Muhammad Wasif Saif
Medical Oncology, Yale University School of Medicine. New Haven, CT, USA
Adenocarcinoma; Carcinoma, Pancreatic Ductal; Fluorouracil; gemcitabine; oxaliplatin; Pancreatic Neoplasms; Radiotherapy; Salvage Therapy; Treatment Failure
Charité Onkologie; FA: folinic acid or leucovorin
Pancreatic cancer remains a major therapeutic challenge in 2008. The annual incidence rate of pancreatic cancer is almost identical to the mortality rate; approximately 37,000 new cases are diagnosed each year in the United States, and approximately 33,000 patients die from this disease [1, 2]. Poor prognosis has been attributed to an inability to diagnose pancreatic cancer at an early stage. Majority of patients have advanced pancreatic cancer at the time of diagnosis. Advanced disease is associated with a dismal outcome, with a median survival of 3-6 months. Below is a summary of the data on pancreatic cancer presented at the 44th ASCO Annual Meeting’, Chicago, IL, USA, May 30 - June 3, 2008 (Table 1).
Adjuvant Therapy of Pancreatic Cancer
A minority of patients (15-20%) present with resectable disease as pancreatic cancer tends to metastasize to regional lymph nodes early in the course of the disease and many patients have subclinical liver metastases at the time of diagnosis. Despite following curatively intended resection, prognosis of patients with pancreatic cancer is dismal. Whereas gemcitabine-based chemotherapy is standard in advanced pancreatic cancer, the role of adjuvant chemotherapy is still under discussion .
Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer so called the CONKO-001 were presented at the meeting .
CONKO-001. A Multicenter Phase III Trial of Adjuvant Chemotherapy with Gemcitabine versus Observation in Patients with Resected Pancreatic Cancer
Study Design. A prospective, open, multicenter, controlled phase III study was designed to evaluate the efficacy and toxicity of gemcitabine in pancreatic cancer patients after complete (R0 or R1) resection (Figure 1). After stratification for R0/R1, nodal tumor involvement and tumor stage patients were randomized to receive either gemcitabine (1 g/m2 days 1, 8, and 15 every 4 weeks) for 6 months or observation. Objectives. Primary study endpoint was disease free survival; secondary endpoints included overall survival and toxicity. The study was powered to detect a significant difference in disease free survival with 90% probability at a significance level of 0.05 on all eligible patients. Results. The results of this study were recently published in JAMA 2007 showing that postoperative gemcitabine is well tolerated and significantly delays the development of recurrent disease after complete resection of pancreatic cancer. At this meeting, 3-year and 5-year overall survival was presented (Table 2). Subgroup analyses also presented at the meeting demonstrate significant increased disease free survival for gemcitabine in all subgroups of stratification as shown in Table 3.
In summary, adjuvant treatment with gemcitabine for 6 months significantly increases disease free survival and overall survival compared with observation alone.
Surgery is often contraindicated by vascular invasion, making the pancreatic cancer unresectable. Neoadjuvant chemo-radiation has theoretical advantages; however, true pathological down-staging is rare with current treatment (1-5%) . Unfortunately, most succumb with distant metastases. Chemoradiation therapy has shown to be associated with improved overall survival as well as better pain control. A recent French study (FFCD-SFRO: Federation Francophone de Cancerologie Digestive and Societe Francaise de Radiotherapie Oncologique) showed improved overall survival with gemcitabine vs. chemo-radiation using 5-FU and cisplatin . The first study that compared gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with locally advanced pancreatic cancer was presented at the meeting (E4201 study) .
E4201. A Randomized Phase III Study of Gemcitabine in Combination with Radiation Therapy versus Gemcitabine Alone in Patients with Localized, Unresectable Pancreatic Cancer
Study Design. Patients with histologically proven, locally advanced pancreatic cancer, Eastern Cooperative Oncology Group (ECOG) performance status less than 2, without prior chemotherapy or radiation therapy were enrolled onto this study as outlined in Figure 2. Objectives. With a planned sample size of 316 eligible patients, the trial was designed to have an 88% power to detect a 50% improvement in median overall survival from 8 to 12 months (onesided log-rank test; significance level P=0.025). Results. From April 2003 to December 2005, 71 patients were enrolled but 69 only were evaluable. The study was closed early because of slow accrual. The summary of the results are described in Table 4. Toxicity. Although tolerable, gemcitabine in combination with radiation therapy for locally advanced pancreatic cancer was more myelosuppressive, and also associated with considerable gastrointestinal toxicity and fatigue.
In summary, addition of radiation therapy to gemcitabine significantly improves overall survival (P=0.034) and triples the survival rate at 24 months for patients with locally advanced pancreatic cancer.
Little progress has been made on the treatment of advanced pancreatic cancer. Gemcitabine has been an acceptable standard for more than a decade. The benefit of singleagent gemcitabine in advanced and metastatic pancreatic cancer is small . Adding other chemotherapy agents to gemcitabine did not result in meaningful improvement in survival. The randomized trials studying the addition of molecular targeting agents (cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors) to gemcitabine compared with gemcitabine alone have been disappointing . A small gain in median survival by adding erlotinib to gemcitabine has recently been reported  (Table 5).
In the phase III, overall survival trial of erlotinib plus gemcitabine vs. gemcitabine the hazard ratio was 0.82 (95% CI: 0.69-0.99; P=0.0328) . The phase II bevacizumab with gemcitabine trial showed a 21% response rate with a median overall survival of 8.8 months . Therefore, a phase III randomized, double-blind, placebo controlled, multicenter study was conducted to evaluate the efficacy and safety of adding bevacizumab to erlotinib and gemcitabine in patients with metastatic pancreatic cancer (AViTA study) .
AViTA. A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase III Trial to Evaluate the Efficacy and Safety of Adding Bevacizumab to Erlotinib and Gemcitabine in Patients with Metastatic Pancreatic Cancer.
Study Design. The study design is shown in Figure 3. Objectives. The primary endpoint was overall survival, and the secondary endpoints included response, progression free survival, safety, and tolerability. Results. As of March 2007, 454 patients (233/221) had died. Efficacy results are summarized in Table 6. Toxicity. No clinically relevant difference observed in grade 3-4 adverse events between the two arms (Table 7).
In summary, the study showed that the triple combination with two biologics combined with gemcitabine significantly improved progression free survival (P=0.0002), but not overall survival (P=0.2087), compared to gemcitabine plus erlotinib.
Current data set on treatment options in second-line setting after gemcitabine failure is scattered and scant. A recently published editorial  highlighted that there is no consensus about second-line therapy after disease progression while receiving gemcitabine, but 5-FU-based regimens are considered. Randomized second line studies in advanced pancreatic cancer are very rare. At this meeting, the results of the CONKO- 003 study were presented .
CONKO-003. A Randomized Trial in Patients with Gemcitabine Refractory Pancreatic Cancer
Study Design. This study randomized 165 patients to FF (5-FU 2 g/m2 (24 h) plus folinic acid or leucovorin (FA) 200 mg/m2 (30 min) on days 1, 8, 15, and 22) or OFF (FF plus oxaliplatin 85 mg/m2, days 8 and 22) (Figure 4). Objectives. The primary endpoint was overall survival and secondary endpoints were disease free survival and toxicity. Results. The results presented at the meeting are summarized in Tables 8 and 9. The study indicated that alternating OFF/FF and continuous FF are feasible and tolerable regimens as second-line treatment of advanced pancreatic cancer after gemcitabine failure. OFF/FF results in significantly longer progression free survival (P=0.012) and overall survival (P=0.014) vs. FF. OFF/FF also results in substantially greater clinical benefit in patients with poor prognostic features (Table 10).
The authors suggested that OFF/FF should be considered standard second-line treatment in patients who progress on gemcitabine.
The author has no potential conflicts of interest