Programme for Primitive and Secondary Tumours of the Peritoneum-Peritoneal Carcinamatosis

The primitive forms of peritoneal tumour (i.e. tumours whose onset occurs primitively in the peritoneum) would seem rarer than secondary ones (metastatic, i.e. resulting from the dissemination of other tumours). Among the most common forms of primitive peritoneal tumour we include peritoneal mesothelioma and the primitive tumour of the peritoneum.

Programme

 

Peritoneal cancer (dissemination of cancer cells within the peritoneal cavity) of colorectal, ovarian and gastric origin are the most common secondary form originating from intraperitoneal viscera.

Once considered the terminal stage of disease permitting only palliation, currently peritoneal cancer is identified rather as a loco-regional disease for which potentially curative therapies are potentially feasible.

 

The multidisciplinary approach

 

The treatment of peritoneal tumours is discussed in the various Interdisciplinary Care Groups (GIC)  on the basis of the primitive disease (e.g. gynaecological GIC in the event of peritoneal metastases from ovarian cancer, Gastrointestinal GIC in the event of carcinomatosis of gastrointestinal origin). Within the GICs surgeons, oncologists, gastroenterologists, radiologists, radiotherapists, nuclear medicine specialists, specialists in pain-relief therapy and other expert figures collaborate synergistically. Any admission is at the discretion of the relevant specialist sector on the basis of the course of therapy agreed upon (thus, oncological surgery where surgical intervention is opportune).

 

Diagnosis-treatment

 

Symptomatology is often tardy and linked to intraperitoneal diffusion of the disease: in most cases it is a question of a worsening clinical picture with the presence of ascites, increase of abdominal circumference, widespread abdominal pains, alterations of the intestine and breathing difficulties.

The appearance of such symptoms warrants a specialist assessment in order to provide any necessary further diagnostic investigations and, in the event of diagnostic confirmation, intervention.

Surgical treatment

Success in the treatment of peritoneal cancer is founded on correct patient selection, appropriate technical-surgical skills and post-operative management, characteristics to be found exclusively in a centre of excellence for the therapy of the spread of this particular disease.

For roughly the last 20 years, the evolution of techniques and the existence of increasingly innovative therapeutics have made it possible to treat peritoneal cancer more effectively. This approach provides for the combination of surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), a complex procedure based on two specific moments: the surgical removal of all tumour matter through the peritonectomy and a subsequent “washing” of the abdominal cavity with chemotherapeutic agents in high  concentrations to attack free cancer cells^(1-3).

The purpose of surgical cytoreduction is to remove all macroscopic peritoneal tumour matter: this derives from the limited penetration power of the chemotherapeutic agents currently in use within the neoplasm, of the order of a few millimetres⁽⁴⁾. This technique consists of two procedures:

- exeresis of the primitive tumour and loco-regional lymphadenectomy;

- exeresis of organs affected by secondary tumours.

When an organ is affected by carcinomatosis, as a rule, removal is undertaken; therefore, splenectomy, cholecystectomy, gastric resection/gastrectomy, hysterosalpingectomy, resections of the small intestine, colic resections including the anterior rectal resection, are the forms of exeresis, variously associated, which are most frequently performed.

The peritonectomy, a now-standard procedure codified for the first time by Sugarbaker, provides for the total or partial removal of the pelvic, lateral, central and diaphragmatic peritoneum where affected by disease^(5-6). Peritonectomy is indicated when there is a reasonable possibility of obtaining an operative field free from macroscopically evident neoplasm, above all if used as a part of a strategy which foresees the use of HIPEC after cytoreductive surgery. It is a proven fact, indeed, that non-radical interventions performed by non-expert surgeons, above all if not followed up with HIPEC, may contribute to the implantation of neoplastic cells in the location from which the peritoneum has been removed, with consequent recurrence of neoplasm in deep-seated positions⁽⁷⁾.

At the end of the surgery phase,  intraperitoneal chemotherapy is undertaken. The procedure is performed in 60 – 90 minutes at a temperature of roughly 41-42°C with the use of different drugs and dosages according to the protocol chosen. Given the presence of the peritoneal-plasmatic barrier, administration of intraperitoneal chemotherapy permits an increase of drug concentrations which go from 20 to 1,000 times greater than the plasmatic levels. The intraperitoneal treatment is based, in fact, on the characteristic of certain drugs of not going beyond the peritoneum. The free neoplastic cells in the abdomen are scarcely  accessible to the agent infused intravenously; moreover, heat has a greater toxic effect on neoplastic tissue compared to healthy tissue, increased further by anomalous vascularization of the malignant tumour. The mechanisms of action of hyperthermia are:

- increased penetration of the chemotherapeutic agent into the tissues;

- inhibition of RNA synthesis;

- structural and functional alteration of the cytoplasm and of the cancer cell nucleus , as a consequence of lysosomal activation, facilitated by the relatively more active anaerobic glycolysis in neoplastic cells.

All this is possible also thanks to the biology of the tumour; in fact, some neoplasms such as the aforementioned ovarian, appendicular and peritoneal origin ones, have the distinctive feature of remaining  confined for long periods in the abdominal cavity, without creating metastases in distant organs.

HIPEC is, however, only effective if preceded by aggressive surgery which has left minimal residue of disease or, better, no disease at all. It is now proven, in fact, that surgery performed by non-expert surgeons has a significant negative influence on the prognosis.

Pseudomyxoma Peritonei

Results also depend on disease type: in the past, Pseudomyxoma Peritonei (PMP), a rare neoplasm originating in the appendix, was treated with repeated debulking with unsatisfactory results; most patients relapsed with the subsequent need for increasingly demanding surgical operations due to adherences and to the distortion of the original anatomy. Patients suffering from PMP who have undergone debulking have displayed rates of survival at 5 years of roughly 6% associated with a perioperative mortality rate of 2.7%^(8-9). As Sugarbaker's pioneering work shows, the combined approach of surgical cytoreduction and HPEC has become the gold standard in the treatment of PMP with survival rates at 10 years close to 80%.^(10-12)

Peritoneal Mesothelioma

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of peritoneal cancer deriving from mesothelium; the incidence of this neoplasm is steadily increasing, in line with its pleural form, due to exposure to asbestos. DMPM is a tumour which is not generally responsive to systemic chemotherapy; the most significant impact of this treatment rests in the possibility afforded to permit a greater secondary surgical cyto reducibility in patients unsuitable in the first instance for cytoreduction and HIPEC.^(13,14)

As early as 2006, the Consensus Conference of the PSOGI (Peritoneal Surface Oncology Group International) concluded that the standard treatment for peritoneal mesothelioma is represented by surgical cytoreduction combined with HIPEC and systemic chemotherapy.¹⁵ The literature shows that we have passed from a global survival of roughly 12 months with systemic chemotherapy alone to over 50 months with the combined approach of cytoreduction + HIPEC + systemic chemotherapy.^(16-17)

Peritoneal carcinomatosis of Colorectal origin

As regards carcinomatosis of colic origin, it is now possible through new therapeutic regimes to achieve a median survival of roughly 24 months, meaning that peritoneal diffusion of this neoplasm alone represents an entity biologically distinct from the other methods of metastization.⁽¹⁸⁾ A recent meta analysis reports a median survival of almost 30 months associated with an interval free from disease of 13.1 months in selected patients treated with cytoreduction and HIPEC⁽¹⁹⁾. These results have meant that this combined approach has been included in the AIOM 2016 guidelines which state: “cytoreductive surgery and hyperthermic intraperitoneal chemotherapy implemented in high-volume expert centres, may be employed in patients with isolated peritoneal cancer”⁽²⁰⁾.

Peritoneal Carcinamatosis of Ovarian origin

Epithelial ovarian cancer is the most lethal of the gynaecological neoplasms, inasmuch  as it is paucisymptomatic at onset and is diagnosed in most cases in stage III/IV. The treatment of advanced ovarian cancer is based on two basic tenets: optimal surgical cytoreduction together with systemic chemotherapy. The characteristics of the spread of the disease, equally in its first manifestation as in its recurrence, have led this disease and the peritoneal cancer associated  thereto to be considered the ideal terrain for the locoregional administration of chemotherapeutic agents. The combination of cytoreduction and HIPEC has long been used in patients suffering from recurrences of the disease, but as one recent study reports, this approach also allows excellent results in patients suffering from disease in its first manifestation⁽²¹⁾. For further information see the Programme for Ovarian Cancer.

Medical Treatment

The treatment of peritoneal cancer is, ever more frequently, based on a multimodal  course of therapy which involves the use of systemic chemotherapy as a neoadjuvant therapy or as adjuvant to cytoreductive surgery, above all if associated with locoregional treatments. The development of increasingly effective drugs contributes, in fact, both to reducing the extent of the disease (and thus to increasing the probability of optimal surgical cytoreduction) and to preventing the onset of extraperitoneal disease.

There are no standardized programmes (number of cycles, timing, drugs) for individual neoplasms causing  peritoneal cancer; if this is true for neoadjuvant chemotherapy, it becomes almost impossible to establish standard criteria for the implementation of adjuvant therapy (the choice of drugs, doses, number of cycles is extremely heterogeneous). Against this backdrop, it is indispensable that interdisciplinary groups for specific treatment of specific disease take responsibility, together with the patient, for undertaking a course of treatment agreed upon by all the figures of reference in the field of oncology. 

Support therapy

Patients suffering from peritoneal cancer are supported throughout the stages of their diagnosis and therapy by specialists in palliative care, feeding and nutrition and psycho-oncology.

Experimental therapy

 

A few years ago a new procedure was introduced known as PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy) which involves the administering of the drug into the abdomen in the form of pressurized aerosol. This procedure increases the penetration of the drug within the tissues, enhances its tumoricidal capacities thus allowing the use of reduced dosages. In this case, the drug is introduced into the abdomen through a small surgical access, with short operating times and a brief postoperative hospital stay. This procedure, born with palliative purposes, is proving to be increasingly useful not only in patients who, due to age, associated pathologies or side effects, cannot be subjected to chemotherapy, but also in association with the same systemic treatment^(22-26).

 

Translational Research

 

Pseudomyxoma peritonei is a disease characterized by an extreme genetic intratumoral heterogeneity also during any recurrences ; this is compounded by its difficult and still controversial anatomical-pathological classification with consequent uncertainty in relative treatments. In our Institute an analysis of the genetic pattern of this neoplasm is performed in order to examine its nature and to identify possible personalized therapies.

 

Staff

 

Doctor. Michele De Simone, Oncological Surgery

 

Bibliography

 

 

1. Sugarbaker PH, Van der Speeten K. Surgical technology and pharmacology of hyperthermic perioperative chemotherapy. J Gastrointest Oncol. 2016;7(1):29-44. 

2. Deraco M, Baratti D, Kusamura S, Laterza B, Balestra MR. Surgical technique of parietal and visceral peritonectomy for peritoneal surface malignancies. J Surg Oncol 2009;100:321-328.

3. Shigeki K, O’Dwyer ST, Baratti D, et al. Technical aspects of cytoreductive surgery. J Surg Oncol 2008;98:232-236.

4. Gomez PA, Kusamura S, Baratti D, et al. The intraoperative staging systems in the management of peritoneal surface malignancy. J Surg Onc 2008;98:228-231.

5. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221(1):29-42.

6. Sugarbaker PH. Peritonectomy procedures. Cancer Treat Res. 2007;134:247-264.

7. Zoetmulder FA. Cancer cell seeding during abdominal surgey: experimental studies. Sugarbaker PH ed. Peritoneal carcinomatosis: principles of management. Boston: Kluwer Acad Publisher, 1996; 155-162.

8. Andreasson H, Graf W, Nygren P, et al. Outcome differences between debulking surgery and cytoreductive surgery in patients with pseudomyxoma peritonei. Eur J Surg Oncol 2012; 38:962-968.

9. Jarvinen P, Jarvinen HJ, Lepisto A. Survival of patients with pseudomyxoma peritonei treated by serial debulking. Colorectal Dis. 2010;12:868-872.

10. Sugarbaker PH. Cytoreductive surgery and perioperative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol. 2001;27:239-243.

11. Moran B, Baratti D, Yan TD, et al. Consensus statement on the loco-regional treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei). J Surg Oncol. 2008;98:277–282.

12. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and longterm outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30:2449–2456.

13. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21: 2636-2644.

14. Van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005;23:6881-6889.

15. Deraco M, Bartlett D, Kusamura S, et al. Consensus statement on peritoneal mesothelioma. J Surg Oncol. 2008;98:268-272.

16. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol. 2009;27:6237-6242.

17. Deraco M, Casali P, Inglese PG, et al. Peritoneal mesothelioma treated by induction chemotherapy, cytoreductive surgery and   hyperthermic intraperitoneal perfusion. J Surg Oncol. 2003;83:147-153.

18. Klaver YL, Lemmens VE, Creemers GJ, et al. Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy. Ann Oncol. 2011;22(10):2250-2256

19. Huang CQ, Min Y, Wang SY, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival for peritoneal carcinomatosis from colorectal cancer: a systematic review and meta-analysis of current evidence. Oncotarget. 2017; 27;8(33):55657-55683. 

20. http://www.aiom.it/

21. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018;378(3):230-240. 

22. Nadiradze G, Giger-Pabst U, Zieren J, et al. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with low-dose cisplatin and doxorubicin in gastric peritoneal metastasis. J Gastrointest Surg. 2016;20(2):367-673. 

23. Demtröder C, Solass W, Zieren J, et al. Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis. 2016;18(4):364-371. 

24. Tempfer CB, Winnekendonk G, Solass W, et al. Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study. Gynecol Oncol. 2015;137(2):223-228.

25. Robella M, Vaira M, De Simone M. Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis. World J Surg Oncol. 2016;14:128.

26. Vaira M, Robella M, De Simone M. Single-port access for Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC): technique, feasibility and safety. Pleura and Peritoneum 2016; 1(4): 217–222.