Any Second-Line Therapy for Advanced

Jia Li
, Man Yee Merl
, Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine;
Yale New-Haven Hospital.
New Haven, CT, USA
Majority of pancreatic cancers are unresectable upon diagnosis. Palliative chemotherapy is usually administered in an attempt of
prolonging survival potentially and providing quality of life. Gemcitabine has been the solo player in the field of pancreatic cancer
treatment after replacing 5-FU since 1997. How to treat a patient with advanced pancreatic cancer failing to respond or progressing
after gemcitabine is a true challenge. No established second-line treatment exists yet. Chinese herbal medicine PHY906 provides
cytoprotective effects without dampening the anti-tumor activity of chemotherapeutic agents. Several combinations such as S-
1/gemcitabine, GTX, FOLFIRINOX showed promising results in retrospective studies. Among single agents, erlotinib and Src
inhibitor failed to show seemingly benefit, while abraxane and pemetrexed deserve further investigation.
Pancreatic cancer remains the 4th cause of cancer death
after lung, prostate (breast in women), and colorectal
cancer since 1970s in the USA [1]. Small localized
tumors can be possibly cured by surgical resection,
however, majority of the tumors are either locally
advanced or metastatic upon diagnosis. Among all
studied chemotherapeutic agents, gemcitabine was the
only one demonstrating a significantly higher clinical
benefit response compared to historical 5-fluorouracil
(5-FU) infusion [2]. Since 1997, gemcitabine
established its unshakable status as first-line therapy
for advanced pancreatic cancer. Various combinations
using gemcitabine as a backbone were subsequently
investigated in large randomized clinical trials; none of
the combinations is proved to be superior to
gemcitabine monotherapy except erlotinib plus
gemcitabine [3].
What if patients are not responding to first-line
gemcitabine-based regimen? Is there a standard
second-line therapy? Unfortunately, the answer is still
no, though there is growing evidence supporting some
benefit of chemotherapy after gemcitabine in selected
patients. Several encouraging abstracts presented on
the 2010 ASCO Gastrointestinal Cancers Symposium
in the field of pancreatic cancer deserve a discussion
here (Table 1).
Combination Therapies
Capecitabine plus Chinese Herbal Medicine PHY906
PHY906 has not only synergistic antitumor activity
with several chemotherapeutic agents including
irinotecan, capecitabine and gemcitabine, but also
cytoprotective effect. Our institute, Yale Cancer
Center, has opened several early phase trials
investigating the use of PHY906 in different types of
cancers such as colorectal, pancreatic cancer and
hepatocellular carcinoma. In our phase II trial, PHY906
is administered with capecitabine for patients
refractory to first-line gemcitabine therapy [4]. The
anti-diarrhea and anti-hand-foot syndrome effects were
very promising. In patients who received more than 2
cycles, median overall survival was 6.8 months.
S-1 Followed by Gemcitabine
Among all combination trials, tegafur, 5-chloro-2,4-
dihydroxyuridine and potassium oxonate (S-1)
followed by gemcitabine sequential use is probably the
most exciting one. Its anti-tumor activity has been
explored beyond gastric cancer in Japan. S-1 and
gemcitabine were administrated sequentially in 29
patients with gemcitabine refractory pancreatic cancer
Keywords: erlotinib; gemcitabine; Pancreatic Neoplasms; S 1
Abbreviations GTX: gemcitabine, docetaxel and capecitabine; S-
1: tegafur, 5-chloro-2,4-dihydroxyuridine and potassium oxonate;
SPARC: secreted protein acidic and rich in cysteine; Src: v-src
sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)
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
Document URL

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JOP. Journal of the Pancreas - - Vol. 11, No. 2 - March 2010. [ISSN 1590-8577]
[5]. One patient (3.4%) achieved complete response
and 5 patients (17.2%) achieved partial response.
Median overall and progression free survivals were
12.3 and 3.5 months, respectively.
5-Fluorouracil, Leucovorin, Irinotecan and Oxaliplatin
Both oxaliplatin and irinotecan are known to have
survival benefit in combination with 5-fluorouracil and
leucovorin (5-FU/LV) in metastatic colorectal cancer.
Breysacher et al. reported a retrospective study
investigating the role of FOLFIRINOX as second-line
therapy [6]. No response was seen in 13 patients and 1-
year survival rate was 62%. GI toxicity was frequent
but mild and manageable.
Gemcitabine, Docetaxel, and Capecitabine (GTX)
GTX regimen has shown activity in both neoadjuvant
and metastatic settings. No data exists on the use of
GTX in second-line. In a retrospective study of 59
patients received GTX after initial standard therapies, a
drop greater than 75% in CA 19-9 after treatment
predicted longer overall survival [7].
Single Agents
Pancreatic cancer cells and surrounding stroma
overexpress SPARC (secreted protein acidic and rich in
cysteine). Abraxane increased tumor accumulation of
paclitaxel through binding of albumin to SPARC.
Abraxane plus gemcitabine did demonstrate clinical
benefit in early phase trials [12]. Abraxane alone
appears to be promising as well. One of 19 patients
(5.3%) achieved partial response [8]. Whether SPARC
expression is a predicative biomarker needs further
In a phase II trial, pemetrexed rendered median
progression free survival of 2 months to patients who
failed gemcitabine [8]. No concerning adverse events
were found except grade 3 neutropenia in two patients
Molecular Target Therapy
Erlotinib with gemcitabine combination gained FDA
approval for a small overall survival benefit. However,
when erlotinib used as single agent, it lost this modest
benefit completely [9]. Src family tyrosine kinases are
overexpressed in pancreatic cancers. The anti-tumor
activity of Src inhibitor saracatinib was demonstrated
in a mouse model [13]. Unfortunately, saracatinib
failed to improve 6-month survival in a phase II trial
[10]. Only 2 of 18 patients survived beyond 6 months
Options for pancreatic cancer in advanced or metastatic
setting remain limited. Gemcitabine as the only FDA-
approved chemotherapeutic agent has been intensively
and extensively investigated in combination with other
drugs; unfortunately, no additional benefit was seen.
Unlike the first-line setting, there is no standard of care
after gemcitabine failure. Drugs in this setting should
consider clinical benefit more importantly than anti-
tumor activity. Several abstracts report either single
agents or combinations with or without gemcitabine
did demonstrate some potential clinical benefit.
Chinese herbal medicine PHY906 provides convincing
cytoprotective effect when used in combination with
chemotherapeutic agents. More clinical trials of
PHY906 are being conducted at Yale Cancer Center.
FOLFIRINOX is also an interesting and promising
combination. Surprisingly, the toxicity profile was not
alarming. Other two combinations continued to use
gemcitabine even after failure in the initial therapy.
Sequential S-1 and gemcitabine should be tested in
clinical trial setting. Among single agents, abraxane
and pemetrexed warrant further investigation.
Conflict of interest The authors have no potential
conflicts of interest
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer
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ML, Modiano MR, et al. Improvements in survival and clinical
Table 1. Summary of trials investigating second-line treatment.
Median survivals (months)
#246 [4]
Phase II
Capecitabine plus PHY906
22% (9 months)
#241 [5]
S-1 followed by gemcitabine
#269 [6]
62% (1 year)
#221 [7]
#165 [8]
Phase II
Src inhibitor: saracatinib
11% (6 months)
#214 [9]
Phase II
63% (6 months)
#276 [10]
Phase II
#258 [11]
Phase II
FOLFIRINOX: 5-fluorouracil, leucovorin, irinotecan and oxaliplatin; GTX: gemcitabine, docetaxel and capecitabine; NR: not reported; S-1: tegafur,
5-chloro-2,4-dihydroxyuridine and potassium oxonat; Src: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

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JOP. Journal of the Pancreas - - Vol. 11, No. 2 - March 2010. [ISSN 1590-8577]
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