Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4–6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4-6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Role of platinum agents in the management of advanced pancreatic cancer

Pancreatic cancer, one of the most common gastrointestinal tumors, has a 5-year survival rate of < 5%. Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the only standard chemotherapy approved by the US FDA for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against and in combination with this standard. Many combination therapy regimens showed encouraging results in Phase II settings, which led to > 12 randomized Phase III trials in the last decade. Some trials showed improved response rates or progression-free survival, but there was no clear improvement in survival. Among these combinations, the combination of gemcitabine plus platinum agents showed improved progression-free survival or time-to-tumor progression, but failed to demonstrate a survival advantage over gemcitabine. This combination has regained attention after a recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine. There are preclinical data showing synergism between gemcitabine and platinum agents. Hence, this review covers the role of platinum doublets in the treatment of metastatic pancreatic cancer.     

Development of nanoliposomal irinotecan (nal-IRI,MM-398, PEP02) in the management of metastatic pancreatic cancer

Introduction: Systemic chemotherapy remains the standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC). The introductions of FOLFIRINOX and nab-paclitaxel/gemcitabine combinations have improved the first-line treatment outcomes of patients with metastatic PDAC; while second-line therapy options are limited. Based on the results of pivotal NAPOLI-1 study, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) became the first US Food and Drug Administration (FDA) approved regimen for patients with metastatic PDAC with previous gemcitabine-based chemotherapy in November 2015.

Areas covered: We reviewed and summarized the rationale, pharmacokinetics, therapeutic efficacy and adverse events of nal-IRI alone or combined with 5-FU/LV for metastatic PDAC with previous gemcitabine-based chemotherapy.

Expert opinion: In the NAPOLI study, nal-IRI plus 5-FU/LV significantly improved the overall survival, progression-free survival and objective response rate compared to 5-FU/LV alone. The nal-IRI plus 5-FU/LV treatment was associated with a manageable toxicity profile and comparable outcomes in patients with negative demographic characteristics. The relatively sparse of neurotoxicity makes nal-IRI plus 5-FU/LV as a more favorable option than oxaliplatin-containing regimens and the current recommended standard treatment for patients with metastatic PDAC after frontline nab-paclitaxel/gemcitabine treatment. The front-line therapeutic role of nal-IRI is currently under investigation.     

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium

Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-na?ve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m² on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.     

Addition of vandetanib to chemotherapy in advanced solid cancers: a meta-analysis

The addition of vandetanib to chemotherapy has been shown to have a marked effect on patients with advanced cancers who had failed previous chemotherapy. We carried out a meta-analysis to determine the efficacy and safety of vandetanib compared with chemotherapy in patients with advanced cancers. For this meta-analysis, we selected randomized clinical trials that compared vandetanib-based therapy (VBT) with the matched chemotherapy or placebo alone in patients with advanced cancers. The outcomes included overall survival (OS), progression-free survival (PFS), the objective response rate, and toxicities. Hazard ratios (HRs) and odds ratios were reported with 95% confidence intervals (CIs). A total of 14 eligible trials were included for the meta-analysis, with 2995 patients in the VBT group and 2479 patients in the control group. A significant improvement was observed in PFS (HR 0.76, 95% CI 0.68-0.86 in all cancers, HR 0.80, 95% CI 0.70-0.90 in lung cancer, HR 0.54, 95% CI 0.40-0.74 in thyroid cancer) and in objective response rate (odds ratio 2.09, 95% CI 1.42-3.07) in the VBT group. However, no significant difference was found in OS (HR 0.96, 95% CI 0.90-1.03). The subgroups of patients with non-small-cell lung cancer who benefited from vandetanib therapy were identified as those with a history of smoking (HR 0.87, 95% CI 0.80-0.95) and an adenocarcinoma histology (HR 0.85, 95% CI 0.77-0.94). In addition, patients who received VBT had an increased incidence of adverse events such as rash, diarrhea, and neutropenia. The addition of vandetanib to chemotherapy significantly improves PFS in patients with locally advanced or metastatic cancers, especially lung and thyroid cancer.     

Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.     

Recent developments in the pharmacological treatment of advanced pancreatic cancer

Metastatic pancreatic cancer is one of the leading causes of cancer-related death in North America and Europe. The high mortality rate associated with pancreatic cancer is related to the fact that the vast majority of patients develop incurable, metastatic disease. Such patients have, in the past, had few treatment options. In recent years, however, the systemic administration of gemcitabine has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer. While treatment with gemcitabine has been shown to result in both clinical benefit and in prolongation of survival, objective tumour responses following therapy with gemcitabine are relatively uncommon and median survival times remain short. Current efforts have, therefore, focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Several such combinations appear to be associated with higher objective response rates than single-agent gemcitabine and have been well-tolerated in early clinical trials. Ongoing, prospectively randomised clinical trials will help better define the efficacy of these new combinations and will determine if they result in a significant benefit when compared to gemcitabine monotherapy. A number of novel chemotherapeutic and biological agents also appear promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Recent developments in the pharmacological treatment of advanced pancreatic cancer

Metastatic pancreatic cancer is one of the leading causes of cancer-related death in North America and Europe. The high mortality rate associated with pancreatic cancer is related to the fact that the vast majority of patients develop incurable, metastatic disease. Such patients have, in the past, had few treatment options. In recent years, however, the systemic administration of gemcitabine has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer. While treatment with gemcitabine has been shown to result in both clinical benefit and in prolongation of survival, objective tumour responses following therapy with gemcitabine are relatively uncommon and median survival times remain short. Current efforts have, therefore, focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Several such combinations appear to be associated with higher objective response rates than single-agent gemcitabine and have been well-tolerated in early clinical trials. Ongoing, prospectively randomised clinical trials will help better define the efficacy of these new combinations and will determine if they result in a significant benefit when compared to gemcitabine monotherapy. A number of novel chemotherapeutic and biological agents also appear promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only approximately 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil-folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of approximately 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

Pharmacokinetic evaluation of gemcitabine hydrochloride for the treatment of cervical cancer

INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.     

Overcoming platinum resistance in ovarian carcinoma

Importance of the field: Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy, including platinum. Because response rates for current treatment regimens are relatively similar and unfortunately low, no standard chemotherapy for platinum-resistant ovarian cancer exists.

Areas covered in this review: A systematic literature review of clinical studies published between January 2005 and March 2010 was conducted using search engines, PubMed and MEDLINE with the entry keywords ‘ovarian cancer’ and ‘platinum resistance’. This search revealed 40 clinical trials (1793 patients).

What the reader will gain: Gemcitabine was the most common drug used in clinical trials reporting higher response rates, ≥ +1 SD of overall response rate (5 out of 8). Gemcitabine-based combination therapy showed an average response rate of 27.2% (95% CI, 22.4 – 32.0). Combination of gemcitabine and pegylated liposomal doxorubicin (PLD) was the most common regimen (n = 3) and was associated with possible additive effects in platinum-resistant ovarian cancer patients: response rate, gemcitabine alone 6.1%, PLD alone 19.8%, and gemcitabine with PLD 28.7% (95% CI, 20.4 – 37.0), respectively.

Take home message: Analysis of recent clinical trials showed that gemcitabine-based combination chemotherapy was associated with the highest antitumor effects in platinum-resistant ovarian cancer patients during the study period.     

Conventional chemotherapy of advanced pancreatic cancer

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.     

Pancreatic cancer: a review of recent advances

Pancreatic cancer is one of the most common causes of cancer-related death. Despite the advances of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is < 5% and only ～ 20% of the 10% of patients with resectable disease survive 5 years. Recently, the European Study Group for Pancreatic Cancer 1 trial demonstrated substantially increased survival from adjuvant chemotherapy with 5-fluorouracil–folinic acid and preliminary data showed prolonged disease-free survival from adjuvant gemcitabine. Current palliative therapeutic approaches mostly focused on evaluating chemotherapy regimens in which gemcitabine is combined with a second cytotoxic agent. Recently, large randomised trials of combinations of gemcitabine with either capecitabine or with erlotinib demonstrated prolonged survival and 1-year survival rates of ～ 25%. The advance of molecular biology has led to the elucidation of molecular events that are important for pancreatic carcinogenesis and has provided a foundation for the development of novel chemotherapeutic and biological agents that appear to be promising and are likely to play a future role in the treatment of patients with advanced pancreatic cancer.     

A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer

Background Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. Patients and Methods Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. Results Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. Conclusion Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.     

Anti-angiogenic agents in pancreatic cancer: a review

Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with a 5-year survival of less than five percent. Since the majority of patients have locally advanced or metastatic disease at the time of diagnosis, there has been little progress made to extend survival. For over ten years, chemotherapy with gemcitabine has been standard treatment for those patients with advanced pancreatic cancer, prolonging survival by only 5-6 months. To improve upon this modest benefit, several investigations have explored other strategies aimed at curbing pancreatic cancer growth. Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer. This review will discuss these therapies and their potential application in a clinical setting.     

Capecitabine: in advanced gastric or oesophagogastric cancer

The oral fluoropyrimidine capecitabine is metabolised preferentially in tumour tissue to the cytotoxic moiety fluorouracil. In a well designed phase III trial in patients with advanced gastric cancer, capecitabine plus cisplatin was noninferior to fluorouracil plus cisplatin in terms of progression-free survival (hazard ratio [HR] 0.81 [95% CI 0.63, 1.04]). In another similarly designed phase III trial in patients with oesophagogastric cancer (REAL 2), pooled capecitabine-based regimens were noninferior to pooled fluorouracil-based regimens in terms of overall survival (HR 0.86 [95% CI 0.80, 0.99]). These data are supported by randomised and noncomparative phase II trials in treatment-naive or pretreated patients with advanced gastric cancer or oesophagogastric cancer receiving capecitabine either as monotherapy or in combination with other antitumour agents. Given the nature of chemotherapy, capecitabine-based regimens were generally well tolerated, with the nature of treatment-related adverse events occurring with capecitabine-based regimens being similar to those of fluorouracil-based regimens.     

吉西他滨和顺铂联合重组人血管内皮抑制素治疗晚期非小细胞肺癌临床观察

目的评价吉西他滨和顺铂联合重组人血管内皮抑制素（恩度）治疗晚期非小细胞肺癌的疗效和安全性。方法 38例病理确诊的晚期非小细胞肺癌患者给予吉西他滨和顺铂联合恩度治疗,吉西他滨1000mg/m2,第1,8天,顺铂75mg/m2,第2天,恩度注射液7.5mg/m2加入500ml生理盐水中,滴注时间3～4小时,第1～14日,每21天为一周期。结果 38例患者入组,部分缓解13例,疾病稳定17例,疾病进展8例,客观有效率为34.2%,疾病控制率为78.9%。本组中位无进展生存期为4.6个月,95%CI为2.600～6.600个月,中位生存期为13.5个月,95%CI为9.599～17.401个月,1年生存率42.1%。结论吉西他滨和顺铂联合恩度治疗晚期非小细胞肺癌,有较好的疗效和安全性,具有较好临床应用前景。