Impact of Splenectomy on Thrombocytopenia, Chemotherapy, and Survival in Patients with Unresectable Pancreatic Cancer

PDAC is the fourth leading cause of cancer-related deaths in the United States, with an overall 5-year survival of 4%. In 2009, 42,770 patients in the USA were diagnosed with PDAC and 35,240 died from their disease.7 The poor outcome of patients with PDAC has been attributed to the advanced stage of disease at diagnosis, the poor response to current systemic and local therapies, and the aggressive biologic nature of the disease. Resection for PDAC provides the only chance for cure, but only about 15% of patients are eligible for surgery.8 Even those patients who undergo a “curative resection” have a 5-year survival rate of 35% in the best series.9 Most patients (85%) present with locally advanced or metastatic tumors, and they have a median survival of less than 12 or 5 months, respectively.7 Chemotherapy can significantly extend DSS and decrease disease-related morbidity.3

PETs have been studied much less frequently than PDAC primarily due to their low prevalence; only about 2,500 new PETs are diagnosed annually in the United States.10‐12 PETs are categorized as functional or nonfunctional depending on whether the secreted peptide is biologically active and produces a clinical syndrome; about 50% of nonfunctional PETs secrete peptides that are clinically silent.13 Insulinomas are the most common type of PET, and a majority are benign.14 In contrast, approximately 60% of non-insulin-secreting PETs are malignant.11,15 Due to their less aggressive clinical behavior than PDAC and resistance to most current chemotherapeutic agents, PETs are treated aggressively with resectional therapy. However, cytotoxic chemotherapy is given to patients with unresectable PETs. Therapy is determined by the grade of the tumor.4‐6 Thus, chemotherapy is the primary goal of treatment for unresectable PET or PDAC for as long as the patient can tolerate it.

Locally advanced or recurrent pancreatic tumors of either histologic type in the head of the gland can involve the splenic vein, SMV, or PV. Tumors in the body or tail can involve the splenic vein. Either can cause venous occlusion from compression by the tumor mass or thrombosis of the vessel.16 Left-sided portal hypertension, hypersplenism, and thrombocytopenia may result, which limits the patients' ability to tolerate aggressive chemotherapy. In this study, we examined the perioperative morbidity and effectiveness of splenectomy on restoring platelet counts to normal, administration of chemotherapy, and survival in our small series of 15 patients. A similar analysis was performed on 11 patients with hepatitis C, cirrhosis, and portal hypertension.17 In this series, splenectomy reversed the hypersplenism-induced thrombocytopenia, and patients could resume pegylated interferon therapy.

A recent meta-analysis3 of 50 trials (7,043 participants) on the effectiveness of 5-FU- or gemcitabine-based chemotherapy and radiotherapy for inoperable pancreatic cancer found that chemotherapy can significantly improve 1-year mortality (p < 0.00001) in patients with locally advanced or metastatic PDAC and can also significantly decrease morbidity. Gemcitabine–platinum combinations significantly reduced 6-month mortality on subgroup analysis (p < 0.001) and currently are the standard of care for the disease. Unfortunately, a number of factors often limit administration of chemotherapy to patients with pancreatic cancers. These include a poor functional or nutritional status; an unresponsive tumor and thus no clinical benefit to giving the drugs; bone marrow suppression that can result in severe anemia, leucopenia, and thrombocytopenia,18 or isolated thrombocytopenia. The potential causes of isolated thrombocytopenia include hypersplenism, bone marrow suppression with preferential inhibition of platelet production, or other very rare causes such as gemcitabine-associated thrombotic microangiopathy,19 or capecitabine (Xeloda)-induced idiopathic thrombocytopenic purpura. In fact, a major side-effect profile listed on the gemcitabine package insert includes thrombocytopenia. Thus, patients who are receiving chemotherapy, particularly gemcitabine-based regimens, are at risk of developing thrombocytopenia. With concurrent hypersplenism, the risk is even higher, as bone marrow production of platelets is usually be suppressed. Hypersplenism may unmask subclinical thrombocytopenia.

A recent study to develop a prognostic score that would predict survival after resection for PETs, using 3,851 patients from the National Cancer Data Base (1985–2004), found that age, grade, and distant metastases were the most significant predictors.20 Administration of adjuvant chemotherapy was not associated with increased survival. Nevertheless, cisplatin and etoposide combination therapy is effective in treating patients with poorly differentiated PETs, while streptozocin, doxorubicin, and 5-fluorouracil is the standard cytotoxic regimen for functional PETs.21 In fact, several studies suggest that PETs are more responsive to chemotherapy than endocrine tumors in other parts of the gastrointestinal tract, most notably carcinoid tumors. Our two patients with PETs who underwent splenectomy and aggressive chemotherapy have had excellent survival outcomes. As listed in Table 2, one patient is still alive with disease after 60 months and recently underwent an extensive resection of the primary tumor and multiple liver metastases. The other patient eventually died of disease after a rather long 9-year course.

Patients, with either PDAC or PET, who are offered splenectomy must demonstrate a good functional status, preferably with thrombocytopenia as the only factor limiting treatment. A complete blood cell count should be obtained preoperatively to exclude cytotoxic chemotherapy-induced bone marrow suppression as the primary cause of thrombocytopenia. If other blood elements are also low, particularly the absolute neutrophil count, then the chemotherapy should be considered as the primary cause of thrombocytopenia and splenectomy deferred. In this case, the dose of chemotherapy should be lowered or combination changed; alternatively, one might elect to give drugs that stimulate bone marrow production, such as granulocyte colony-stimulating factor or erythropoietin. If isolated thrombocytopenia is present, with the other elements normal, and there is evidence of hypersplenism on high-resolution imaging (e.g., portal vein thrombosis or an enlarged spleen), then splenectomy should be pursued. Ideally, we prefer that patients have a good response to chemotherapy, as measured by a decrease in tumor size or extent of disease on imaging and tumor markers; although, this was not the case in the present series, as patients underwent splenectomy over a wide time range from the time of diagnosis. CA19-9 is the best serum marker of response for PDAC;22 chromogranin, synaptophysin, pancreatic polypeptide, or gastrin can be used for PET.23 Patients must not have end-stage disease and severe malnutrition. We require that patients have a preoperative abdominal CT or MRI scan, which are usually being done for disease surveillance during treatment. The primary tumor is evaluated to ensure that it is not growing into the splenic hilum or to note additional features (varices, etc.) that will help in planning the procedure. In addition, the abdomen is evaluated for any signs of carcinomatosis and/or ascites. By using these stringent preoperative criteria prior to splenectomy, perioperative morbidity and mortality can be minimized, and platelet counts are likely to respond.

Patients who are not operative candidates can alternatively undergo splenic artery embolization or external beam splenic irradiation, as these two treatments can also potentially reverse hypersplenism-induced thrombocytopenia.24 Embolization should be considered as second-line treatment after splenectomy because it can be associated with significant postoperative pain and splenic abscesses.25 Furthermore, splenic irradiation is rarely performed for hypersplenism but can be effective for relief of pain associated with splenomegaly in patients with hematologic disorders.26 In our experience, as discussed previously, splenectomy is safe and can be performed with minimal morbidity and a short hospital stay.

There were no deaths in our series; hospital stay was short (median 3 days), and patients' platelet counts responded rapidly with quick resumption of chemotherapy (median 11.5 days). The median follow-up for all survivors was 35 months (range 13–63) from the time of diagnosis. The 13 patients with PDAC had a median survival of 20 months (range 4–67) with a 5-year DSS of 25% from the time of diagnosis, and a median survival of 10.6 months (range 0.6–39.8) from the time of splenectomy.