- (2006) Volume 7, Issue 5
Gian Paolo Spinelli1, Angelo Zullo2, Adriana Romiti1, Marisa Di Seri1, Federica Tomao1, Evelina Miele1, Bruno Spalletta1, Annarita Eramo2, Cesare Hassan2, Silverio Tomao3
1Department of Experimental Medicine and Pathology, ‘La Sapienza’ University; 2Gastroenterology and Digestive Endoscopy, ‘Nuovo Regina Margherita’ Hospital; 3‘Regina Elena’ National Cancer Institute. Rome, Italy
Received: June 8, 2006 Accepted: 18 July 2006
Chemotherapy, Adjuvant; Drug Therapy; Pancreatic Neoplasms; Survivors
Pancreatic cancer remains one of the most severe neoplastic diseases since it is rarely detected in an early stage [1]. Although a small number of patients may be encountered in clinical practice some years after surgical resection integrated with other therapies, long-term survivors are actually uncommon. Indeed, in the past decades, the prognosis of pancreatic cancer - mainly correlated with tumor stage - has not been significantly improved by any procedure [2]. The pattern of growth of pancreatic cancer is characterized by early spread to local tissues, lymphatic and perineural invasion, venous infiltration, and peritoneal metastases. Free cancer cells in the peritoneal cavity have been observed in 20-40% of cases, even in patients without nodal involvement who undergo early resection [2]. After surgical resection, the prognosis is affected by cancer dissemination and tumor cell differentiation. Patients with lymph-node metastases, perivascular and vessel invasion have a poor prognosis, even following an apparent complete resection. For such reasons, both locally advanced and metastatic pancreatic cancers remain a very difficult challenge for surgeons and oncologists. The investigation of new integrated approaches and new drugs for such a dreadful disease should always be encouraged [3].
A 47-year-old man presented with severe upper abdominal pain in June 1995. An echotomography and CT were carried out showing a rounded expansive retroperitoneal mass, with a central hypodense area and without well-differentiated margins, localized in the uncinate process of the pancreas. Moreover, multiple hepatic lesions evocative of metastatic localizations were detected. The lesion together with the adjacent intestinal loop was resected in December 1995. A rounded yellowish neoformation with a maximum diameter of 5.5 cm was removed, together with a 14 cm contiguous digiunal loop, and the peridigiunal fat tissue surrounding the neoplasia. Histological examination revealed a poorly differentiated adenocarcinoma of the pancreatic tail (Figures 1 and 2) with metastatic lesions in the pancreatic nodes and liver metastases at biopsy (pT1b pN1 pM1; stage III and histopathological grading G3). Starting in January 1996, chemotherapeutic treatment with a FEM schedule (5-FU: 600 mg/m2 at days 1, 8, 29, 36; epirubicin: 30 mg/m2 at days 1 and 29; mitomycin: 10 mg/m2 at day 1) was given for 6 cycles. The CT restaging showed multiple liver lesions, the biggest measuring 6 cm in diameter. Thus, a second chemotherapeutic treatment with weekly gemcitabine (1,000 mg/m2) was given from December 1996 for 6 cycles. Stability was obtained and a monochemotherapeutic regimen with gemcitabine was performed. In October 2001 a CT revealed invasion of both the portal vein and the intrahepatic portal vessels. Chemotherapy using the De Gramont schedule (5-FU: 400 mg/m2 i.v. bolus at days 1 and 2; 5-FU: 600 mg/m2 i.v. at days 1, 2 by 22-h infusion; folinic acid: 200 mg/m2 i.v. at days 1 and 2 by 2-h infusion) was administered. In May 2002, following 6 cycles of this treatment, a CT control revealed a voluminous conglobated mass of about 20 cm in diameter in the liver with involvement of hilar nodes. An OctreoScan scintigraphy of the liver showed a captation of the somatostatin-like tracer by the metastatic lesions and, therefore, lanreotide treatment was started. In July 2003, ascites were repeatedly drained, and the cytological assessment failed to find neoplastic cells. Therefore, the ascites were attributed to the portal hypertension caused by the tumoral obstruction of the portal vein system. A new chemotherapeutic approach with a GEMOX schedule (oxaliplatin 100 mg/m2 at day 1; gemcitabine 1,500 mg /m2 at days 1 and 8) every 3 weeks for 12 cycles was carried out. The treatment was given until July 2004 with acceptable tolerance and toxicity and a good control of the disease. The patient was supported with weekly administration of darbopoietin alpha for G2 anemia and repeated infusions of albumin. In September 2004 a restaging with total body CT showed lung progression disease and peritoneal carcinosis. Starting in October 2004, treatment with 5-fluorouracil 200 mg/m2 (from day 1 to 7 by continuous infusion) concomitant with hyperthermia was started, but the treatment was stopped after a few applications due to elevated toxicity. Some episodes of hematemesis were successfully controlled by endoscopic treatment. To date, 10.5 years after the diagnosis, the patient is in an acceptable general condition without any oncological therapy.
Figure 1. Cells with hyperchromatic and pleomorphic nuclei which define irregular glands.
Figure 2. Perineural invasion.
Treatment of metastatic pancreatic cancer still remains a challenge and the median survival time of locally advanced or metastatic disease is very poor (3-6 months) [4], the 5-year survival rate being only 3-4.2%, even in patients who underwent resection [1, 4]. Due to such a dismal prognosis, it is very difficult to conceive guidelines for a multidisciplinary treatment of the disease. For a long time, only 5-fluorouracil (5-FU) [5] has been used, having shown an acceptable response rate (20%) and low toxicity in pancreatic cancer [6, 7], also supported by colorectal and gastric cancer studies. The increasing interest in this drug has led to its larger use in randomized studies, searching schedules or modulators improving its activity and reducing its toxicity. The results have shown that the combination of 5-FU with other drugs such as doxorubicin (FA), cisplatin or the association of doxorubicin plus mitomycin (FAM), are not advantageous in terms of time to progression, objective response rate and median survival time [8, 9, 10, 11, 12, 13, 14], with increased toxicity as compared to the use of 5-FU alone (Table 1). Survival improvement and clinical benefits found in a phase III trial [15], including palliation of symptoms and disease regression, suggest the use of gemcitabine as a standard therapy for patients with advanced pancreatic cancer. However, only 25% of patients had significant clinical benefits, with tumor regression in only 5% of the cases [16]. The need for new approaches has led to several trials to test the combination of gemcitabine with other cytotoxic agents. In the phase II study carried-out by Alberts et al. [16], the efficacy of gemcitabine and oxaliplatin was analyzed, showing moderate activity in patients with advanced pancreatic cancer. Other studies [5, 17] have confirmed that this combination provides a better response rate and progression free survival with a limited toxicity than gemcitabine alone (Table 2). Despite the low median survival time of resected and pluritreated patients, a small subset of long-term survivors does exist. Very few cases of patients with advanced pancreatic cancer surviving for more than 5 years have been described [18, 19, 20], and an 8% 7-year survival for patients with surgically resected cancer has been reported [21]. To date, only four patients living more than 10 years have been described in the literature [22, 23]. Interestingly, all these very long-term survivors were Japanese and all had resectable disease. Some negative prognostic factors of survival have been suggested, including tumor size (greater than 2 cm), positive nodes, poor histological differentiation, vessels and capsule invasion, and positive pathologic margins [24, 25]. Others considered invasion of both retroperitoneal tissues and the portal venous system as the main negative predictors for a post-operative prognosis [24, 26]. It has also been found that patients with initial jaundice have a significantly better prognosis than other patients [27]. In addition, long-term survivors were more frequently female [1]. Surprisingly, despite the fact that several of these negative predictive factors (tumor size, positive nodes, poor differentiation, portal invasion, no jaundice, male sex) were present, long-term survival has been observed in our patient.
Unfortunately, we only know unfavorable prognostic factors whereas there is a lack of information on clinical or biological parameters predictive of a better outcome.
Recent studies suggest that interferon gamma polymorphism seems to be correlated with the duration of survival in pancreatic cancer, the presence of allele 2 (12 CA-repeat sequences) being associated with long survival in nonresectable pancreatic cancer [28]. Therefore, such assessment may be useful in the near future as a positive prognostic predictor. Moreover, a complex network of chemokines and receptors exists in the tumor microenvironment, regulating a variety of functions such as angiogenesis, activation of matrix metalloproteases, growth-promoting effects and inhibition of apoptosis. In particular, the expression of CXCR4 on metastatic pancreatic carcinoma cells promotes tumor cell migration, matrix degradation and invasion, proliferation and survival, opening new ways for valuable therapeutic targets [29]. Indeed, immunotherapy and antiangiogenesis therapy might be a hopeful strategy in the near future, as has emerged in animal models [3].
In conclusion, this is the fifth case reported in the literature showing that long-term survival may be achieved even in advanced pancreatic cancer. Moreover, this is the first patient with inoperable metastases at the time of diagnosis who has survived for more than 10 years.
