HIGHLIGHT ARTICLE

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JOP. J Pancreas (Online) 2008; 9(4):391-397.

New Developments in the Treatment of Pancreatic Cancer
Highlights from the “44th ASCO Annual Meeting”. Chicago, IL, USA. May 30 - June 3, 2008

Muhammad Wasif Saif

Medical Oncology, Yale University School of Medicine. New Haven, CT, USA

Summary

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. 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. The author summarizes the key studies presented at the 44th ASCO Annual Meeting, Chicago, IL, USA, May 30 - June 3, 2008. CONKO-001 study: final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer. E4201 study: a randomized phase III study of gemcitabine in combination with radiation therapy vs. gemcitabine alone in patients with localized, unresectable pancreatic cancer. AViTA study: 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. CONKO-003 study: final results of a randomized trial in patients with gemcitabine-refractory pancreatic cancer.


Introduction

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).

Table 1. Key studies in pancreatic cancer presented at the Annual Meeting of ASCO 2008.

Abstract #

Author

Study

Title

LBA4504

Neuhaus et al. [3]

CONKO-001

Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer

4506

Loehrer et al. [4]

E4201A

A randomized phase III study of gemcitabine in combination with radiation therapy vs. gemcitabine alone in patients with localized, unresectable pancreatic cancer

4507

Vervenne et al. [5]

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

4508

Pelzer et al. [6]

CONKO-003

A randomized trial in patients with gemcitabine-refractory pancreatic cancer: final results of the CONKO-003 study

 

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 [7].

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 [3].

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.

Figure 1. Study design CONKO-001: adjuvant chemotherapy in patients with resected pancreatic cancer.
URL: upper reference limit

 

 

Table 2. Final results of the CONKO-001 study.

 

Gemcitabine

Observation

P value

Median disease free survival

13.4 months

6.9 months

<0.001

Median overall survival

22.8 months

20.2 months

0.005

1-year overall survival

72%

72.5%

Not reported

3-year overall survival

36.5%

19.5%

Not reported

5-year overall survival

21%

9.0%

Not reported

 

Table 3. Subgroup analyses of the CONKO-001 study.

Gemcitabine
vs. observation

P value

Hazard
ratio

R0 resection

0.018

0.74

R1 resection

0.088

0.62

N- disease

Not reported

0.57

N+ disease

Not reported

0.80

T1-2

0.120

0.58

T3-4

0.018

0.74

 

In summary, adjuvant treatment with gemcitabine for 6 months significantly increases disease free survival and overall survival compared with observation alone.

Locally Advanced Pancreatic Cancer

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%) [8]. Unfortunately, most succumb with distant metastases. Chemo-radiation 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 [9]. 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) [4].

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 (one-sided 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.

Figure 2. Study design of E4201: gemcitabine in combination with radiation therapy in locally advanced pancreatic cancer.

 

 

Table 4. Preliminary results of the E4201 study.

 

Gemcitabine alone
(n=37)

Gem plus radiation therapy
(n=34)

P value

Objective response rate

5%

6%

Not reported

Partial response

5%

6%

Not reported

Stable disease

35%

68%

Not reported

Median progression free survival

6.7 months

6.0 months

0.50

Median overall survival

9.2 months

11.0 months

0.034

6-month survival

76%

74%

Not reported

18-month survival

11%

29%

Not reported

24- month survival

4%

12%

Not reported

 

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.

First-Line Treatment of 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 single-agent gemcitabine in advanced and metastatic pancreatic cancer is small [10]. 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 [2]. A small gain in median survival by adding erlotinib to gemcitabine has recently been reported [11] (Table 5).

Table 5. Summary of evolution of chemotherapy in advanced pancreatic cancer.

Pre-1996

Many drugs tested, nothing worked

1996

Gemcitabine is FDA approved

1996-2005

No drug or drug combination better than gemcitabine

2005

Gemcitabine-erlotinib is FDA approved

2005

Gemcitabine-capecitabine is better than gemcitabine?

2006

Gemcitabine plus oxaliplatin and fixed-dose rate gemcitabine are not better than gemcitabine (30 minutes)

2006

Gemcitabine plus bevacizumab no benefit

2007

Gemcitabine plus cetuximab no benefit

 

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) [11]. The phase II bevacizumab with gemcitabine trial showed a 21% response rate with a median overall survival of 8.8 months [12]. 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) [5].

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).

Figure 3. Study design of AViTA: addition of bevacizumab to erlotinib and gemcitabine in advanced pancreatic cancer.

 

 

Table 6. Results of the AViTA study.

 

Gemcitabine plus erlotinib, plus:

P value

Placebo (n=301)

Bevacizumab (n=306)

Objective response rate

8.6%

13.5%

Not reported

Complete response

0

0.7%

Not reported

Partial response

8.6%

12.8%

Not reported

Stable disease

45.2%

49.2%

Not reported

Median progression free survival

3.6 months

4.6 months

0.0002

Median overall survival

6.0 months

7.1 months

0.2087

 

Table 7. Toxicity summary of the AViTA study: frequency of grade 3-4 adverse events.

 

Gemcitabine + Erlotinib + Placebo
(n=287)

Gemcitabine + Erlotinb + Bevacizumab
(n=296)

Neutropenia

17%

21%

Thrombocytopenia

7%

8%

Rash

3%

8%

Arterial thromboembolism

3%

3%

Hypertension

1%

3%

Abdominal pain

1%

3%

Proteinuria

0

2%

 

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.

Second-Line Treatment of Advanced Pancreatic Cancer

Current data set on treatment options in second-line setting after gemcitabine failure is scattered and scant. A recently published editorial [13] 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 [6].

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.

Figure 4. Study design of CONKO-003: patients with gemcitabine refractory pancreatic cancer.
FF: 5-FU 2 g/m2 (24 h) plus FA 200 mg/m2 (30 min) on days 1, 8, 15, and 22
OFF: FF plus oxaliplatin 85 mg/m2, days 8 and 22
FA: folinic acid or leucovorin

 

 

Table 8. Efficacy results of the CONKO-003 study.

 

OFF/FF (n=76)

FF (n=84)

P value

Median progression free survival

13 weeks

9 weeks

0.012

Median overall survival

20 weeks

13 weeks

0.014

FF: 5-FU 2 g/m2 (24 h) plus folinic acid or leucovorin 200 mg/m2 (30 min) on days 1, 8, 15, and 22
OFF: FF plus oxaliplatin 85 mg/m2, days 8 and 22

 

Table 9. Toxicity summary of the CONKO-003 study: grade 3-4 adverse events.

 

OFF/FF
(n=76)

FF
(n=84)

Anemia

3

2

Thrombocytopenia

1

0

Neurologic

3

0

Nausea

1

3

Diarrhea

1

0

FF: 5-FU 2 g/m2 (24 h) plus folinic acid or leucovorin 200 mg/m2 (30 min) on days 1, 8, 15, and 22
OFF: FF plus oxaliplatin 85 mg/m2, days 8 and 22

 

Table 10. Benefit of OFF/FF in poor prognostic patients with advanced pancreatic cancer.

 

Median progression free survival (months)

P value

 

OFF/FF (n=76)

FF (n=84)

 

Stage:
- IVa (M0)
- IVb (M1)


13
13


13
8

0.311

Karnofski performance status:
-
90-100%
- 70-80%


14
11


10
7

0.012

FF: 5-FU 2 g/m2 (24 h) plus folinic acid or leucovorin 200 mg/m2 (30 min) on days 1, 8, 15, and 22
OFF: FF plus oxaliplatin 85 mg/m2, days 8 and 22

References

  1. Saif MW. Is there a standard of care for the management of advanced pancreatic cancer?. Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 25-27, 2008. JOP. J Pancreas (Online) 2008; 9:91-8. [More details]

  2. Strimpakos A, Saif MW, Syrigos KN. Pancreatic cancer: from molecular pathogenesis to targeted therapy. Cancer Metastasis Rev 2008 Apr 22. [More details]

  3. Neuhaus P, Riess H, Post S, Gellert K, Ridwelski K, Schramm H, et al. CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC). J Clin Oncol 26: 2008 (May 20 suppl; abstr LBA4504). [More details]

  4. Loehrer PJ, Powell ME, Cardenes HR, Wagner L, Brell JM, Ramanathan R K, et al. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4506). [More details]

  5. Vervenne W, Bennouna J, Humblet Y, Gill S, Moore MJ, Van Laethem J, et al. A randomized, double-blind, placebo (P) controlled, multicenter phase III trial to evaluate the efficacy and safety of adding bevacizumab (B) to erlotinib (E) and gemcitabine (G) in patients (pts) with metastatic pancreatic cancer. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4507). [More details]

  6. Pelzer U, Kubica K, Stieler J, Schwaner I, Heil G, Görner M, et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4508). [More details]

  7. Saif MW. Controversies in the adjuvant treatment of pancreatic adenocarcinoma. JOP. J Pancreas (Online) 2007; 8:545-52. [More details]

  8. Kim R, Saif MW. Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer? JOP. J Pancreas (Online) 2007; 8:279-88. [More details]

  9. Chauffert B, Mornex F, Bonnetain F, Triboulet JP, Bouche O, Rougier P, et al. Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study. J Clin Oncol 2006; 24(18S, Part I):4008. ASCO Annual Meeting. [More details]

  10. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15:2403-13. [More details]

  11. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25:1960-6. [More details]

  12. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23:8033-40. [More details]

  13. Kang SP, Saif MW. Optimal second line treatment options for gemcitabine refractory advanced pancreatic cancer patients. Can we establish standard of care with available data? JOP. J Pancreas (Online) 2008; 9:83-90. [More details]

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Keywords Adenocarcinoma; Carcinoma, Pancreatic Ductal; Fluorouracil; gemcitabine; oxaliplatin; Pancreatic Neoplasms; Radiotherapy; Salvage Therapy; Treatment Failure

Abbreviations CONKO: Charité Onkologie; FA: folinic acid or leucovorin

Conflict of interest The author has no potential conflicts of interest

Correspondence
Muhammad Wasif Saif
Yale Cancer Center
Yale University School of Medicine
333 Cedar Street, FMP 116
New Haven, CT
USA
Phone: +1-203.737.1569
Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu

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