Treatment of Peritoneal Surface Malignancies
Preface Tr e a t m e n t o f P e r i t o n e a l S u r f a c e Ma l i g n a n c i e s
Jesus Esquivel, MD, FACS Guest Editor
Ten years have gone by since the first issue on the Management of Peritoneal Surface Malignancies by the Surgical Oncology Clinics of North America. As such, I thought it would be appropriate to start this preface with a summary of the comments, challenges, and future directions outlined by Drs Sugarbaker and Petrelli in the first issue. I will follow with a description of the current articles and, finally, this preface concludes with an analysis of where we are now, a decade later, and where we are headed over the next decade in respect to the current challenge for multidisciplinary management of peritoneal surface malignancies. TEN YEARS AGO
The first issue presented the current state-of-the-art and provided the possible directions for future research over the next decade for peritoneal surface malignancies. Dr Sugarbaker pointed out that there are often disagreements concerning the time at which a clinical research project matures into “standard of practice” but that, in his opinion, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) represented the current standard of practice for patients with Pseudomyxoma peritonei of appendiceal origin as well as for patients with malignant peritoneal mesothelioma. In regards to colorectal cancer with peritoneal dissemination, he mentioned the phase III study by Drs Verwaal and Zoetmulder and commented that this unique trial may stand alone as the only randomized study required in this group of patients. He added that perhaps 15,000 colorectal cancer patients in the United States would be candidates for evaluation for this therapy. In regards to gastric and ovarian cancers, he indicated the need to establish the role of hyperthermic intraoperative intraperitoneal chemotherapy.
Surg Oncol Clin N Am 21 (2012) xv–xviii http://dx.doi.org/10.1016/j.soc.2012.07.006 surgonc.theclinics.com 1055-3207/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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He concluded by stating that it may be recognized that a requirement for change in the standard of practice exists in patients with peritoneal surface malignancy and that what is less clear is the proper choice of perfusion techniques and chemotherapeutic options that will optimize these favorable results. More phase III studies are necessary to establish the knowledgeable use of perioperative intraperitoneal chemotherapy in the adjuvant treatment of gastrointestinal and ovarian cancers and Sugarbaker emphasized that quantitative prognostic indicators are extremely important; they will continue to play a role in the refinement of the most important aspect of this treatment to date, proper selection of patients. Dr Petrelli asked the readers to be careful when distinguishing between standard of care and investigational treatment and recognized that this is sometimes a difficult issue to resolve. He added that what we do know is that the standard of care for patients with peritoneal surface malignancies involves a multidisciplinary team approach. He praised the commitment of all the authors to finding the best treatment for this group of patients and that continued research and development of prospective randomized trials will allow the field to move forward successfully. He outlined four areas for which there is room for research: 1. The proper choice of perfusion techniques and chemotherapeutic options. 2. The amount of heat necessary for an optimal cell kill, which would result in acceptable morbidity and mortality. 3. A simpler and less costly perfusion apparatus. 4. Finding quantitative prognostic indicators that will allow proper selection of patients for therapy. TEN YEARS LATER
This second issue represents once more the state-of-the-art description by experts from around the world on the current status and future directions regarding the management of the most common peritoneal surface malignancies. Much has happened in this last 10 years and the readers will witness through these articles the tremendous efforts around the world dedicated to advance this field of peritoneal dissemination from gastrointestinal and gynecological malignancies. We have included articles that focus on patient selection for multimodality treatments that combine cytoreductive surgery to eradicate all visible metastatic disease to the abdomen and pelvis, coupled with HIPEC to eradicate microscopic residual disease, and the different methods to deliver the heated intraperitoneal perfusion. Readers will become familiar with the steep learning curve for this procedure, the anesthetic challenges as a result of induced hyperthermia in the setting of lengthy operations, and the role of laparoscopy in evaluating patients for cytoreductive surgery and treating intractable ascites. Additional articles describe the important contribution of pharmacodynamic and pharmacokinetic data to the science of HIPEC; the need for replacing histological examinations with genetic signatures in order to select patients better for intravenous systemic chemotherapy before, after, or in place of cytoreductive surgery and HIPEC; results from the only prospective randomized study comparing HIPEC versus no HIPEC after cytoreductive surgery in patients with gastric cancer with peritoneal dissemination; the ongoing prospective randomized studies and the incredible frustration with trying to conduct such trials; an excellent article on ovarian cancer, the ultimate biological model to study HIPEC; and, finally, an article with a suggestion for intriguing roles for HIPEC in the prophylactic setting.
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ANALYSIS OF 2003 AND 2013
There is no doubt that the number of patients that are experiencing a good longterm result from the treatment of their peritoneal surface malignancy in 2013 is far superior to the number in 2003. Another uncontested statement is the fact that this difference is for the most part due to improvements in CRS and HIPEC regarding patient selection, operative technique, and better ways to deliver the heated perfusion. That being said, numerous important questions remain unanswered. To return to Dr Petrelli’s four points in 2003, there is still tremendous variation when it comes to (1) the proper choice of perfusion techniques and chemotherapeutic options and (2) the amount of heat necessary for an optimal cell kill, which would result in acceptable morbidity and mortality. Progress has been made in (3) simpler and less expensive apparatus to deliver the perfusion and (4) finding quantitative prognostic indicators. Precise preoperative staging is mandatory in neoadjuvant trials to compare treatments, identify subgroups that will benefit the most, and prevent overtreatment in patients who will not benefit from an aggressive surgical procedure. At the present time, our selection criteria remains ill-defined and the biggest challenge in the treatment of patients with peritoneal surface malignancies may well be moving from demonstrating what can be done to learning what should be done. Many of us have done extensive surgical procedures with multivisceral resections and HIPEC in patients with signet ring cell carcinomas of colorectal origin just to find out that the patients did not benefit at all from our operative intervention. Also, at the present time, we accept CRS and HIPEC as a package, without knowing what the added benefit of HIPEC is to a complete surgical eradication of metastatic disease to the abdomen and pelvis. While the ongoing French trial (Prodige 7) will answer this question in a highly selected group of patients, it is going to take a long time before we know the results and, in my opinion, it will not show the expected difference in survival because patients are randomized after having cleared too many hurdles: limited disease, good response to neoadjuvant chemotherapy, and the achievement of a complete cytoreduction. In addition, the choice of HIPEC versus no HIPEC becomes even more important in patients with low tumor burden from a tumor with a low level of biological aggressiveness like P peritonei. Almost everybody agrees that we need prospective randomized trials that compare systemic therapy to CRS 1 HIPEC and trials that compare CRS with and without HIPEC. During this last 10 years, 2 ACOSOG trials have attempted to answer both questions. The first trial was closed in 2004 before it even started and the second trial closed in 2012 because only 1 patient was accrued to the trial in 18 months. In my opinion, conducting prospective randomized phase III trials that compare HIPEC versus no HIPEC, at least in the United States, is a lesson in human nature and unlikely to contribute to evidence-based medicine. Rather, what we need to focus on now is collaboration between medical and surgical oncologists in order to discuss the selection criteria and timing to introduce CRS 1 HIPEC as another therapeutic tool in the individualized, multimodality treatment of colorectal cancer patients with peritoneal dissemination. The American Society of Peritoneal Surface Malignancies (ASPSM) was created in 2009 to facilitate such a collaboration and to try to do the best that we can with what we have and what we know while trying to answer important questions, preferably under the auspices of a clinical research protocol.
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NEXT TEN YEARS
What will happen over the next decade? There will be data on systemic therapy in patients with colorectal cancer with peritoneal dissemination. The Peritoneal Surface Disease Severity Score will become a tool to stratify patients according to the severity of their carcinomatosis. Systemic therapy will continue to improve with numerous “.ibs” and “.abs” coming into the clinical arena; this will increase the number of patients that will be eligible for cytoreductive surgery. The question of HIPEC or no HIPEC after complete cytoreduction will have to be addressed for each individual histology. There will be an increased use of laparoscopy not only to score the severity of the peritoneal dissemination but also to perform the cytoreductive surgery in patients with low tumor burden and to do HIPEC in patients at high risk of developing carcinomatosis. MRI will become the imaging study of choice for patients with mucinous appendiceal neoplasms with peritoneal dissemination. The ASPSM will continue to increase its membership, currently 144 members from 17 countries, and through scientific research collaboration between medical and surgical oncologists and support personnel, the society will lead the development and conduct of relevant clinical trials that will determine the optimal treatment of patients with peritoneal surface malignancies while maximizing benefits and minimizing side effects. Areas that we need to work on over the next decade: 1. Pretherapy staging as precise as possible. 2. Standardization of HIPEC delivery. 3. Incorporation of CRS 1 HIPEC to the treatment armamentarium of patients with peritoneal surface malignancies. 4. Discussions with the medical oncologist regarding timing of CRS 1 HIPEC. 5. Prospective phase II studies that can lead to expert opinion guidelines. In conclusion, I think there is a bright future for Cytoreductive Surgery in the treatment of patients with peritoneal surface malignancies. For now, recognizing that even evidence has its limits, the question of whether HIPEC needs to be added to a complete cytoreduction or not needs to be answered on an individual basis; this answer needs to come from a prospective multidisciplinary discussion at a tumor board conference. Jesus Esquivel, MD, FACS Peritoneal Surface Malignancy Program St. Agnes Hospital 900 Caton Avenue Mail Box 207 Baltimore, MD 21229, USA E-mail address:
[email protected]
