Cytoreduction and HIPEC in the treatment of “unconventional” secondary peritoneal carcinomatosis

Peritoneal carcinomatosis from breast cancer (BC) is rare but carries high morbidity and mortality [30‐32], and no clear guidelines are available regarding the role of CRS with or without HIPEC for those patients [33, 34]. Literature reports are sporadic and only Gusani, one patient in 2008 [1], and Glehen, two patients in 2010 [15], reported PM from BC treated by CRS and HIPEC. Our study provides previously unavailable information on the treatment of women with PM from BC showing that once the correct diagnosis has been established [30], these patients can benefit from treatment and possibly argues against previous reports describing a poor prognosis. In our patients, a median 18 years (range 10–30) elapsed after BC was diagnosed and peritoneal carcinomatosis developed and accords with previous reports describing breast carcinoma as one of the most slowly growing solid tumors given that metastases may appear even decades after the initial diagnosis [34, 35]. Of the five patients treated, four achieved long-term survival, one surviving even for 10 years with good QOL.

Although CRS and HIPEC cannot be proposed as a standard care for patients with PM from primary breast cancer, the survival observed in our small series suggests that in highly selected patients with no extra peritoneal disease and in whom surgery can achieve adequate cytoreduction this combined procedure can offer patients a promising approach for long-term survival.

Management of patients with PM from small bowel adenocarcinoma is unclear with literature reports episodic, even if PM is a frequent manifestation of small bowel carcinoma [36, 37]. Typically, these tumors present after a significant delay in diagnosis for the vagueness of symptoms and imaging difficulty. Prognosis is poor with survival varying from 10 to 40 months. Marchettini and Sugarbaker [38] reported a median survival of 12 months with two of the patients treated with CRS and HIPEC with prolonged survival (57 and 59 months). Chua [39] reported seven cases treated with CRS and HIPEC (mitomycin C and EPIC with 5-FU), with a median disease-free survival of 12 months, and also reported a Kaplan-Meier analysis for a combined group of 19 patients treated with CRS and HIPEC with a median survival of 29 months. Shen et al. [40] reported a median survival of 45 months after treatment with CRS and HIPEC. Another large multi-institutional experience is reported by the French Surgical Association [41], with a median survival for patients treated by CRS and HIPEC of 32 months. In the four patients treated in our Institution, mean survival was 31.2 months, with two patients alive disease-free at 43 and 22 months and two alive with disease at 33 (pulmonary metastases) and at 27 (abdominal recurrence) months. All the series reported show better results when compared to conventional treatments. Moreover, it has to be considered that CRS and HIPEC could represent the only valid surgical option for palliation in obstructed patients, in whom a simple surgical procedure aimed at bowel decompression is often impossible due to small bowel mesentery retraction or for the treatment of associated ascites.

Endometrial cancer is still the most common cancer of the female reproductive tract, and its treatment is surgical, alone or in combination with brachy and/or radiotherapy. Survival rates are approximately 90 % at 5 years [42]. When compared to type I tumors, type II endometrial cancers are more likely to present or develop metastatic disease and have a less favorable diagnosis. In the presence of peritoneal metastases, the management becomes more complex and prognosis is poor, with a median survival not reaching 1 year. Bakrin [43] reported five patients with endometrial cancer treated by this combined modality, with a median survival of 19.4 months. Two patients experienced recurrent disease and died, while three patients are alive disease-free at 7, 23, and 39 months after treatment. Glehen [44] in a multi-institutional review of the French Surgical Association of 1290 patients with peritoneal metastases from various primary tumors reported the treatment of 17 patients with uterine adenocarcinoma and epidermoid carcinoma (4 patients), failing to give specific survival data for this specific group of patients. Delotte [42] in 2014 reported CRS and HIPEC in 13 patients with endometrial cancer. Five patients died of the disease and three are alive with disease at 14, 26, and 28 months, while four patients are alive disease-free at 1, 60, 60, and 124 months. In our Institution, we treated eight patients with a diagnosis of type II UPSC with CRS and HIPEC. In four patients, we observed recurrent disease, and two of them died of the disease at 9 and 13 months, while two are alive with disease at 19 and 26 months. Four patients are alive disease-free at 9, 14, 26, and 33 months. Treatment strategies for stage IV endometrial cancer remain controversial. Some reports highlight the histologic characteristics and extent of the disease as the main prognostic determinants, while others favor the effects of a more aggressive surgical cytoreduction. The long-term survival reported in these observational studies, higher when compared to those reported in literature with conventional treatments, seems to justify a more aggressive surgical attitude with the aim to leave the patients without residual visible disease.

Survival of patients with gastrointestinal stromal tumors (GIST) greatly improved with the clinical use of molecular-targeted therapies [45]. However, the prognosis of imatinib-resistant GIST disseminated to the peritoneum (spontaneously or during surgery) is poor. Accepted conventional treatments including palliative surgery, chemo, and/or radiotherapy are ineffective [46]. As with PM from other gastrointestinal or gynecologic epithelial tumors, a strong rationale favors aggressive locoregional treatment in these patients including peritonectomy procedures combined with HIPEC [47‐48] even if its use is controversial due to the rarity of the condition and the few available published reports [49]. The results of our small series of three small bowel imatinib-resistant GIST treated with CRS and HIPEC (two patients alive disease-free at 34 and 108 months, one patient died of disease at 38 months) are in line with similar reports (Table 2) and compare favorably with historical control groups justifying an effort to optimize treatment of the primary or recurrent GISTosis.

The optimal management of patients with rare and unusual primary tumors metastatic to the abdominal cavity is a matter of intense debate. Systemic chemotherapy for PM improved but remains limited because of poor diffusion of the drugs into the peritoneum. This is why many authors [1, 34, 35, 50‐55] reported small observational series of patients with PM from various unconventional tumors treated by CRS and HIPEC (Table 2). This combined treatment modality has been used in peritoneal metastases from pancreatic, abdominal sarcomas, gallbladder, liver, cholangiocarcinoma, adrenal, urachal, esophageal, and kidney tumors. In a multi-institutional review of the French Surgical Association on 1290 cases of PM from various primary tumors treated with CRS and HIPEC [41], the unconventional indications were 29. Mortality was 4.1 % with a rate of major (grade 3 and 4) complications of 33 %, similar to those reported after other major surgical procedures. Obviously, the numbers are too small to draw any conclusion on survival figures for each specific primary tumor, but an overall median survival of 34 months, with a 5-year disease-free survival of 22 %, compares favorably with survival figures reported in literature of palliative treatments for the same tumors.