Gemox: a widely useful therapy against solid tumors-review and personal experience.

Gemcitabine and oxaliplatin have been demonstrated to have synergistic activity in several human cancer cell lines and varying patterns of toxicity. Gemcitabine is a very well tolerated drug with mild myelosuppression, asthenia and nausea/vomiting as its main toxicities. On the other hand, cumulative peripheral neurotoxicity is the main side effect of oxaliplatin. Therefore, there is a strong preclinical rationale to combine gemcitabine and oxaliplatin (Gemox) and to test this regimen as an alternative approach to gemcitabine with cisplatin or carboplatin as a treatment for different tumors. By reviewing the literature we found that the Gemox regimen seems to be active in the treatment of various kinds of tumors and is well tolerated. Further studies, especially to determine the optimal schedule, are clearly warranted. In addition, we report here our single-institution experience with this combination as salvage treatment for heavily pretreated cancer patients.

Epidermal growth factor receptor tyrosine kinase inhibitors for elderly patients with advanced non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality in both men and women and approximately 219,440 new cases of nonsmall cell lung cancer (NSCLC) were estimated to occur in the USA in 2009, which caused 159,390 NSCLC-related deaths. More than 50% of cases of advanced NSCLC are diagnosed in patients older than age 65, and recent Surveillance Epidemiology and End Results (SEERs) data suggest that the median age at diagnosis is 70 years. Until recently, the disease has been undertreated in this patient population, with a perception among many clinicians that elderly patients do not tolerate chemotherapy or radiotherapy. So, single agent chemotherapy is the recommended approach by the ASCO and International Expert Panels in unselected patients. The introduction of novel targeted therapies, such as Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) which improved survival versus placebo in patients who had previously failed on chemotherapy, gives clinicians new, effective, and better tolerated options to consider when treating NSCLC in elderly patients. This paper describes the advances of EGFR TKIs for elderly patients with advanced NSCLC.

The use of bevacizumab and trastuzumab beyond tumor progression: a new avenue in cancer treatment?

The use of the Monoclonal Antibodies (MoAbs) Bevacizumab (B) and Trastuzumab (T) beyond clinical progression in colorectal and breast cancer treatment is among the hottest topics in today's clinical oncology. Both observational and prospective studies, based on a sound preclinical basis, seem to support the notion that, simply replacing the cytotoxic drugs combined with the two MoAbs would provide an additional clinical benefit without stopping the biological agent. The aim of this review is to provide a critical analysis of the available clinical data, while waiting for the confirmatory prospective clinical trials still ongoing. The strength and the weakness of this innovative strategy, as well as the associated expense and toxicity issues will be discussed.

Anti-EGFR therapy in colorectal cancer: how to choose the right patient.

The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.

The Renaissance of platinum-based chemotherapy for metastatic breast cancer.

Although anthracyclines and the taxanes comprise the most active first-line cytotoxic treatments in patients with hormone-insensitive or life-threatening metastatic breast cancer, many patients progress and require other chemotherapeutic agents. Platinum compounds have shown activity in a broad spectrum of human tumors in vitro and in vivo. For patients with metastatic breast cancer resistant to anthracyclines or taxanes, or who have received anthracyclines with or without taxanes in the adjuvant or neoadjuvant setting, no standard regimen exists and platinum-based chemotherapy is one of the several options available. Moreover, platinum compounds have shown synergistic activity with trastuzumab, a monoclonal antibody against overexpressing HER2 breast cancer. However, the definitive role of platinum compounds in the treatment of breast cancer is not yet well established and further trials are needed.

The potential role of pemetrexed in gastrointestinal cancer.

In 2004, the new-generation multitargeted antifolate pemetrexed was approved by the US Food and Drug Administration for the treatment of malignant pleural mesothelioma and as second-line monochemotherapy for advanced non-small cell lung cancer. However, pemetrexed as a single agent showed activity in preclinical and clinical studies, as well as in many other neoplasms such as gastrointestinal tumors, breast, head and neck, bladder and cervix cancer. Its tolerability profile is very favorable since the introduction of oral folic acid and vitamin B(12) supplementation in December 1999, and therefore, the maximum tolerated dose as single agent is probably higher than the dose actually utilized in clinical practice. Gastrointestinal tumors are the most common malignancies in the world, accounting for more than 25% of all cancers. In phase II studies exploring this multitargeted antifolate in advanced gastrointestinal tumors, pemetrexed showed an interesting degree of clinical activity, encouraging further trials evaluating the synergism with other drugs such as oxaliplatin, irinotecan and gemcitabine.

Extended lymphadenectomy in cephalic pancreatoduodenectomy. Personal observations.

BACKGROUND/AIMS: Long-term survival in patients with cancer of the pancreatic head is disappointing. Surgery is the only curative therapy. Unfortunately the prognosis of resected patients (10-15%) is extremely poor due to loco-regional cancer recurrence (50%). Lymphatic and perineural invasion may account for local recurrence. Japanese studies have reported the importance of an extended lymphadenectomy during the classic Whipple exeresis (40% of patients present lymph node metastases). METHODOLOGY: At the General Surgical Clinic of Pavia University 20 patients (14 men, 6 women, mean age 62.4 yr) with pancreatic head cancer (17 adenocarcinoma, 1 lymphoma, 2 carcinoma) underwent Whipple's exeresis with a regional (peripancreatic or R1) and juxta-regional (para-aortic or R2) lymphadenectomy according to the Ishikawa technique, between 1996-2000. R1 nodes consisted of lymph nodes at the pylorus, superior pancreatic head, common bile duct, anterior pancreaticoduodenal region, inferior pancreatic head and superior mesenteric vessels. R2 nodes consisted of lymph nodes at the superior and inferior pancreatic body, mid colic region, common hepatic duct, celiac axis and para-aortic region. RESULTS: The wide dissection was quite easy in patients with a serious cholestatic disease. Intraoperative mortality was 0%. Operative mortality was 5%. Postoperative complications (20%) consisted of 1 sepsis, 1 hepato-renal syndrome with hepatic coma, 1 intestinal obstruction by adhesive bands, and 1 wound infection. Eight patients (40%) died during a mean follow-up period of 6 months (neoplastic recurrence 50%). Notwithstanding the advanced disease (stage III 50%; N1+ 50%), 12 patients (60%) had a median postoperative survival rate of 18.4 months (range 1-48 months) without neoplastic recurrence. Tumor diameter was less than 4cm in 83.3% of cases. CONCLUSIONS: An earlier diagnosis (with tumor diameter <4 cm) can improve pancreatic head cancer prognosis. A wide surgical exeresis with R2 lymph nodes clearance together with surrounding connective and nervous tissue can remove micrometastases and better control local recurrence.

The emerging role of oxaliplatin in the treatment of gastric cancer.

Gastric cancer is often diagnosed in locally advanced or metastatic stages and, therefore, of poor prognosis. Many controversies exist about surgery, neoadjuvant, adjuvant and palliative treatments of gastric cancer. So we need to explore a variety of novel management options including the use of new agents and new combinations. Some of these agents include oral fluoropyrimidine, irinotecan, docetaxel and oxaliplatin. Oxaliplatin is a diaminocyclohexane-platinum compound that is significantly different from cisplatin and carboplatin with respect to its activity and toxicity. Oxaliplatin is an alkylating agent inhibiting DNA replication by forming adducts between two adjacent guanines or guanine and adenine molecules. However, the adducts of oxaliplatin appear to be more effective than cisplatin adducts in regard to the inhibition of DNA synthesis. In contrast to cisplatin, oxaliplatin has demonstrated efficacy alone and in combination with 5-fluorouracil in advanced colorectal cancer. Many studies are ongoing to test the combination in noncolorectal gastrointestinal tumors and other malignancies. This review focuses on the increasing amount of data concerning the clinical activity of oxaliplatin-based regimens in advanced gastric cancer.

[Radical surgical treatment of gastric cancer. Personal experience]. / Terapia chirurgica radicale del cancro gastrico. Esperienza personale.

After surgical therapy the survival outcome of gastric cancer is still poor. Early diagnosis and radical surgery are the two most important means to improve the prognosis. Radical surgery must include all lymph nodes embryologically related to stomach. The aim of this study was to verify whether an aggressive surgical strategy can increase postoperative survival rate. In the period 1990-1994 eighty two patients with gastric cancer were operated on. The M:F ratio was 1.6:1 and the mean age was 65.3 years (range 23-89). Palliative operations (6 gastroenterostomy) were performed in 7.3% of cases. In the other patients, 36 total gastrectomies (43.9%), 8 total gastrectomies extended to spleen, pancreas and colon (9.7%), 32 distal subtotal gastrectomies (39.1%) were performed. Gastric exeresis was always associated with lymph node dissection extended to level I and II (R2). In some cases level III and IV lymphadenectomy (R3) was performed according to Maruyama-Mishima technique. There were no intraoperative deaths. The operative mortality was 13.6% for total gastrectomies and 3.1% for subtotal gastrectomies. Postoperative complications occurred in 15.9% of total gastrectomies (3 anastomotic fistula, 2 wound infection, 1 subphrenic abscess, 1 melena) and in 3.1% of subtotal gastrectomies (1 sepsis). Stage III and IV cancers represented 74.4% of all cases (stage IIIA 19.6%, IIIB 21.9%, IV 32.9%). Metastatic lymph node involvement (N2+) affected 53.1% of T3 and 88.2% of T4 cancers. The mean survival rate of patients subjected to gastroenterostomy was 6 months. The 2-year survival for total gastrectomies was 42%, for subtotal gastrectomies 28.1%. In our experience, wide removal of lymph nodes and total or extended gastrectomies were performed without any increase of mortality and morbidity. In advanced stages, a wider exeresis increased survival and prevented local recurrence.

[Extended lymphadenectomy for carcinoma of pancreatic head. Personal experience]. / Linfadenectomia radicale nella duodenocefalopancreasectomia. Esperienza personale.

Long-term survival in patients with cancer of the pancreatic head is disappointing. Surgery is the only curative therapy. Unfortunately the prognosis of patients resected (10-15%) is extremely poor due to loco-regional cancer recurrence (50%). Lymphatic and perineural invasion might account for local recurrence. Japanese studies reported the importance of an extended lymphadenectomy during the classic Whipple exeresis (40% of patients present lymph node metastases). During the period 1996-2000 at our Institution 20 patients (14 M, 6 F, mean age 62.4 years) with pancreatic head cancer (17 adenocarcinoma, 1 lymphoma, 2 carcinoma) underwent Whipple's exeresis with a regional (peripancreatic or R1) and juxta-regional (para-aortic or R2) lymphadenectomy according to Ishikawa technique. R1 nodes consisted of lymph nodes at the pylorus, superior head, common bile duct, anterior pancreaticoduodenal region, inferior head and superior mesenteric vessels. R2 nodes consisted of lymph nodes at the superior body, inferior body, mid colic region, common hepatic duct, coeliac truncus and para-aortic region. This wide dissection was quite easy also in patients with a serious cholestatic disease. Intraoperative mortality was 0%. Operative mortality was 5%. Postoperative complications (20%) were 1 sepsis, 1 hepato-renal syndrome with hepatic coma, 1 mechanical intestinal obstruction, 1 wound infection. Eight patients (40%) died in 6 months in average (neoplastic recurrence 40%). Notwithstanding the advanced disease (stage III 50%; N1+ 50%), twelve patients (60%) have a mean postoperative survival rate of 18.5 (range 1-48) months without neoplastic recurrence. Tumour diameter was less than 4 cm in 83.3% of cases. An earlier diagnosis (with tumour diameter < 4 cm) can improve pancreatic head cancer prognosis. A wide surgical exeresis with a R2 lymph nodes clearance together with surrounding connective and nervous tissue can remove micrometastases with a better control local recurrence.

[Surgical resection of hepatic hilar tumors]. / Chirurgia exeretica dei tumori dell'ilo epatico.

Hepatic hilar cancer has an extremely poor prognosis and resection for cure is a realistic possibility in only 15-20% of patients. Tumours confined strictly to the biliary confluence can often be excised locally without resorting to hepatic resection (Bismuth's type I, II). Tumours extending beyond the second order bifurcation (Bismuth's type III) require hepatic resection. In the period 1996-1998 ten patients with hilar cancer (adenocarcinoma) underwent curative resection at our Institution. There were 9 men and 1 women with a mean age of 61.7 years (range 49-76 yrs). One neoplastic lesion was Bismuth's type I, five type II, four type III. The mean preoperative bilirubin level was 20 mg% and the mean duration of jaundice was 4 weeks. Four patients had skeletonization resection of the tumour and extrahepatic bile ducts, clearing all lymphocellular and other tissue from the hepatic pedicle and coeliac axis. Bilioenteric continuity was reestablished by a Roux-en-Y jejunal loop with separate biliary duct anastomoses. Six patients required also hepatic resection to adequately remove the tumour (1 right hepatectomy, 2 right lobectomy, 2 left hepatectomy, 1 segmentectomy III). Three patients had liver metastases. One patient had involvement of the left arterial and portal branch. The postoperative staging was 2 stage II, 1 stage III, 7 stage IV. In 5 patients hepatic lymph nodes (N1) were involved. In no patient the tumour was found at the margin of resection. The median estimated blood loss for hepatic resection was 1,000 ml and for skeletonization 500 ml. Intraoperative mortality was 0%. Operative mortality was 20%. Three patients had a complicated postoperative course (1 cerebral TIA, 1 multiorgan failure, 1 ictus cerebri). All patients died. The mean postoperative survival was 7.4 months. Four patients (N1+) died of local tumour recurrence at 8, 11, 6, and 8 months. In our experience resective procedures can achieve a longer survival and a better quality of life. The operative mortality may be kept to a minimum by adequate selection of patients and technical expertise.

Primary carcinoid tumor of the ovary: report of an unusual case.

Carcinoid tumors are endocrine malignancies that are often associated with a characteristic syndrome, the malignant carcinoid syndrome, which is most common in patients with small bowel tumors and liver metastases. In the rare instances when the syndrome is present without liver metastases the primary tumor is usually localized to the bronchus or ovary and secretes hormones directly into the systemic circulation. About two thirds of patients with carcinoid syndrome have evidence of carcinoid heart disease. We report on a case of a primary ovarian carcinoid tumor with an unusual clinical presentation.

[Neoplastic obstruction of the vena cava inferior in general surgery]. / Ostruzione neoplastica della vena cava inferiore in chirurgia generale.

Patients with primary or secondary tumoral occlusion of the inferior vena cava are difficult to be managed with safety and success. Nevertheless, their survival may be prolonged by an aggressive surgical approach according to the technical advances of liver transplantation. In fact, it is possible to perform a tumoral exeresis including the inferior vena cava by a total vascular exclusion of the liver (HVE) and a pump-driven veno-venous bypass (ECC). The Authors report the management of 8 patients with inferior caval tumoral involvement (8 M, 1 F, mean age 63.7 yrs). Vascular occlusion was caused by caval leiomyosarcoma (n 1), renal cell carcinoma (n 3), hepatocellular carcinoma (n 1), liver metastases (2 colorectal, 1 renal). Five patients (62.5%) underwent surgical treatment (2 laparotomy, 2 wide nephrectomy with partial caval wall resection in HVE, 1 ex vivo liver resection with caval venoplasty in HVE and ECC). Operative mortality was 40%. Three patients underwent medical treatment (radio-chemotherapy, chemoembolization). Total survival rate was 75% at 3 months, 50% at 6 months, and 25% at 24 months. Two patients (25%) are still alive at 3 months from the diagnosis and at 36 months from the operation.

[The surgery of lung metastases of melanoma]. / La chirurgia delle metastasi polmonari di melanoma.

Melanoma is considered one of the most lethal cancers and surgical therapy of its pulmonary metastases is rarely indicated. The only hope for a successful surgical treatment of secondaries from melanoma is a radical resection. Considering the very frequent multiorgan involvement of melanoma metastases, surgery is usually possible in less than 5% of cases. Nevertheless, in selected cases without lymph nodal involvement a 5-year survival rate of 31% has been reported. In any way, it must be remembered that about 10% of lung tumours thought to be metastases are primary cancers. In this occurrence surgery could be a rescuing solution. So, a pulmonary resection is always imperative when some diagnostic doubt exists.

[Surgical therapy of metabolic liver diseases (glycogenosis, hypercholesterolemia)]. / Terapia chirurgica delle malattie metaboliche epatiche (glicogenosi, ipercolesterolemia).

Up-to-date, most patients with serious chronic hepatic disease are best treated by liver transplantation. It has been confirmed the striking benefit of liver transplantation also for patients with glycogen storage disease or homozygous familial hypercholesterolemia who were refractory to medical treatment. Nevertheless, the advantage of achieving palliation without transplantation, thereby avoiding the need for chronic immunosuppression, is obvious. With reference to the mentioned above diseases, end-to-side portacaval shunt was used. A favourable effect was noted on body growth and a number of metabolic abnormalities. Hepatic failure did not occur, although in a few patients blood ammonia concentrations and serum alkaline phosphatase levels increased relative to preoperative values. To avoid an incomplete palliation provided by portacaval shunt, appropriate case selection is a problem. The Authors report their personal experience with portacaval shunt for the treatment of glycogenosis and familial hypercholesterolemia.

Paclitaxel, ifosfamide, and carboplatin for the treatment of stages IIIB and IV non-small cell lung cancer: preliminary results.

We have treated 26 consecutive chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer with an innovative regimen based on a 1-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 125 to 250 mg/m2, ifosfamide 3 g/m2 (with mesna), and carboplatin dosed to an area under the concentration-time curve of 5, every 21 days for a total of six cycles in responding or stabilized patients. Among 22 fully evaluable patients, 14 (64%) achieved a partial remission, six had disease stabilization, and two had disease progression. Hematologic toxicity was remarkably mild; only one patient had grade 3 neutropenia (on day 21). Arthralgias/myalgias (grade 3 in nine patients, grade 4 in one patient) and neurologic toxicity (a cumulative sensory neuropathy of grade 3 or 4 in five patients) were the most common side effects and seem to be dose related. To date, few patients are fully evaluable and survival data are clearly immature. Nevertheless, this regimen seems highly active and quite well tolerated, and deserves further evaluation.

[Primary and secondary pulmonary tumors associated with head and neck carcinoma]. / Tumori polmonari primitivi e secondari in associazione con carcinomi della testa e del collo.

The authors analyze personal and literature results in surgery of primary and secondary lung cancer associated with head and neck malignancies. Eighteen patients with primary lung cancer associated with head and neck cancer were compared with six patients affected by pulmonary metastases from head and neck cancer. In the first group the 3-year postoperative survival rate was 60.5%, in the second group 33%. Differential diagnosis between primary and metastatic lung tumours may be easy when multiple pulmonary nodes are present. When only one pulmonary node is present, diagnosis is more difficult. Thoracotomy is necessary to perform the correct diagnosis and the best postoperative medical treatment.

[Surgical treatment of pulmonary metastasis from breast carcinoma. Personal contribution and considerations on the experience in the literature]. / A proposito del trattamento chirurgico delle metastasi polmonari di carcinoma mammario. Contributo personale e considerazioni sulle esperienze della letteratura.

Considering a series of twelve patients operated on at the General Surgical Clinic of the University of Pavia, the authors discuss the results of surgical therapy of pulmonary metastases from breast cancer. According to literature data their results are not so good with a 5-year survival rate of 11%. Nevertheless, selected series of patients have been reported with a 5-year survival rate of 43% after pulmonary resection. So, by a careful selection of the indications the possibility of a surgical treatment would not be eliminated. After breast cancer exeresis it is certain that surgery is the best treatment for a solitary pulmonary nodule when there is some doubt about the diagnosis of primary or secondary lung cancer.