Chemotherapy: HIPEC and IPC

Episode Notes

1. Definitions

1. Intraperitoneal Chemotherapy: IPC

1. Catheters placed at time of cytoreductive surgery > chemo administered as an outpatient

2. Heated Intraperitoneal Chemotherapy (HIPEC)

1. Heated chemotherapy is delivered intraoperatively, and all catheters are removed before closing the abdomen

2. Biologic Rationale

1. Research into intraperitoneal delivery of chemotherapy driven by peritoneal dialysis, which demonstrated that intraperitoneal delivery may allow for more exposure of chemo to the tumor, while decreasing plasma levels and subsequent toxicities

2. Benefits of heating:

1. Heated chemotherapy increases formation of cisplatin-DNA strand adducts > increased cell kill

2. Heated chemo has increased depth of penetration

3. Heated chemotherapy also increases blood flow to tissue/tumor, counteracting the hypoxic tumor microenvironment

4. Heating impairs HRD in cells > increased killing potential

5. Heated chemotherapy stimulates the tumor immune microenvironment (increased CD4, CD8 cell infiltration)

3. Choice of agent

1. Options: carboplatin, cisplatin, paclitaxel (and more agents under study)

2. Cisplatin most common agent utilized in trials with statistical benefit to IPC or HIPEC (i.e. positive trials). Can achieve higher tissue penetration than other agents

4. Trials on IPC in ovarian cancer

1. GOG 104: phase III RCT: stage III ovarian cancer and up to 2cm residual disease after PDS

1. Intervention: IV cyclophosphamide + IV vs. IP cisplatin (100mg/m2) 

2. Results: Median OS: 49 vs. 41m, favoring IP chemo 

1. Reduced ototoxicity and neurotoxicity in IP arm

2. GOG 114: Phase III RCT (similar patient presentation to GOG 104)

1. Intervention: 6 cycles IV taxol/cisplatin q 3 weeks vs. IV carboplatin q4w x 2 cycles followed by 6 cycles IVtaxol/IP cisplatin q 3 weeks

2. Results

1. OS: 52m vs. 63m IV vs. IV/IP arms (p=0.05, considered “borderline improvement” by authors)

2. PFS: 22 vs. 28m IV vs. IV/IP arms

3. Toxicities: higher in IV/IP arm

3. Takeaway: given no clear OS benefit, this regimen should not be recommended

3. GOG 172: Phase III RCT in stage III EOC w/ ≤1cm residual disease after PDS

1. Intervention: IV cis/taxol x6 cycles q 3w vs. IV taxol/IP cis/taxol x 6 cycles q 3w

1. Higher cisplatin dose in the IP arm, and higher dose density for taxol (given combined IV and IP administrations)

2. Results:

1. PFS: 23.8m vs. 18.3m, favoring IV/IP arm

2. OS: 65.6m vs. 49.7m, favoring IV/IP arm

3. Toxicities: increased in IP arm (grade III pain, fatigue, hematologic,metabolic, neurologic)

4. Only 42% of patients in IV/IP arm completed all 6 cycles

4. GOG 252: Phase III RCT, three arms. Patients = stage II-IV EOC with optimal or complete cytoreductive surgery

1. Intervention arms (all six cycles)

1. Dose-dense IV taxol + IV carboplatin q 3 weeks

2. Dose-dense IV taxol and IP carboplatin q 3w

3. IV taxol day 1, IP cisplatin day 2, IP taxol day 8, q3w

4. ALL study patients received bevacizumab q 3 weeks

2. Results

1. ITT population: no difference in PFS or OS

3. This trial is difficult to interpret: investigating dose-dense chemo, IP chemo, and the use of bevacizumab. Also included stage II patients (better prognosis group)

5. IPOCC/JGOG 2019: Conducted in Japan

1. Dose dense taxol + IV vs. IP carboplatin

2. Results: PFS improved in the IP arm, no difference in OS

3. High rates of catheter-related complications in IP arm

6. IPC at the time of IDS

1. Provenchar 2018: Phase II RCT

1. IP carbo + IV and IP taxol vs. IV carbo/taxol

2. Underpowered to detect a difference in PFS; no observed difference

5. HIPEC

1. Up-front setting

1. OV-HIPEC I: phase III RCT, patients with stage III EOC with at least stable disease after 3 cycles NACT (carbo/taxol)

1. Arms

1. HIPEC with cisplatin 100mg/m2

2. No HIPEC

3. All patients subsequently got 3 cycles adjuvant chemo

2. Results

1. HR for recurrence or death: 0.66

2. PFS 14.2 vs. 10.7 months, favoring HIPEC

3. OS 45.7 vs. 33.9m, favoring HIPEC

4. 10-year follow up published 2023: confirmed original findings

2. Antonio et al, 2022: phase III RCT.  NACT > interval debulking +/- HIPEC with cisplatin 75 mg/m2

1. Results: 

1. PFS 18m vs. 12m, favoring HIPEC

2. OS: no significant difference

2. Trial closed early due to low recruitment, was underpowered to detect an OS difference

3. Lim et al 2022: Phase III RCT. HIPEC vs. no HIPEC at PDS OR IDS

1. Results

1. IDS group:

1. PFS 17.4m vs. 15.4m favoring HIPEC

2. OS: 61.8m vs. 48.2m, favoring HIPEC

2. PDS group:

1. OS: 71m vs. not reached, favoring NO HIPEC

2. Takeaway: in the up front setting, HIPEC may be harmful in the PDS setting but improves OS in the IDS setting

2. Recurrent Disease

1. Spiliotis et al, 2015: phase III. recurrent stage IIIC-IV disease.

1. CRS > HIPEC > systemic chemo vs. CRS> systemic chemo

2. Results:

1. OS: 13.4m vs. 26.7m, favoring HIEPC

2. Exploratory analyses: in the platinum resistant group, those receiving HIPEC had worse OS. 

2. Zivanovic et al 2021: phase II trial. 

1. Secondary cytoreductive surgery: patients randomized to HIPEC vs. no HIPEC during surgery

2. Results

1. PFS worse with addition of HIPEC, 15.7m vs. 12.3m, p value 0.05

2. No difference in median OS

3. Mixed: Villarejo Campos et al, 2024: patients at PDS, IDS, or secondary cytoreudction

1. Intervention: HIPEC with taxol vs. no HIPEC > catbo/taxol x 6 cycles for all. N=57

2. No difference in outcomes in any of the surgery subgroups

3. 5-year OS significantly higher in the HIPEC group, despite no difference in median OS or PFS

4. Takeaway: per the NCCN, based on the trial results above, HIPEC with 100mg/m2 cisplatin can be considered in patients undergoing IDS for stage III ovarian cancer

6. Complications

1. IPC

1. Mostly related to indwelling catheter: infection, blockage, leakage, abdominal pain, bowel issues

2. Low rates of treatment completion

2. HIPEC

1. Increased intraoperative time: longer anesthesia time, increased blood loss, higher insensible fluid loss

1. Risk of intraoperative acidosis is associated with increased rate of ICU admission

2. monitor/correct metabolic acidoses

2. Electrolyte disturbances

1. Consider potassium chloride administration if using paclitaxel

2. monitor/replace electrolytes PRN

3. Nephrotoxicity and acute renal failure with IP cisplatin

1. Administer preoperative sodium thiosulfate to prevent

2. Consider preoperative furosemide (controverisal)

4. Hypersensitivity reactions: pre-administer antihistamines

5. N/V: pre-medicate with antiemetics, consider combination with PPI

7. Practical considerations

1. Employ ERAS principles as in other surgeries

2. Routine ICU admission not necessary; postop disposition individualized to patient 

3. Patient selection:

1. Increased risk in patients with hypoalbuminemia/poor nutritional status, renal impairment, hepatic impairment, hematologic aberrations

2. Patients should have optimal cytoreduction; the less disease the better

4. Intraoperative considerations: open vs. closed technique, temperature selection, chemotherapy exposure precautions, duration of administration; no standard regimen

Takeaways: 

1. IPC and HIPEC describe two separate techniques for delivering chemotherapy directly to the peritoneal surface. IPC is performed outpatient after completion of surgery, while HIPEC is heated chemotherapy delivered at the time of cytoreduction, after completion of the surgery, and does not have an outpatient component.

2. The biologic rationale for delivery of intraperitoneal chemotherapy is that the drug may have decreased peritoneal clearance (i.e. better exposure to tumor) while allowing higher concentrations than via IV route. Heating the chemotherapy increases formation of cisplatin-DNA strand adducts, as well as increasing the depth of chemotherapy penetration, impairing homologous recombination, stimulating immune-related tumor killing, and improving oxygenation of the tumor.

3. GOG 104, GOG 114, GOG 172, GOG 252, and JGOG 2019 are all RCTs which evaluated the use of IPC in ovarian cancer. These trials had mixed results; while some of the trials demonstrated improved survival with IP regimens, this wasn’t true in all studies, and there was high toxicity leading to low treatment completion rates.

4. HIPEC at the time of interval debulking surgery following neoadjuvant chemotherapy can be considered for patients with stage III ovarian cancer; the NCCN recommends cisplatin at a dose of 100mg/m2.  The trials that informed this recommendation include OV-HIPEC-I, a trial by Antonio et al in 2022, and a trial by Lim et al in 2022. HIPEC is not recommended at the time of primary debulking surgery currently, and at this time is generally not recommended in the recurrent setting.  Ongoing trials are evaluating changing doses, temperatures, and methods of administration. 

5. Preventable complications with the administration of HIPEC include nephrotoxicity (which can be prevented by administering sodium thiosulfate), electrolyte disturbances and acidosis. It’s important to do careful lab monitoring and repletion of electrolytes as needed. You can also see hypersensitivity and emesis. 

6. HIPEC can be administered with an open or closed technique, and a standard has not been established. Administration of HIPEC requires a specialized setup in the OR and a knowledgeable team. Routine admission to the ICU isn’t generally necessary, and ERAS principles should be applied postoperatively.

References

Reference List

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