuscript version to be published: Garg R
Have read and approved the manuscript: Ray MD, Kuppusamy R, Kumar N, Garg R
The data (operative pictures, further case details, follow up data) to support the findings of this study are available on request from the corresponding authors.
None.
All authors declared that there are no conflicts of interest.
The study has been performed following the “Declaration of Helsinki” and approved by the “institutional ethics committee, AIIMS, New Delhi, India” vide reference no: IEC-592/03.11.2017, AA-3/29. Informed consent to participate in the study has been obtained from participants.
Not applicable. No identifying images or other personal or clinical details of participants are presented in the manuscript that compromise anonymity.
© The Author(s) 2020.