Rau/Glehen/Sugarbaker: With the Results of PRODIGE 7 Published, Is HIPEC No Longer to Be Used for Treatment of Peritoneal Metastases from Colorectal Cancer?Choudry

The role for HIPEC in colorectal cancer remains unclear/unanswered despite the publication of PRODIGE 7. Despite the importance of the study and the tremendous efforts of the team involved, there are a number of flaws in the trial that have been discussed and written about at length (e.g., drug used, HIPEC duration, primary endpoint selection, overly optimistic predicted improvement of survival with HIPEC, etc.). HIPEC has a number of components (drug, duration, etc.) that can impact its efficacy (e.g., HIPEC has shown benefit in randomized trials for other histologies using different drugs and timing of HIPEC compared to PRODIGE 7). Further studies are needed, but at this time, I feel HIPEC should still be offered for peritoneal metastases from colorectal cancer.

Yonemura

I continue to use HIPEC for colorectal peritoneal metastases. I have two important problems in the setting of PRODIGE 7. One is the temperature in the PRODIGE 7 trial. Temperature in HIPEC used in PRODIGE 7 was 43°C, and the treatment time was only 30 min. I seriously doubt that a 43°C temperature was uniformly maintained throughout the entire abdomen and pelvis, especially in the small bowel regions. Thermal dose is the index for damage of cells by heat [1]. In reality, the likelihood of an optimal thermal dose delivered in 30 min in all patients is small.

After treatment of cells by 43°C for 60 min, 90% of cells could be killed by heat alone. Schaaf et al. [2] reported that a temperature of 40°C appears to be a critical threshold for potentiating cytotoxic chemotherapy in vitro and in peritoneal carcinomatous in patients undergoing HIPEC. However, thermal dose by 40°C for 30 min is less than 2.0 min and will kill less than 10% of cancer cells. The thermal dose delivered by HIPEC in PRODIGE 7 is insufficient for eradicating residual micrometastasis left after cytoreductive surgery (CRS).

The second problem is the drugs used in PRODIGE 7. We studied in vitro chemosensitivity test in 84 peritoneal metastases from colorectal cancer. Oxaliplatin showed low sensitivity against peritoneal metastasis from colorectal cancer in patients already treated with oxaliplatin-based neoadjuvant chemotherapy. Good chemosensitivity was found in 67% (16/24) of tumors that were not treated with nonoxaliplatin-based NACT but was only 39% (10/51), treated with oxaliplatin-based neoadjuvant chemotherapy (NACT) (p = 0.046). However, there was no relation in mitomycin C chemosensitivity between oxaliplatin-based NACT and nonoxaliplatin-based NACT.

In vitro, chemosensitivity test showed good sensitivities against docetaxel and gemcitabine. From these results, mitomycin C or other drugs except oxaliplatin should be used for HIPEC after NACT. We now use docetaxel in HIPEC for peritoneal metastases from colorectal cancer.

Morris

Incorrect, it has an important role.

Stintzing

PRODIGE 7 is the first randomized study investigating the use of HIPEC in addition to a complete peritoneal resection. The primary endpoint was not met. Reasons are manifold and need to be further investigated. Therefore, we are using HIPEC in addition to a complete cytoreduction (CCRS) or PIPAC if CCRS cannot be achieved. In comparison to PRODIGE 7, we use different dosing and timing schedules for HIPEC.

Ryan

I do not recommend the addition of HIPEC to cytoreductive surgery for the management of metastatic colorectal cancer based on the PRODIGE study.

Rau/Glehen/Sugarbaker: With 8 Single Institution RCTs Published for Prophylactic Treatment of Serosal-Positive Gastric Cancer, Should HIPEC Be Recommended in This Clinical Scenario Prior to the Results of GASTROCHIP RCT Being Published?Choudry

Currently, prophylactic HIPEC should be offered as part of a clinical trial or prospective registry. While the published data are promising in terms of potential reduction in peritoneal recurrence and perhaps improvement in survival, these data are predominantly from Asian populations that have different tumor biology, are mostly older studies prior to implementation of the more effective modern multidrug chemotherapy regimens, often include patients with positive cytology (which has a worse prognosis than serosal-positive gastric cancer only) or fail to assess cytology status. The GASTROCHIP RCT will help inform this discussion in a non-Asian population.

Yonemura

According to the reasons mentioned in the answer of question 1, we are performing 43°C-40 min. HIPEC for gastric cancer peritoneal metastases and after CCRS resection for T3, T4 curable gastric cancer patients for the prophylaxis of peritoneal recurrence.

Morris

Yes.

Stintzing

The data in gastric cancer is different from colorectal cancer. We therefore recommend due to the existing data HIPEC in addition to CCRS in gastric cancer.

Ryan

I do not think that HIPEC can be recommended for gastric cancer prior to the results of RCTs.

Rau/Glehen/Sugarbaker: With the Data Currently Available for Treatment of Peritoneal Metastases from Gastric Cancer with PCI <10, Do You Currently Recommend HIPEC for Gastric Cancer at Your Institution?Choudry

At my institution, we offer CRS/HIPEC to a small subset of highly selected patients with resectable gastric cancer (preferably not needing a total gastrectomy), PCI <10 or positive peritoneal cytology, near-complete or complete response of the primary cancer and peritoneal metastases/cytology to a prolonged duration of systemic therapy (>6 months), no imageable peritoneal disease/ascites, and have a good performance status.

Yonemura

We finished a RCT for peritoneal metastases from gastric cancer to confirm the survival effects of HIPEC. Two-hundred and 66 patients were treated with neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), using oral S1 (60 mg/m2) for day 1–14 and intraperitoneal docetaxel 40 mg plus CDDP 40 mg total dose on day 1 and 14. One month after 3 cycles of NIPS, 239 patients were selected for CRS by laparoscopy or CT/MRI. These patients were randomly allocated into CRS plus HIPEC and CRS alone group. There was no statistical significance in clinicopathologic parameters including CCRS rates, PCI, cytologic status, age, gender, lymph node status, and histologic type between HIPEC and non-HIPEC group. HIPEC was performed at 43°C, 40 min using 40 mg of docetaxel and CDDP. Thermal dose was higher than 40 min in all patients of HIPEC group. Additionally, no significant difference in postoperative morbidity and mortality rates was found between the two groups (Grade 3–4 morbidity of 21.3% and 26.8% in the non-HIPEC and HIPEC group and Grade 5 mortality rates of 1.2% and 2.5%, respectively).

Median survival time of non-HIPEC and HIPEC group was 15.6 and 17.6 months, respectively. Five-year survival rates were 6.7% and 16.4% (p = 0.035). The results were reported in PSOGI meeting in Beijing, 2021, and were accepted in 14th IGCC 2022 Houston. However, results are not published yet.

From this evidence, we are treating gastric cancer patients with peritoneal metastases by NIPS + CRS + HIPEC. Essential point for better prognosis is performing CCR-0 resection because significant survival difference was found in patients of CCR-0 resection. There was no statistical survival difference in patients receiving CCR-1 resection between HIPEC and non-HIPEC group. We are now performing a RCT trial consisting of 42°C and 43°C HIPEC after 3 cycles of NIPS and CRS.

Morris

Yes.

Stintzing

Yes.

Ryan

No, I do not recommend HIPEC for gastric cancer at my institution.

Rau/Glehen/Sugarbaker: Can PIPAC Be Recommended outside of a Clinical Trial for Colorectal, Gastric Cancer, or Ovarian Peritoneal Metastases?Choudry

Currently, PIPAC should only be offered as a palliative therapeutic option for unresectable peritoneal metastases as part of a clinical trial or prospective registry.

Yonemura

Alyami et al. [3] reported that adverse events greater than grade 2 after NIPS occurred after 12–15% of procedures. An objective clinical response of 50–91% was reported for patients with gastric cancer (median survival of 8–15 months). PIPAC was safe and objective response, and quality of life was encouraging. Therefore, PIPAC can be considered as a treatment option for refractory, isolated peritoneal metastasis.

Different from HIPEC, PIPAC effects on cancer cells comes from only chemotherapeutic drugs. Accordingly, PIPAC will only attack cancer cells in the proliferating phase.

In contrast, HIPEC may be more effective than PIPAC because heat not only attacks cancer cells by enhancing cell killing effects of chemotherapeutic agents but also kills cancer cells by heat alone, when heat is higher than 43°C and treatment time is longer than 30 min. So, I speculate that HIPEC is more effective on cancer cells than PIPAC. Accordingly, an RCT should be performed to clarify the survival benefit by PIPAC.

Morris

Perhaps if they are outside the criteria for HIPEC.

Stintzing

Unfortunately, the number of patients and entities is larger than the open trials. With PIPAC as a new and emerging technique, centers need to use this technique to control tumor symptoms like ascites. The influence on overall survival is unclear and needs to be evaluated.

Ryan

It should be restricted to clinical trials.

Rau/Glehen/Sugarbaker: What about Long-Term Intraperitoneal Chemotherapy Often Referred to as NIPEC (Normothermic Intraperitoneal Chemotherapy)? What Is Your Assessment of NIPEC as a Treatment Option for Established Peritoneal Metastases? Can This Approach Be Used at Your Institution?Choudry

While my institution has not adopted NIPEC, the theory behind NIPEC-long term and the data for long-term neoadjuvant and adjuvant NIPEC are promising. My institution has not adopted this strategy so far but would be willing to offer this as part of a trial or prospective registry.

Yonemura

We previously compared the PCI reduction by 1 time of laparoscopic HIPEC (LHIPEC) and by 3 cycles of NIPS. Dosages of docetaxel and CDDP used in LHIPEC and one cycle of NIPS were the same [4]. PCI reduction by 1 time of LHIPEC was 1.85 and by 1 time of IP docetaxel and CDDP was 0.39. Accordingly, LHIPEC has 4.74 times higher power than one cycle of IP chemotherapy. From these results, I recommend intraoperative HIPEC just after CRS instead of intraoperative IP chemotherapy. To achieve complete eradication of residual micrometastasis just after CRS, I recommend HIPEC rather than NIPEC. If the NIPEC is performed 4 times, the effects of HIPEC and NIPEC may be the same.

Morris

We use EPIC for Appendix tumors.

Stintzing

Rarely used as HIPEC is preferred. Peritonitis is always a clinical problem.

Ryan

This should be restricted to clinical trials for patients with gastrointestinal cancers.

Rau/Glehen/Sugarbaker: There Is a Vast Proliferation of Targeted Therapies for Gastrointestinal and Ovarian Cancer. Is It Advisable to Pursue Further Clinical Trials with Intraperitoneal Chemotherapy? Or Have Promising Systemic Therapies Made Research with This Regional Approach Uninteresting?Choudry

Regional intraperitoneal delivery of therapy remains a promising strategy with unique advantages. Further studies of treatments/drugs (cytotoxic, targeted, immuno, etc.), formulations (drug solution, nanoformulations, etc.), and delivery (tumor targeting) are needed.

Yonemura

Clinical trials such as RCT need a long-time and consume money for accomplishment. I doubt that a multi-institutional study will succeed when the trial has many risks. If we start a RCT to confirm the effects of targeted therapies combined with CRS, the study should begin at institutions with experienced surgical oncologists and a multi-professional team. Of course, I am awaiting promising systemic chemotherapy or immunotherapy. Unfortunately, chemotherapy and molecular targeting therapy currently used have limitations for cure. If we have more effective treatment with high fractional kill higher than 99% for residual micrometastasis, the prognosis after NACT, CRS plus HIPEC with combination of these drugs could dramatically improve the survival of peritoneal metastasis.

Morris

We need much more research on intraperitoneal chemotherapy. I do not believe systemic therapy will reduce the need for CRS/HIPEC.

Stintzing

Absolutely, the clinical problem of peritoneal metastases derives from symptoms and the difficulty to assess the burden of peritoneal metastases over time. HIPEC enables us to (a) diagnostically investigate the burden of peritoneal metastases and (b) adds a treatment option in addition to the systemic treatment.

Ryan

There are settings where clinical trials are appropriate, and I would be supportive.

Rau/Glehen/Sugarbaker: The PRODIGE 7 RCT Limited Enrolment of Colorectal Peritoneal Metastases Patients to Those with No Symptoms and No Progression by CT. Most Patients, in Practice, Come from the Medical Oncologist because They Are Symptomatic or Show Disease Progression as Systemic Chemotherapy Is failing. Are These Patients Still Considered for CRS and HIPEC or Are They Ineligible?Choudry

In general, patients with significant symptoms (related to diffuse peritoneal metastases and not the primary tumor itself) or those with significant progression on chemotherapy (except for enlarging ovarian metastases) are not considered for CRS/HIPEC. However, we do make case by case decisions and may offer CRS/HIPEC for mild-moderate symptoms (vague abdominal complaints without multifocal obstructive issues) and those with limited progression on chemotherapy if other patient selection criteria are not prohibitive (e.g., lower grade, lower PCI, CCR-0 resection achievable at laparoscopic staging, good performance status, mucinous histology, etc.).

Yonemura

These patients are still candidates for CRS when diagnosed to perform CCR-0 resection because CCR-0 resection is the most powerful prognostic factor. Patients for CRS should be selected by PET, CT, or laparoscopy. Another selection criterion is PCI level. PCI should be less than the threshold level. PCIs of 21 and 10 in colorectal and gastric cancer are our threshold level because patients with PCI higher than threshold level have poorer prognosis even after CCR-0 resection. Patients with PCI less than threshold levels may be potentially curable after CCR-0 resection plus HIPEC [5].

If we treat the patients with no symptoms or patients in PR/CR status by a comprehensive treatment, we have a more favorable prognosis. At present, we are treating patients already treated with several systemic chemotherapy and/or molecular targeting drugs, like Bevacizumab or monoclonal antibodies. These tumors have drug resistance against the chemotherapeutic agents, already used. When we treat such patients, drugs for HIPEC should be different than drugs except drugs used previously.

Morris

Yes, very eligible.

Stintzing

These patients with peritoneal metastases from colorectal cancer are considered for two reasons for HIPEC: (a) limited disease that can be removed CCR-0: to optimize local control (b) patients with symptoms and extensive disease to control symptoms (e.g., ascites).

Ryan

I do not recommend HIPEC outside of a clinical trial for patients with metastatic colorectal cancer.

Conflict of Interest Statement

Beate Rau: No conflicts of interest to declare. Olivier Glehen: Consultant for Gamida. Paul H. Sugarbaker: No conflicts of interest to declare. M. Haroon A. Choudry: No conflicts of interest to declare. Yukata Yonemura: No conflicts of interest to declare. David L. Morris: Co-inventor of BromAc; Director of and a Shareholder in Mucpharm. Sebastian Stintzing: Advisory Role: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda. Honoraria for Talks: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda. Research Funding: Merck KGaA, Pierre-Fabre, Servier, Roche. David P. Ryan: Uptodate; Johns Hopkins University Press; Exact Sciences; MPM Capital; Boehringer Ingelheim.

Chair

Prof. Beate Rau

Klinik für Chirurgie

Universitätsmedizin Berlin

Charité Campus Virchow-Klinikum

Augustenburger Platz 1

13353 Berlin, Germany

beate.rau@charite.de

Prof. Olivier Glehen

Department of Surgical Oncology

CHU Lyon Sud, Hospices Civils de Lyon

Chemin du Grand Revoyet

69495 Pierre-Bénite, Lyon, France

olivier.glehen@chu-lyon.fr

Prof. Paul H. Sugarbaker

Washington Cancer Institute

Program in Peritoneal Surface Malignancy

3629 Fulton St. NW

Washington, DC 20007, USA

Paul.Sugarbaker@outlook.com

Participants

Prof. M. Haroon A. Choudry

Division of Surgical Oncology

University of Pittsburgh Medical Center, Hillman Cancer Center

5150 Center Avenue, Suite 424

Pittsburgh, PA 15232, USA

choudrymh@upmc.edu

Prof. Yukata Yonemura

Peritoneal Surface Metastasis Center

Kishiwada Tokushukai Hospital

4-27-1, Kamori-Cho, Kishiwada City

Osaka, Japan

y.yonemura@coda.ocn.ne.jp

Prof. David L. Morris

Department of Surgery, Peritonectomy Unit

St George Hospital & University of New South Wales

L3 Pitney Building, Short Street

Kogarah NSW 2217, Australia

david.morris@unsw.edu.au

Prof. Sebastian Stintzing

Department of Hematology, Oncology,

and Cancer Immunology (CCM)

Charité - Universitaetsmedizin Berlin

Charitéplatz 1

10117 Berlin, Germany

sebastian.stintzing@charite.de

Dr. David P. Ryan

Massachusetts General Hospital Cancer Center

32 Fruit Street

Boston, MA 02114, USA

DPRYAN@mgh.harvard.edu

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