Uncommon indications for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Patient demographics

Median age for all patients was 46.5 years (range: 19–70), and there were seven female and three male patients. The median follow-up was 14 months (range: 2–100).

Tumor biology

The median disease-free interval from the date of surgery for the primary tumor to diagnosis of PM was 18 months (range: 7–70). The median PCI was 9 (range: 2–18) and complete cytoreduction with a CC-0 was achieved for all patients.

The median time to recurrence from CRS and HIPEC was 16.0 month by Kaplan–Meier estimate. The patients with SLCT (Patient 2) and endometrioid adenocarcinoma (Patient 9) went on to have one repeat CRS and HIPEC and currently, both remain disease-free, while one patient with SLCT (Patient 1) had two subsequent CRS and HIPEC and is alive with disease. Detailed patient and tumor characteristics can be found in Table 1 and patient outcomes and survival data can be found in Table 2.

Peri-operative details

The median duration of CRS, including 60 minutes of HIPEC, was 317.5 minutes (range: 200–500). HIPEC was performed for all patients. The median blood loss was 550 mL (range: 200–2500) and five patients (Patients 3, 6, 7, 8, 10) required intra-operative blood transfusions.

Median length of hospitalization was 15.5 days (range: 8–87). Only 4 patients (Patients 1, 7, 8, 9) required an intensive care unit (ICU) stay, with a median of 1.5 days (range: 1–12). Additional operative details are presented in Table 3.

Peri-operative morbidity

Seven patients suffered from post-operative complications, of whom only 2 experienced high-grade (grade 3–5) complications. Of the 2 patients with high-grade complications, one (Patient 7) suffered from acute tubular necrosis requiring temporary renal replacement therapy, and respiratory failure secondary to pneumonitis requiring intubation, while the other patient (Patient 8) had a left subphrenic fluid collection, requiring percutaneous drainage and cope loop insertion. Table 4 details morbidity and length of stay for the remaining patients.

Recurrence and survival

At the time of this study, four patients were alive and disease-free, five were alive with disease, and one had succumbed to her disease. None of the patients were lost to follow-up. Median survival was not reached after a median follow-up of 14 months. The Kaplan–Meier curve illustrating the time to recurrence and time to death is presented in Figure 1.

Figure 1:

Kaplan–Meier curve of time to recurrence and death.

Small bowel adenocarcinoma

Small bowel cancers are rare, accounting for about 1 % of all gastrointestinal cancers, with adenocarcinoma making up about 45 %, the others being carcinoid, lymphomas, and sarcomas [13, 14, 15].

Small bowel cancers typically present with vague symptoms similar to a myriad of diseases (e. g. epigastric discomfort, anemia, weight loss), which in turn results in a delayed presentation and diagnosis. These patients often have a poor prognosis. The most common recurrence pattern in small bowel cancers is in the peritoneum [14]; however, there have been few reports on the management of recurrent cases [16, 17, 18]. The EVOCAPE 1 multicenter study showed natural progression of PM from non-gynecological cancers treated with palliation as having mean and median overall survivals of 6 and 3.1 months respectively [19].

There have been a number of reports of CRS and HIPEC for the treatment of small bowel cancers; however, all are limited by the small number of patients, due to the rarity of these cancers as a whole. Marchettini and Sugarbaker reported six patients with a median survival of 6 months after CRS and HIPEC, with two patients achieving prolonged survival of 57 months [17]. In 2015, van Oudheusden et al. reported 16 patients with small bowel cancer undergoing CRS and HIPEC, and a median overall survival of 31 months, although median disease-free survival was only 9.5 months [25]. A larger study by Elias et al. reported 31 small bowel patients with a median survival of 47 months and 3-year survival of 50.7 % [26]. While we are unable to report an overall survival for the two cases (Patients 3 and 4) in our study, the time to recurrence of 6 and 16 months observed correlates with these studies. Neither had repeat CRS or HIPEC done and both are alive with disease, having survived 20 and 10 months from their CRS and HIPEC, a significant improvement from the reported median 3.1 months with palliation alone.

The limited literature for small bowel cancer suggests that CRS and HIPEC can offer improved survival rates with maintained quality of life in carefully selected patients. The combined benefits of CRS and HIPEC with adjuvant therapy in treating small bowel cancer are yet unknown but are a potential avenue for better outcomes; studies with palliative chemotherapy used in metastatic small bowel cancer suggest improved mortality and increased overall survival [27, 28, 29].

Sertoli-Leydig cell tumor

Ovarian sex cord-stromal tumors are rare, comprising only 1.2 % of all primary ovarian cancers [30], with SLCT making up only 0.5 % of all ovarian neoplasms [31]. SLCT can contain heterologous elements and the presence of non-epithelial correlates with a malignancy rate of 20 % and poor prognosis [32, 33]. Most SLCT are confined to the ovary at the point of diagnosis with less than 20 % demonstrating metastasis or recurrence [32].

Few studies on initial therapy for SLCT have been done, and much less for those with recurrent or metastatic disease. Surgery with complete removal of tumor remains the mainstay of treatment of SLCT, with the addition of chemotherapy if high-risk features (such as high grade, advanced stage, or heterologous elements) or relapse occurs; however, there is no standard therapy [34, 35, 36] and some studies suggest that there is limited benefit in adjuvant chemotherapy after initial surgery [35, 37].

While there is little available data on metastatic and recurrent SLCT, conventional surgeries and systemic chemotherapy are unable to adequately control disease. Sigismondi et al. reported seven patients with recurrent SLCT after primary surgery, with five of the patients dying of disease; median time to recurrence was 14 months (range: 4–98) [35], while Schneider et al. reported 12 out of 44 patients having relapses after primary surgery, of which seven had loco-regional recurrence [36]. With the advantage of direct contact between the drug and tumor in HIPEC, local control of disease may be improved.

There have been few reports of CRS and HIPEC done for SLCT. Honore et al. reported one patient with a median PCI of 11 and who remained disease-free after more than 8 years at time of publishing [23]; the authors suggested that CRS provides benefit while HIPEC is still debatable. Hayes-Jordan et al. reported one SLCT who died of disease 5 months after CRS and HIPEC; however, there was no active tumor seen at the time of operation [38]. The two patients in our study show good outcomes with repeat CRS and HIPEC, with one patient surviving beyond 5 years although disease is present, while the other remains disease-free 10 months after her initial CRS and HIPEC.

Our two patients with SLCT were young (aged 19 and 39 years) and had good performance status (ECOG 0) when they presented for CRS and HIPEC. Patient 1 underwent a total hysterectomy and bilateral salpingo-oophrectomy for the primary disease and recurred in the pelvis 32 months later, which was treated with a low anterior resection and appendicectomy; she recurred for a second time in the peritoneum 18 months after, where she presented for CRS and HIPEC. Patient 2 had a right salpingo-oophrectomy and recurred 10 months later in the right iliac fossa and mesentery, prompting CRS and HIPEC. Time to recurrence from the first CRS and HIPEC was variable in both cases, concurring with Sigismondi et al., but both our patients remain alive. Patient 1 had five recurrences and had undergone three CRS and HIPEC but has been alive for more than 5 years since the first CRS and HIPEC. The time to recurrence between her operations had become progressively shorter, with 29 months between the first two CRS and HIPEC, then 15 and 11 months respectively. A tumor board decision was made for palliative chemo- and radiotherapy at her fifth recurrence. Patient 2 has recurred twice and undergone two CRS and HIPEC and remains alive without evidence of disease.

More studies are required to elucidate the optimal treatment for recurrent and metastatic SLCT, but CRS and HIPEC should be offered to the carefully selected patient at centers that routinely do such procedures.

Ovarian granulosa cell tumor

As with SLCT, OGCT is an ovarian sex-cord stromal tumor and account for a small percentage of all ovarian neoplasms. OGCTs tend to exhibit less malignant activity than most ovarian carcinomas and tend to have a more indolent course, with local recurrence occurring many years after the initial diagnosis and surgery [39]. They are characteristically detected at an early stage, which correlates to better survival rates [39, 40]. Optimal treatment and follow-up protocols have not been established due to rarity and indolent course of this disease.

Lee et al. described 10 patients whose mean time to recurrence was 48 months (range: 4–109), with multivariate analysis showing that adjuvant chemotherapy was not statistically significant [40].

Canbay et al. reported a median time to recurrence of 4.7 years, while Al-Badawi et al. reported six patients who were still alive and disease-free at publishing with a mean follow-up of 27 months [41, 42]. A Korean study in 2008 showed a median time to recurrence of 75 months (range: 55–137) and found that the liver and bowel were the most common extra-pelvic sites of metastasis, suggesting abdominal and pelvic surveillance was absolutely necessary after initial surgery [43].

The case we reported (Patient 8) was in keeping with the natural progression of OGCT being indolent and presenting with late recurrence patterns [39, 40, 43]. Her first recurrence was 5.9 years after her initial surgery, and she was treated by a resection of the solitary retroperitoneal metastasis. She recurred again 3.3 years later and was then treated with CRS and HIPEC. The next recurrence happened 5 years later, and she died 3 years after that from advanced OGCT, surviving 8 years after her last CRS and HIPEC.

There is conflicting evidence for significant factors for recurrence; however, both stage and residual disease seem to be the most likely relevant factors associated with local recurrence [40, 43]. Hence CRS and HIPEC should be investigated as a modality of treatment of OGCT, especially so for those with local recurrence, as the goal of CRS and HIPEC is the eradication of all visible disease and treatment of microscopic disease with HIPEC.

In treatment of OGCT with CRS and HIPEC, Gouy et al. reported seven patients who had a median follow-up of 32 months and discouraged the use of oxaliplatin-based HIPEC for OGCT [44].

Other etiologies

CRS and HIPEC done for PM from other uncommon primary tumors are still rare; however, consideration is increasing as seen in Table 5. Data for ovarian TCC, endometrioid adenocarcinoma, and endocervical adenocarcinoma remains limited in the literature.

However, there are an increasing number of studies looking at CRS and HIPEC in sarcomas [2, 3, 20, 22, 24] in particular. Sarcomas treated with HIPEC had a median overall survival of 21 to 39.6 months [2, 3, 22] with Randle et al. reporting a similar survival to pre-HIPEC data, throwing into question the utility of HIPEC [22].

Limitations

We acknowledge that few conclusions can be made from a small series of 10 patients with differing histologies. However, we believe that this study adds to the current literature regarding rare indications for CRS and HIPEC.