Treatment of peritoneal carcinomatosis from breast cancer by maximal cytoreduction and HIPEC: A preliminary report on 5 cases

The Breast 22 (2013) 845e849

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Original article

Treatment of peritoneal carcinomatosis from breast cancer by maximal cytoreduction and HIPEC: A preliminary report on 5 casesq Maurizio Cardi a, *, Paolo Sammartino a, Maria Luisa Framarino b, Daniele Biacchi a, Enrico Cortesi c, Simone Sibio a, Fabio Accarpio a, Claudio Luciani a, Antonella Palazzo c, Angelo di Giorgio a Dipartimento di Chirurgia “P. Valdoni”, Università di Roma “Sapienza”, Azienda Policlinico Umberto I
, Viale del Policlinico 161, 00155 Rome, Italy Dipartimento di Ostetricia e Ginecologia, Università di Rome “Sapienza”, Azienda Policlinico Umberto I
, Viale del Policlinico 161, 00155 Rome, Italy c Dipartimento Scienze Radiologiche, Oncologiche, Anatomopatologiche, Università di Roma “Sapienza”, Azienda Policlinico Umberto I
, Viale del Policlinico 161, 00155 Roma, Italy a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 June 2012 Received in revised form 19 February 2013 Accepted 27 February 2013

Although peritoneal carcinomatosis from breast cancer is a rare event it frequently causes morbidity and mortality. Current literature provides scarce information on its management. We report outcomes in 5 patients (mean age 59.4 years) with peritoneal carcinomatosis from breast cancer treated with maximal cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) by the closed technique, at 40
C for 1 h with cisplatin 75 mg/m2. The primary breast cancer was a ductal carcinoma in 3 patients and a lobular carcinoma in 2. Mean peritoneal cancer index was 20.2. In 4 of the 5 patients surgery achieved macroscopic complete cytoreduction. One patient died of disease at 56 months, 4 are alive and diseasefree at 13, 45, 74 and 128 months. These encouraging outcomes suggest that cytoreduction and HIPEC is a promising approach to offer to highly selected patients with peritoneal carcinomatosis from breast cancer and that this approach merit investigation in a larger series. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Peritoneal metastases Cytoreduction HIPEC

Introduction Breast cancer (BC) remains among the most frequent malignancies in western countries.1,2 The most common sites of haematogenous metastases include bone, lung liver and brain.3e5 As local and systemic treatments improve, breast cancer metastasis patterns change so that metastatic disease now manifests at unusual sites. Among them, peritoneal carcinomatosis is a rare event but one that carries high morbidity and mortality.6e8 No clear guidelines are available regarding the role of cytoreduction with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis from BC,1,9 nor does q The study was presented at the Seventh International Symposium on Regional Cancer Therapies, South Seas Island Resort, Captiva, Florida February 18e20, 2012. * Corresponding author. Via Bolzano 32, 00198 Roma, Italy. Tel.: þ39 06 85352278, þ39 06 49972278; fax: þ39 06 49970685. E-mail addresses: [email protected] (M. Cardi), paolo.sammartino@ uniroma1.it (P. Sammartino), [email protected] (M.L. Framarino), [email protected] (D. Biacchi), [email protected] (E. Cortesi), [email protected] (S. Sibio), [email protected] (F. Accarpio), [email protected] (C. Luciani), [email protected] (A. Palazzo), [email protected] (A. di Giorgio). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.02.020

the literature provide reliable information on these patients’ prognosis, most papers being case reports.6,10e17 Patients and methods From a series of 221 consecutive patients admitted to our Institution from November 2000 to December 2011 with a diagnosis of peritoneal carcinomatosis from various primary tumours and treated by maximal cytoreduction18 and HIPEC we selected for this retrospective review 5 patients who gave informed written consent, had a clear histological diagnosis of peritoneal carcinomatosis from BC, performance status 0e2,19 adequate cardiac, hepatic, renal and bone marrow function, and resectable disease.20 Exclusion criteria were progressive and unresponsive disease, extraperitoneal spread, other malignancies, unresectable disease and active infection or severe associated medical conditions. To rule out the differential diagnosis with a primary ovarian tumour, samples from peritoneal carcinomatosis and primary BC were assayed with an immunohistochemical panel consisting of human epidermal growth factor receptor-2 (HER-2), Wilms’s tumour 1 suppressor gene (WT1), cancer antigen 125 (Ca 125), cytokeratin-7 (CK7), cytokeratin-20 (CK20), oestrogen receptor (ER),

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Table 1 Clinical characteristics related to the primary breast cancer. Patient

Age (years)

Histology

Stage

Surgery

Radiotherapy

Adjuvant chemotherapy

Pt Pt Pt Pt Pt

58 54 55 77 53

IDC ILC ILC IDC IDC

T2 N1 T2N3 T2 N1 M1 (bone) T2 N1 T1 N0

Radical mastectomy Quadrantectomy Radical mastectomy Radical mastectomy Radical mastectomy

No Yes No No No

CMF Refused CMF Refused None

1 2 3 4 5

IDC: infiltrating ductal carcinoma. ILC: infiltrating lobular carcinoma. CMF: cyclophosphamide/methotrexate/5-fluorouracil regimen.

progesterone receptor (PR) and gross cystic disease fluid protein (GCDFP-15). Nuclear staining for WT1 and cytoplasmic staining with the other markers was graded as negative or positive on a scale ranging from 1 to 4þ, according to the percentage of reactive cells (<1%: negative; 1e25%: 1þ; 25e50%: 2þ; 50e75%: 3þ; >75%: 4þ). Tumours in Grade 1þ or more were considered positive. In all cases the histopathological samples allowed us to compare histological features in the primary and secondary tumours. At laparotomy, the extent of peritoneal carcinomatosis was recorded using the peritoneal cancer index (PCI) according to Sugarbaker’s criteria.21 Surgical cytoreduction was then undertaken with the aim to leave the patient with no macroscopically visible residual disease. Depending on the extent of peritoneal carcinomatosis one or more peritonectomy procedures were required.18 Small nodules of scattered peritoneal implants were ablated or excised with highvoltage electrocautery, Tissue-link (BPS 6.0, Dover NH) or an argonbeam coagulator. The completeness of cytoreduction (CC) score was calculated according to Sugarbaker’s criteria (CC0: no visible residual disease; CC1: residual nodules measuring less than 2.5 mm; CC2: between 2.5 mm and 2.5 cm; CC3: larger than 2.5 cm).22 HIPEC was then given by the closed technique.20 Four surgical drains were positioned for inflow/outflow and temperature monitoring and connected to a sterile closed extra-peritoneal circuit with up to 6 L of perfusate circulating by means of a peristaltic pump at a flow rate of 500 ml/min. HIPEC was given at 40
C (outflow temperature) for 60 min with cisplatin at a dose of 75 mg/ m2. Trendelenburg/anti-Trendelenburg and latero-lateral inclinations were changed every 5 min to guarantee that the whole peritoneal surface was perfused. As a final step, the abdomen was rinsed with 3e4 L of sterile saline at 37
C. After surgery the patients were admitted to the ICU for at least 24 h. Chemotherapy toxicity was recorded using WHO toxicity

grades for chemotherapy.23 Treatment-related morbidity and mortality were classified from grade I to V according to National Cancer Institute Common Toxicity Criteria24 as follows: Grade I/II: minor complications requiring no treatment or medical treatment; Grade III: major complications requiring interventional radiology; Grade IV: reoperation or ICU admission; grade V: in-hospital mortality. Quality of Life (QOL) was assessed using the QOL-CS according to Ferrel.25 The patients were referred to the medical oncologist staff to plan eventual systemic adjuvant chemotherapy. A total body computed tomographic (CT) scan was acquired to evaluate eventual measurable residual disease. Patients with residual disease (CC > 0), were advised to undergo adjuvant systemic treatment, according to tumour biological features (ER, PR and HER-2 expression) and patients’ clinical conditions. Aromatase inhibitors were used for postmenopausal ER- or PR-positive peritoneal disease or both and patients with HER-2-positive tumour expression at histology underwent combination therapy with trastuzumab. Patients with no residual disease (CC0), were advised to undergo adjuvant systemic treatment as a precautional option. Every 6 months patients attended follow-up to assess clinical conditions, serum markers, and CT scan findings as well as other diagnostic or laboratory measures if needed on clinical grounds.

Results Of the 221 patients who underwent maximal cytoreduction and HIPEC for various primary cancers, 5 had a histological diagnosis of peritoneal carcinomatosis from BC. Their mean age at cytoreduction and HIPEC was 59.4 years (range 53e77). The clinical characteristics and related treatments are reported in Table 1.

Table 2 Immunohistochemical panel findings in the 5 patients at primary diagnosis and at peritoneal relapse. Patient

BRCA carrier status

Pt 1

Neg

Pt 2

Pt 3

Pt 4

Pt 5

Neg

Neg

Neg

Neg

ER PR Her-2

WT1

Primary

Relapse

þ þ Neg þ Neg þ þ Neg Neg Neg Neg Neg Neg Neg Neg

þþþ Neg Neg þ Neg þþ þþ Neg þþ Neg Neg Neg þþ þ Neg

Primary

GCDFP-15

Relapse

Primary

CK7 CK20 Ca-125 Relapse

Neg

Neg

Neg

þ

Neg

Neg

Neg

þ

Neg

Neg

Neg

þþ

Neg

Neg

Neg

þþ

Neg

Neg

Neg

þþþ

Primary

Relapse

Pos Neg Pos Pos Pos Neg Pos Neg Pos Pos Neg Neg Pos Neg Neg

Pos Neg Neg Pos Neg Neg Pos Neg Neg Pos Neg Neg Pos Neg Neg

BRCA: breast cancer gene; ER: oestrogen receptors; PR: progesterone receptors; HER-2: human epidermal growth factor receptor-2; WT1: wilms’s tumour 1 suppressor gene; GCDFP-15: gross cystic disease fluid protein; CK7: cytokeratin-7; CK20: cytokeratin-20.

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Table 3 Perioperative data. Patient

Post-operative stay (days)

Length of procedure (min)

Blood loss (ml)

ICU stay (hrs)

Morbidity (grade, type)

Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Mean

16 24 20 21 11 18.4

220 230 200 210 190 210

1300 2000 1100 1400 600 1280

18 18 12 24 12 16.8

II, wound infection e IV, TIA II, pleural effusion, wound infection e e

TIA: transient ischemic attack. ICU: intensive care unit.

Immunohistochemical features of the primary BC and peritoneal relapse differed in the 5 patients and are reported in Table 2. None of the 5 patients studied were breast cancer (BRCA) gene mutation carriers, and all patients’ tumours tested negative for WT1 and Ca-125 and positive for GCDFP-15. After receiving HIPEC 1 patient experienced transient Grade I cisplatin renal toxicity reversed by medical treatment (Table 3). The mean PCI ranged from 15 to 24. Of the 5 patients, 4 are alive and disease-free at 13, 45, 74 and 128 months (Table 4).

Case presentations Patient 1. In 1994 this 58-year-old patient underwent a left radical mastectomy for a T2 N1 IDC, followed by 6 cycles of cyclophosphamide/methotrexate/5-fluoracil (CMF). In 2004 an ovarian mass and peritoneal carcinomatosis developed with ascites, nodules on the Douglas pouch, bilateral ovarian masses, malignant disease infiltrating the rectum and left colon and diffuse small nodules on the transverse and right colon (PCI 15). Her ECOG performance status was 1. The patient underwent pelvic peritonectomy, total colectomy with ileorectal anastomoses, greater omentectomy and HIPEC (CC0). An aromatase inhibitor was prescribed for 5 years. The patient is alive and has been disease-free for 9 years. Patient 2. This 54-year-old woman underwent a left radical mastectomy for T2 N1 ILC in 1997 and refused adjuvant chemotherapy. In 2006 she was referred to our Institution to investigate ascites. The diagnostic work-up disclosed a bilateral ovarian mass and peritoneal carcinomatosis. Laparotomy showed peritoneal disease involving the pouch, omentum, right and sigmoid colon, small bowel and spleen (PCI 22). Her ECOG performance status was 1. The patient underwent pelvic peritonectomy, right colectomy omentectomy, splenectomy, multiple ablation procedures for small scattered small bowel and mesenteric implants and HIPEC (CC1). Immunohistochemistry disclosed an HER2-positive tumour (þþ) and the patient underwent a 2-year treatment course with

Herceptin (trastuzumab) and hormone therapy combined. She is currently alive with no evidence of disease at 6 years follow-up. Patient 3. In 1986 this 52-year-old woman underwent a radical mastectomy for T2 N1 M1 (bone) ILC followed by adjuvant chemotherapy with CMF. In 2007 she was admitted in emergency for intestinal obstruction. At operation she was found to have peritoneal carcinomatosis involving the omentum, bilateral ovarian masses, implants of the small bowel and ascending colon, and ascites (PCI 22). Her ECOG performance status was 2. The patient underwent pelvic peritonectomy, right colectomy, small bowel resection, and omentectomy. Scattered small peritoneal implants in the pouch, lateral colic gutters and small bowel mesentery were ablated by argon-beam coagulation. Visible residual disease <2.5 cm was left in the pelvis attached to the presacral fascia (CC2). HIPEC was given to prevent ascites developing. HER2 testing was positive (þþ) and the patient underwent a 2-year treatment course with Herceptin combined with hormone therapy. In 2009 the patient experienced progressive disease and died in 2011. Patient 4. This 77-year-old woman underwent a left upper quadrantectomy and lymph-node dissection for a T2 N1 IDC in 1994. After operation she refused adjuvant chemo and radiotherapy. In 2008 an ovarian mass developed with peritoneal carcinomatosis and bilateral uveitis with hypopyon, considered as an immune response to the concurrent tumour and successfully treated with corticosteroid therapy.26 Laparotomy disclosed diffuse peritoneal disease including the omentum, bilateral ovarian masses, Douglas pouch, bilateral latero-colic gutters, small bowel mesentery and splenic hilum, with no ascites (PCI 24). Her ECOG performance status was 1. The patient underwent pelvic peritonectomy, appendectomy, omentectomy, splenectomy and HIPEC (CC1). Considering her age and biological tumour features no adjuvant treatment was proposed. The patient is alive and diseasefree at 45 months. Patient 5. This 71-year-old woman underwent a left radical mastectomy for a T1 N0, IDC in 1993. Eighteen years later, in 2011, she was referred to our Institution to investigate a bilateral ovarian mass and peritoneal carcinomatosis. At operation, no ascites was

Table 4 Surgical treatment of peritoneal relapse and survival. Patient

Years after breast cancer

Surgery

PCI

CC

Survival (months)

QOL (3 months)

Pt 1 Pt 2

11 30

15 22

0 1

Alive DF, 128 Alive DF, 74

8.1 7.4

Pt 3

21

PP þ total colectomy greater omentectomy PP þ small bowel resection, greater omentectomy, splenectomy appendectomy PP þ right colectomy, small bowel resection, greater omentectomy

22

2

5.3

Pt 4 Pt 5

14 18

PP þ, greater omentectomy, splenectomy, appendectomy Hysteroadnexectomy, greater omentectomy, appendectomy

24 18

1 0

Dead, 56 with disease progression Alive DF, 45 Alive DF, 13

PCI: peritoneal cancer index. CC: completeness of cytoreduction. QOL: quality of life. PP: Pelvic peritonectomy (en-bloc removal of uterus, ovaries, rectosigmoid colon, parietal peritonectomy to the transverse umbilical line). DF: disease-free.

6.7 7.8

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found, and metastatic disease involved both ovaries, the omentum, pouch, pelvic peritoneum and small bowel mesentery (PCI 18). Her ECOG performance status was 0. The patient underwent total hysterectomy, bilateral oophorectomy, appendectomy, omentectomy, multiple ablation procedures for small scattered small bowel and mesenteric implants followed by HIPEC, leaving no visible residual disease (CC0). She received an aromatase inhibitor and is alive and disease-free at 1 year. Discussion In patients such as those we describe here, all of whom had peritoneal carcinomatosis and an ovarian mass, with a history reporting a previous BC, reaching a correct histopathological diagnosis is essential for proper treatment yet can be a difficult task. In our study the histopathological reports allowed us to compare the features for the primary BC and the metastatic cancer. As reported by other authors27 the panel of immunohistochemical stains showing combined negative WT1 and Ca-125 tumour expression associated with positive GCDFP-15 expression in the peritoneal disease invariably strengthened the diagnosis. WT1 is a tumour-suppressor gene that is positive in over 90% of primary ovarian tumours28 and never found in primary and metastatic BC.27 Ca 125 is a glycoprotein expressed in up to 90% of ovarian malignancies and from 10 to 30% of primary BC.29 GCDFP-15 is a relatively specific and sensitive marker for BC (expressed in about 50% of the cases),30 and never in ovarian malignancies.27 Our retrospective study provides hitherto unavailable information on the results of cytoreduction and HIPEC for women with peritoneal carcinomatosis from BC. Of the 5 patients treated 4 achieved longterm survival, 1 surviving even for 10 years. Despite the small series, we feel that this information may be useful to oncologists and surgeons who will face this type of metastatic spread of BC more and more often in the future.9,10 In our patients a median 18 years (range 10e30) elapsed after BC was diagnosed and peritoneal carcinomatosis developed. This lengthy time lapse accords with other series describing an interval reaching up to 30 years.1,10,31,32 It also underlines previous reports describing breast carcinoma as one of the most slowly growing solid tumours given that metastases may appear many years, even decades, after the initial diagnosis.1,12 No clear guidelines are reported in literature regarding the treatment of these patients because cases are sporadic, rarely referred to the surgeon by the oncologist, and therefore comparison between different reported treatments, as well as the design of prospective or randomized trials is difficult. In their study enrolling 44 patients with peritoneal disease from BC treated only by chemotherapy or hormonal therapy, Tuthill et al.6 reported a median 1.5 month survival and underlined the need to include such patients in specific clinical trials. Studying patients with gastrointestinal (GI) or peritoneal metastases from BC, or both, McLemore32 reported that surgery (mostly palliation for obstruction) showed a trend to improved survival (median 44 vs. 9 months, p: ns) only in the group of 23 patients with GI metastases, whereas surgery had no effect on median survival (14 vs. 26 months, p:ns) in the 32 patients with carcinomatosis. In their study investigating aggressive surgery for managing metastatic malignancies to the ovaries Ayhan et al.33 noted a better mean survival rate (39 vs. 23, p: ns) advancing from biopsy alone to aggressive debulking. Similarly Petru et al.34 discussed the importance of residual tumour volume in women with metastatic cancers other than ovarian to the abdomen and pelvis, reporting a higher 5-year survival rate for patients with residual disease <2 cm than those with >2 cm (16% vs. 3%). Finally reviewing the records for 59 patients with BC metastatic to the abdomen or pelvis, Abu-Rustum et al.9 observed a

trend towards better survival in the absence of residual abdominal disease (median 41.6 vs. 18.4 months) although statistically not significant, p ¼ 0.624, concluding that surgical resection could be important in managing this disease and should be considered in candidate patients. After maximal cytoreduction and HIPEC morbidity and mortality rates in our patients were in line with those reported for similar procedures35 and this combined treatment allowed good survival and QOL. Cytoreduction and HIPEC already provided promising results in patients with peritoneal metastases not only from pseudomyxoma peritonei from appendiceal tumours36 and peritoneal mesotheliomas,37 but also from various other primary cancers such as colon38e40 and ovary.18,20,41 Cisplatin is one of the most common chemotherapy agent used for HIPEC.42 In the management of untreated and pretreated metastatic breast cancer patients intravenous platinum compounds (cisplatin and carboplatin) have shown activity both as single agent and in combination regimens.43,44 Considering its well known systemic activity and its proved safety in HIPEC technique also reported in our previous experience20 cisplatin has been considered the drug of choice for our limited series of peritoneal metastases from breast cancer treated with HIPEC. This study does not enable us to distinguish whether survival in our patients depended on cytoreduction, HIPEC or both,45 nor do our findings indicate whether these patients should undergo adjuvant systemic chemotherapy. In conclusion, the long disease-free and overall survival observed in our small series suggests that in highly selected patients with no extraperitoneal disease and in whom surgery can achieve adequate cytoreduction this combined procedure is a promising approach for patients with peritoneal carcinomatosis from BC. This finding merits further investigation in larger studies. Conflict of interest statement None of the authors report any conflict of interest, nor commercial interest in the subject of the study, and received no financial or material support. For this retrospective study institutional review board approval was not required. Acknowledgements We thank Mrs Alice M Crossman for her precious help in revising our manuscript. References 1. Abu-Rustum NR, Aghajanian CA, Venkatraman ES, Freoz F, Barakat RR. Metastatic breast carcinoma to the abdomen and pelvis. Gynecol Oncol 1997;66:41e4. 2. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics 1996, CA. Cancer J Clin 1996;46:5e27. 3. Haagensen CD. Diseases of the breast. Philadelphia: Saunders; 1971. 4. Asch MJ, Wiedel PD, Habif DV. Gastrointestinal metastases from carcinoma of the breast. Arch Surg 1968;96:840e3. 5. Borst MJ, Ingold JA. Metastatic pattern of invasive lobular versus invasive ductal carcinoma of the breast. Surgery 1993;114:637e42. 6. Tuthill M, Pell R, Giuliani R, Lim A, Gudi M, Contractor K, et al. Peritoneal disease in breast cancer: a specific entity with an extremely poor prognosis. Eur J Cancer 2009;45:2146e9. 7. Saunders Y, Stebbing J, Broadley K, Johnston SR. Recurrent locally advanced breast cancer. The treatment of chest wall disease with further chemotherapy. Clin Oncol (R Coll Radiol) 2001;13:195e9. 8. Stebbing J, Crane J, Gaya A. Breast cancer (metastatic). Clin Evid 2006:2331e59. 9. Eitan R, Gemignani ML, Verkatraman ES, Barakat RR, Abu-Rustum RR. Breast cancer metastatic to abdomen and pelvis. Role of surgical resection. Gynecol Oncol 2003;90:397e401. 10. Nazareno J, Taves D, Preiksaitis HG. Metastatic breast cancer to the gastrointestinal tract: a case series and review of the literature. World J Gastroenterol 2006;12:6219e34.

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