\ Challenging Cases/Rare Cancers J
`
`Treatment update for metastatic
`pancreatic cancer
`
`•
`
`Maureen R. Hewitt, MD, and Kenneth Yu, MD
`
`Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA
`
`The treatment of metastatic pancreatic cancer continues to be a major unresolved health problem and a therapeutic
`challenge, with a poor median survival averaging 3-6 months. Di sappointing response rates to standard single-agent
`therapy have led to a sea rch for more effective agents. Early study results with gemcitabine indicate a potential survival
`benefit in these patients, which is illustrated here in a case report of a 75-year-old man with metastatic pancreatic
`adenocarcinoma who has defied the odds. Chemotherapy with GEMOX (gemcitabine and oxaliplatin) was initiated, and
`the patient has enjoyed a good quality of life, with long-term disease control (stable disease 21 month s after diagnosis).
`
`ancreatic cancer is the fourth most
`common cause of cancer death in men
`and the fifth most common cause of
`cancer death in women in the United
`States. In 2006, an estimated 33,730
`new cases of pancreatic cancer and
`32,300 deaths due to the disease are expected in the
`United States. 1 Only 1 %-4% of patients diagnosed
`with this neoplasm are alive 5 years after diagnosis.
`Due to their anatomic location, pancreatic tumors
`typically do not produce specific signs or symptoms
`until they are significantly enlarged. As a result, most
`patients with pancreatic cancer have locally advanced
`or metastatic disease at the time of presentation. Un(cid:173)
`fortunately, the median survival of those with meta(cid:173)
`static disease averages 3-6 months.
`
`Case history
`A 75-year-old man had a history of diet-con(cid:173)
`trolled diabetes for several decades. Nine months
`prior to presentation, he initiated insulin therapy
`due to worsening control of his diabetes. He also
`reported mild mid-thoracic back pain and a 10-
`pound weight loss about 3 months prior to presen(cid:173)
`tation. Other than diabetes, his medical history is
`notable for a myocardial infarction and coronary ar(cid:173)
`tery bypass surgery. He has a remote history of to(cid:173)
`bacco use and consumes alcohol in moderation.
`Computed tomography of the chest and abdomen
`revealed multiple pulmonary lesions (measuring up
`to 2.5 cm) and a poorly defined mass in the body of
`the pancreas (Figures 1 and 2). A fine-needle aspi(cid:173)
`rate of the pancreatic mass revealed groups of atypical
`glandular cells. A lung wedge biopsy ciemonstrated
`a moderately differentiated metastatic adenocarcino(cid:173)
`ma. Immunohistochemical stains of this tissue were
`
`positive for CK7 and CK20 and negative for TTF-1
`(thyroid transcription factor-1, expressed in epithe(cid:173)
`lial cells of the thyroid gland and the lung), favoring
`a gastrointestinal primary tumor. The CA 19-9 level
`was elevated at 276 U/mL (normal, 0-37 U/mL).
`On initial physical examination, he was afebrile,
`with a blood pressure of138/65 mm Hg and a pulse of
`72 beats/min. He weighed 144 pounds at 5'6" tall and
`had mild temporal wasting. There was no evidence of
`scleral icterus. Cardiac examination revealed a normal
`Sl and S2. His lungs were clear to auscultation, and
`his abdominal examination was normal. There was no
`palpable lymphadenopathy. His Eastern Cooperative
`Oncology Group (ECOG) performance status was 1.
`After his initial presentation, chemotherapy with
`GEMOX (gemcitabine [Gemzar], 1,000 mg/m2 over
`100 minutes on day 1, plus oxaliplatin [Eloxatin], 100
`mg/m2 over 2 hours on day 2, both administered every
`2 weeks) was started. Two months after starting ther(cid:173)
`apy, imaging studies revealed regression of the pancre(cid:173)
`atic mass and stable pulmonary disease. The CA 19-9
`level decreased to within normal limits (36 U/mL).
`Although the patient tolerated therapy well, after 12
`cycles of treatment, he developed grade 2 neuropathy
`of his hands and feet. As a result, oxaliplatin was dis(cid:173)
`continued, and the neuropathy decreased to grade 1;
`over the next several cycles, however, the CA 19-9 lev(cid:173)
`el elevated slightly to 60 U/mL. He was maintained
`on a fixed dose rate of gemcitabine every 14 days.
`
`-
`-
`- - -- - --
`Manuscript received May 1, 2006; accepted June 7, 2006 .
`
`Correspondence to: Maureen R. Hewitt, MD, Abramson
`Cancer Center of the University of Pennsylvania, 16 Penn Tow(cid:173)
`er, 3400 Spruce Street, Philadelphia, PA 19104; telephone: 215 -
`662-3915; fax: 215-349-8144; e- mail: 1nauree11.hewin@\1phs.
`upcnn.edu.
`Commun Oncol 2006:3:428-430 © 2006 Elsevier Inc. All rights reserved.
`
`428 COMMUNITY ONCOLOGY • July 2006
`
`www.CommunityOncology.net
`
`Th is m at,er ial w asco?ied
`at the NLM and m ay t>e
`
`NOVARTIS EXHIBIT 2006
`Roxane v. Novartis, IPR 2016-01461
`Page 1 of 3
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`

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`M eta static pancreatic cancer
`
`CHALLENG ING CASES/RA RE CAN CERS
`
`One year after his initial diagnosis,
`the treatment course was interrupted
`for 4 weeks while he underwent a her(cid:173)
`ni orrhaphy. During that time, the CA
`19-9 level rose to 121 U/mL, and the
`pulmonary lesions worsened. Postoper(cid:173)
`atively, a fixed close rate of gemcitabine
`was restarted, and he has been main(cid:173)
`tained on this chemotherapy since then.
`The most recent CA 19-9 level was 97
`U/mL, and imaging studies revealed
`stable disease, 21 months after diagno(cid:173)
`sis. Clinically, the patient is doing well
`and reports only mild diarrhea.
`
`Standard treatment
`Single-age nt chemotherapy has
`been the primary treatment of meta(cid:173)
`stati c pancreatic cancer. However, the
`response rates associated with single(cid:173)
`agent therapy, typi cally < 10%, have
`bee n di sappointing.
`5-Fluorouracil (5-FU) has been
`available since the late 1950s and re(cid:173)
`mains the foundation of treatment fo r
`most gastrointestinal tumors. Its ad (cid:173)
`ministration, both as a single age nt
`and in conjunction with modulators,
`has been extensively studied over the
`past 50 years. Unfortunately, the most
`rece nt studies of leucovorin- modulat(cid:173)
`ed 5- FU in pan creatic can cer sugges t
`a low response rate (0%- 9%) using
`infusional as well as bolus administra(cid:173)
`ti on schedules and a median survival
`ranging from 10 to 24 weeks. 2•3
`
`Use of gemcitabine
`The early clinical trials of gem(cid:173)
`citabine took a novel approach to de(cid:173)
`termine benefit in metastatic disease.
`In 1996, a phase II study was conduct(cid:173)
`ed in patients with metastatic pancre(cid:173)
`atic cancer refractory to gemcitabine.~
`The primary endpoint was alleviation
`of can cer-related symptoms, not over(cid:173)
`all survival or tumor response. In thi s
`tri al, 27% of patients derived a clini(cid:173)
`cal benefit from therapy (ie, improve(cid:173)
`ment in pain, perfo rmance status, or
`weight), whereas only 11 % of patients
`derived an objective tumor response.
`This study led to US Food and Drug
`
`Volum e 3/Number 7
`
`Administration (FDA) approval of
`single-agent gemcitabine for the treat(cid:173)
`ment of metastatic pancreatic cancer.
`A follow-up trial to assess clinical
`benefit and survival included previous(cid:173)
`ly untreated patients with unresectable
`pancreati c cancer who were random(cid:173)
`ly assigned to receive weekly 5-FU or
`gcmcitabine.5 Although the study de(cid:173)
`sign had several flaws, including lack
`of blinding to those determining clini(cid:173)
`cal response and failure to administer
`leucovorin with 5-FU, gemcitabine
`was associated with a significantly bet(cid:173)
`ter clinical response (24% vs 5%) and
`1-year survival (18% vs 2%).
`Pharmacokinetic data suggested
`that longer infusion times of gem(cid:173)
`citabine may have an advantage over
`shorter infusion times, since the acti(cid:173)
`vation of gemcitabine to gemcitabine
`triphosphate by deoxycytidine kinase
`is saturated at infusion rates of approx(cid:173)
`imately 10 mg/m2 per minute.6 Based
`on these findings, a phase II study was
`conducted in whi ch patients with ad(cid:173)
`vanced disease were randomly as(cid:173)
`signed to receive gemcitabine at 1,500
`mg/m2 over 150 minutes (fixed close
`rate) or 2,200 mg/m2 over 30 minutes
`(constant dose rate). 7 The fixed dose
`rate was associated with a significantly
`better median survival (8 months vs 5
`months) and 1-year survival (29% vs
`2%) than the constant close rate.
`To improve upon the benefit pro(cid:173)
`vided by gemcitabine alone, various
`doublet regimens have been proposed.
`Gemcitabine has been combined with
`both bolus and infusional 5-FU. Sev(cid:173)
`eral clinical trials have failed to show
`any advantage in overall survival with
`the combination co mpared with gem(cid:173)
`9
`citabine alone.8
`·
`G emcitabine has also been combined
`with oxa1platin. A mLJticenter trial of
`326 patients with umesectable pancre(cid:173)
`atic cancer (GERCOR) randomly as(cid:173)
`signed patients to receive gemcitabine
`(30-minute infosion) versus GEMOX
`(gemcitabine [1,000 mg/m2 over 100
`minutes on day 1] plus oxaliplatin [100
`mg/m2 over 2 homs on clay 2], admin-
`
`FIGURE 1 Abdominal CT scan demonstrating atrophy
`of the pancreatic tail with prominence of the pancre(cid:173)
`atic duct which is related to a poorly defined mass in
`the body of the pancrea s.
`
`in
`FIGURE 2 Chest CT scan demonstrating a ma ss
`the right lower lobe . Wedge resecti on of thi s mass re(cid:173)
`vea led meta static adenocarcinoma consistent wi th a
`gastrointestinal pri mary.
`
`isterecl every 2 weeks). 10 The GEM OX
`study m-rn was associated with signifi (cid:173)
`cantly higher response rates (27% vs
`17%) and progression-free surviv,J (5.8
`months vs 3.7 months). Although there
`was a trend towm·d improved median
`survival (9 months vs 7 months), it was
`not statistically significant (P = 0.13).
`One criticism of th.is study is the
`nonunifo rm administration of gem(cid:173)
`citabine between the study arms. Pa(cid:173)
`tients receiving GEMOX were given
`a fixed-dose-rate gemcitabine, whereas
`those receiving gemcitabine alone were
`given a constant dose rate. As a result,
`it is not cbu- whether the benefit seen
`in the GEM OX arm was at least partly
`clue to the differences in administration
`of gemcitabine. To answer this question,
`
`Thii.s. m ate·ri a I w as oo~i e-d
`:ot th11 NI M ,. n,i m-" V h P·
`
`July 2006 • COMMUN ITY ONCOLOGY 429
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`NOVARTIS EXHIBIT 2006
`Roxane v. Novartis, IPR 2016-01461
`Page 2 of 3
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`

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`CHALLENG ING CASES/RARE CANCERS
`
`Hewitt/Yu
`
`Resources
`Pancreatic Cancer Actian Netwark
`www.pancon.org
`For a listing of clinical trials go to:
`www.pancrea lica.org
`MedlinePlus
`www.n lm.nih.gov/medlineplus/
`pancrealiccancer. html
`
`a phase III ECOG trial was conducted
`(ECOG 6201) which compared fixed(cid:173)
`dose-rate gemcitabine (1,500 mg/m2
`over 150 min) with and without oxali(cid:173)
`platin (100 mg/m2
`) to standard infosion
`gemcitabine (1,000 mg/m2 over 30 min(cid:173)
`utes).11 The patients who received fixed(cid:173)
`dose-rate gemcitabine and GEMOX
`had an increase in overall survival (6.0
`months and 5.9 months respectively)
`comp1u-ed with standard infusion gem(cid:173)
`citabine (4.9 months); however, this in(cid:173)
`crease was not statistically significant.
`
`Radiation therapy
`Currently, there is no proven role for
`the use of radiation therapy in the treat(cid:173)
`ment of metastatic pancreatic cancer.
`H owever, in patients with locally ad(cid:173)
`vanced, unresectable disease, radiation
`therapy with and without chemother(cid:173)
`apy has been explored to help extend
`overall survival in these patients. These
`trials have failed to show a survival ad(cid:173)
`vantage of chemoradiotherapy over che(cid:173)
`motherapy alone.12·11 Importantly, one
`of these trials revealed that while gem(cid:173)
`citabine is a potent radiosensitizer, the
`toxicity associated with combined gem(cid:173)
`citabine and radiation is significant and
`not tolerable. It is not yet clear if 5-FU
`plus radiation is superior to gemcitabine
`alone or a combination regimen in pa(cid:173)
`tients with locally advanced disease.
`
`Biologic agents
`The success of biologic agents in
`the treatment of metastatic colon can(cid:173)
`cer offers hope for similar outcomes in
`the treatment of metastatic pancreatic
`cancer. Pancreati c tumors frequ ent(cid:173)
`ly exp ress receptors fo r epiderm al
`growth factor (EGFR)' ' and vascular
`endothelial growth factor (VEGF)' \
`therefore, age nts that target these re-
`
`ceptors are of parti cular interest.
`Erlotinib (Tarceva), an EGFR ty(cid:173)
`rosine kinase
`inhibitor, has already
`shown efficacy in the treatment of
`metastatic pancreatic cancer. A recent
`phase III study in which patients with
`unresectable or metastatic pancreat(cid:173)
`ic cancer were randomized to receive
`gemcitabine or gemcitabine plus er(cid:173)
`lotinib (100 mg/cl) revealed a statisti(cid:173)
`cally significant survival benefi t in the
`combination arm.16 Although the sur(cid:173)
`vival benefit was modest (median sur(cid:173)
`vival, 6.4 months vs 5. 9 months; 1-year
`survival, 24% vs 17%), this study led to
`FDA approval of erlotinib in combina(cid:173)
`tion with gemcitabine for unresectable
`or metastatic pancreatic cancer.
`trials
`There are several ongoing
`studying the role ofbevacizumab (Avas(cid:173)
`tin) and cetuximab (Erbitux) in combi(cid:173)
`nation with chemotherapy for metastat(cid:173)
`ic pancreatic cancer. These results are
`anxiously awaited, and we hope these
`agents will provide benefit to our pa(cid:173)
`tients with this devastating disease.
`
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`
`ABOUT THE AUTHORS
`Affiliolions: Dr. Hewitt is a hematology/ oncol(cid:173)
`ogy fellow and Dr. Yu is Instructor of M edicine al
`the Abra mson Cancer Center of the University of
`Pen nsylvania, Philadelphia.
`Conl/icls of interest: None repor ted.
`
`www. Commun ityOncology. net
`
`NOVARTIS EXHIBIT 2006
`Roxane v. Novartis, IPR 2016-01461
`Page 3 of 3