Chapter 29: Pancreatic Cancer

Ramesh K. Ramanathan; Daniel D. Von Hoff

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

46,420 (male: 23,530; female: 22,890. Estimated new cases for 2014 in the United States)

Stage at presentation:

(13.9 per 100,000 males; 10.9 per 100,000 females)

Stage I:

20%

Deaths:

Estimated 39,590 in 2014 (male: 20,170; female: 19,420)

Stage II:

40%

Median age:

71 years

Stage III–IV:

40%

Male to female ratio:

~1:1

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology, and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Takhar AS et al. BMJ 2004;329:668–673

Pathology

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Pathology

Most cancers of the pancreas arise in the head of the pancreas (60–70%), 15% in the body, and 5% in the tail; in 20%, the neoplasm diffusely involves the entire gland

Malignant Tumors of Pancreatic Origin

Ductal adenocarcinoma

85–90%

Acinar cell carcinoma

1–2%

Undifferentiated carcinoma (anaplastic giant cell, osteoclastic giant cell)

<1%

Sarcomatoid carcinoma/carcinosarcoma

<1%

de Braud F et al. Crit Rev Oncol Hematol 2004;50: 147–155

Solcia E et al. Tumors of the pancreas. In: Atlas of Tumor Pathology, 3rd series. Washington, DC: Armed Forces Institute; 1997

Work-up

The diagnosis of pancreatic cancer is based on imaging studies and histologic confirmation performed by fine-needle aspiration by endoscopic ultrasonography (EUS), biopsy under CT or US guidance, or during laparotomy

History and physical examination
CBC and differential, serum electrolytes, creatinine, LFTs, PT, PTT, CA19-9
Imaging:
- Spiral CT: Spiral or a helical CT of the abdomen according to a defined pancreatic protocol is essential. CT provides localization, size of the primary tumor, and evidence of metastasis and evaluates major vessels adjacent to the pancreas for neoplastic invasion or thrombosis. CT is almost 100% accurate in predicting unresectable disease. However, the positive predictive value of the test is low and approximately 25–50% of patients predicted to have resectable disease on CT turn out to have unresectable lesions at laparotomy
- Endoscopic retrograde cholangiopancreatography (ERCP) can also be useful in patients whom a CT scan is equivocal, because fewer than 3% of patients with pancreatic carcinoma have normal pancreatograms
- EUS is a relatively new technique and provides useful information. However, EUS needs to be performed in centers with experience in this procedure. EUS is useful for characterizing cystic lesions and assessment of vascular invasion by tumor. In addition, an aspirate can be done for histologic diagnosis. A celiac plexus block can be done via EUS for relief of abdominal pain

Agawam B. Am J Gastroenterol 2004;99:844–850

Tamm EP et al. Radiographic Imaging: Daniel D. Von Hoff, Douglas B. Evans, Ralph H. Hruban, eds. Pancreatic Cancer, 1st ed. Jones & Bartlett Publishers, 2005:165–180

Staging

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Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ

Tumor limited to the pancreas, 2 cm or less in greatest dimension

Tumor limited to the pancreas, more than 2 cm in greatest dimension

Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery

Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

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Staging

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Regional lymph node metastasis

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Staging

Distant Metastasis (M)

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

Distant metastasis

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Staging

Stage

Tis

IIA

IIB

III

Any N

Any T

Any N

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

Expert Opinion

Pancreatic cancer can be broadly divided into 2 groups: surgically resectable or unresectable/advanced cancer. Patients should be enrolled to suitable clinical trials for all stages of pancreatic cancer if possible

Surgery

The only curative therapy for pancreatic cancer is resection of the tumor and the surrounding tissues. Patients with resectable disease comprise the smallest group (~15%)
Criteria for unresectable tumors include:
- Distant metastases
- SMA, celiac encasement
- SMV, portal vein occlusion
- Aortic or IVC invasion, or encasement
- Invasion of SMV below the transverse mesocolon
Borderline resectable pancreatic cancer
- Patients who present with localized pancreatic cancer but who have a high likelihood of a positive surgical margin (R1) are classified as borderline resectable. A commonly used criteria is as follows:
  - Severe unilateral SMV/Portal impingement
  - Tumor abutment on SMA
  - GDA encasement up to origin of hepatic artery
  - SMV occlusion, if of a short segment with open vein both proximally and distally
  - Adrenal, colon or kidney invasion

Key: GDA, Gastroduodenal artery; IVC, inferior vena cava; SMA, superior mesenteric artery; SMV, superior mesenteric vein

Preoperative Therapy

Treatment regimens include chemoradiation with fluorouracil similar to the regimen used in RTOG 97-04 (Regine et al.). Concurrent involved field radiation with gemcitabine is an alternate regimen. The E4201 study (Loehrer et al.) administered concurrent gemcitabine with RT to patients with locally advanced cancer. RT (50.4 GY in 28 fractions) plus gemcitabine (600 mg/m² per week for 6 weeks)

Loehrer P et al. Proc Am Soc Clin Oncol 2008;26(15S, Part I of II):214s [abstract 4506]

Regine WF et al. JAMA 2008;299:1019–1026

Adjuvant Therapy

Following surgery, adjuvant therapy should be considered for patients who have recovered from surgery. Approximately 20–25% of patients will have a prolonged convalescence and/or a suboptimal performance status following surgery and will not be candidates for adjuvant therapy
Evaluate all patients for adjuvant therapy. Gemcitabine 1000 mg/m² administered intravenously, may be given weekly for 3 consecutive weeks every 4 weeks for 6 cycles
Administer radiation with chemosensitizing fluorouracil or capecitabine in addition to gemcitabine as a component of adjuvant therapy for patients at high risk of recurrence. These are patients with a microscopic positive margin (R1 resection), extracapsular lymph node extension, and multiple involved regional nodes (≥4) at resection
Adjuvant therapy with gemcitabine with or without concurrent chemoradiation with fluorouracil should be considered in most patients
The efficacy of combined radiation and fluorouracil as adjuvant therapy for pancreatic cancer was first demonstrated by a small prospective randomized study conducted by the Gastrointestinal Tumor Study Group (GITSG). Twenty-two patients were randomized to no adjuvant treatment and 21 patients were assigned to receive combined modality therapy

Radiation Therapy

Two courses of 2000 cGy, each given for 5 days separated by an interval of 2 weeks +
Fluorouracil 500 mg/m² per day, administered intravenously in 25–250 mL 0.9% sodium chloride (0.9% NS) or 5% dextrose injection (D5W), USP, over 10–30 minutes for 3 consecutive days for the first 3 days of each 2000-cGy segment of radiation therapy (total dosage/3-day course = 1500 mg/m²). Subsequently, treatment resumed 1 month after completion of radiation with fluorouracil 500 mg/m² per dose administered intravenously for 3 consecutive days, on days 1–3 of each week for 2 years of therapy
The median survival for the treatment group was 20 months vs. 11 months for the control group, and the median disease-free survival was 11 months for the treated group vs. 9 months for the control group

This study and data from a subsequent confirmatory study of an additional 30 patients treated with the similar regimen of fluorouracil and RT provided evidence for the role of adjuvant therapy in resected pancreatic cancer

Gastrointestinal Tumor Study Group. Cancer 1987;59:2006–2010

Kalser MH et al. Arch Surg 1985;120:899–903

The benefit of gemcitabine monotherapy was demonstrated by Oettle et al. This multicenter study randomized 368 patients following surgery to observation or adjuvant therapy starting 6 weeks after surgical resection:

Gemcitabine 1000 mg/m² per dose administered intravenously in 0.9% NS, over 30 minutes for 3 doses on days 1, 8, and 15 every 4 weeks for 6 months (total dosage/4-week cycle = 3000 mg/m²)
Therapy with gemcitabine was well tolerated. The primary endpoint of disease-free survival was significantly improved in the treatment group (13.4 months vs. 6.9 months, P <0.001); the median survival (22.1 vs. 20.2 months) was similar in both groups

Oettle H et al. JAMA 2007;297:267–277

The European Study Group for Pancreatic Cancer (ESPAC 1, 2, and 3) evaluated the role of fluorouracil, gemcitabine, and RT as adjuvant therapy and support the role of chemotherapy alone as adjuvant therapy. The role of RT and the detrimental effect of RT seen in these studies have been controversial as a result of the lack of quality control and central review. ESPAC-3 (n = 1088) compared gemcitabine to fluorouracil as adjuvant therapy. The median survival for both groups was approximately 23 months. However, the safety profile favors gemcitabine as the preferred regimen for adjuvant therapy

Neoptolemos JP et al. N Engl J Med 2004;350:1200–1210. Erratum in: N Engl J Med 2004;351:726

Neoptolemos JP et al. Br J Cancer 2009;100:246–250

Neoptolemos JP et al. Proc Am Soc Clin Oncol 2009;27(Suppl):18s [abstract LBA-4505]

Therapy of Patients with Metastatic Pancreatic Cancer and "Good" Performance Status—First line regimen

In this group are patients with an ECOG performance status of 0 or 1 and with minimal cancer-related symptoms. Meta-analyses have indicated that patients with a good performance status can benefit from combination therapy with gemcitabine regimens. Two regimens are considered to have activity and are recommended in first line:

nab-Paclitaxel + gemcitabine: MPACT was a large, international study performed at community and academic centers. nab-Paclitaxel + gemcitabine was superior to gemcitabine monotherapy across all efficacy endpoints, had an acceptable toxicity profile. nab-Paclitaxel + gemcitabine is a new option for the treatment of metastatic pancreatic cancer that will now be studied in the adjuvant and locally advanced setting
FOLFIRINOX: As compared with gemcitabine, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin] was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and a good performance status [younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels]

Therapy of Patients with Metastatic Pancreatic Cancer and "Good" Performance Status—Second line regimen

In second line one can consider the alternate regimen of the two above or the OFF regimen

Conroy T et al. N Engl J Med 2011;364:1817–1825

Pelzer et al. European J Cancer 2011;47:1676–1681

Von Hoff DD et al. J Clin Oncol 2011;29:4548–4554

Von Hoff et al. J Clin Oncol 31, 2013(Suppl; abstr 4005)

An intergroup study (RTOG 97-04) provides support for concurrent chemoradiation as adjuvant therapy. This study provided central review and quality assurance for RT. Regine et al., randomly assigned patients (n = 451) to 1 of 2 chemotherapy regimens following a pancreatectomy for 3 weeks prior to chemoradiation therapy, and then for an additional 12 weeks, starting 3–5 weeks after completing chemoradiation:

Pre-chemoradiation regimens
- Group 1:
  
  Fluorouracil 250 mg/m² per day in 25–500 mL 0.9% NS or D5W administered intravenously over 10–30 minutes, daily for 3 weeks (total dosage/3-week course = 5250 mg/m²)
- Group 2:
  
  Gemcitabine 1000 mg/m² per dose diluted with 0.9% NS to concentrations as low as 0.1 mg/mL administered intravenously over 30 minutes once weekly for 3 weeks (total dosage/3-week course = 3000 mg/m²)
During chemoradiation
- Groups 1 and 2:
  
  Fluorouracil 250 mg/m² per day in 25–1000 mL 0.9% NS or D5W administered by continuous intravenous infusion over 24 hours, daily throughout radiation therapy
Post-chemoradiation regimens:
- Group 1:
  
  Fluorouracil 250 mg/m² per day in 25–500 mL 0.9% NS or D5W administered intravenously over 10–30 minutes, daily for 4 consecutive weeks (28 days) every 6 weeks for two 6-week cycles (total dosage/6-week cycle = 7000 mg/m²)
- Group 2:
  
  Gemcitabine 1000 mg/m² per dose diluted with 0.9% NS to concentrations as low as 0.1 mg/mL, administered intravenously over 30 minutes once weekly for 3 consecutive weeks every 4 weeks for three 4-week cycles (total dosage/4-week cycle = 3000 mg/m²)
Chemoradiation was given for a total dose of 50.4 Gy with fluorouracil. On multivariate analysis, patients with pancreatic head tumors (n = 388) had a survival advantage when treated in the gemcitabine arm with median survival of 20.5 months and 3-year survival of 31% compared to 16.9 months and 22%, respectively, in the fluorouracil arm (P = 0.5). There were no differences in survival for the overall study population

Regine WF et al. JAMA 2008;299:1019–1026

Patients who have positive margins following surgery have a poor outcome. In this group of patients who have "borderline resectable" cancer, preoperative chemoradiation could be administered with or without 2–4 months of systemic chemotherapy followed by pancreatic resection

Treatment for Metastatic Disease

Chemotherapy similar to treatment of patients with metastatic disease is preferred. Concurrent chemoradiation is also an option. Evaluate patients after 4–6 cycles of systemic therapy. Patients who continue to have disease confined to the pancreas may be considered for concurrent chemoradiation therapy. Continuous infusion fluorouracil or capecitabine administration with radiation to the pancreas is preferred. There is limited experience with concurrent radiation and gemcitabine and these regimens should be administered with caution

We evaluate patients for therapy based on either a "good" or "poor" performance status

Therapy of Patients with "Poor" Performance Status

Outcome and survival are poor for a patient with an ECOG performance status ≥2 with severe fatigue, rapid weight loss, and/or biliary obstruction. This group of patients may be considered for treatment with gemcitabine alone or gemcitabine and erlotinib. Palliative care with symptom management should also be discussed with the patient and family

Gemcitabine may be administered over 30 minutes or at a fixed dose rate (10 mg/m² per minute)
The addition of erlotinib to gemcitabine was demonstrated in a randomized phase III trial to improve survival and progression-free survival in advanced pancreatic cancer. In this phase III trial, a total of 569 patients were randomly assigned to receive gemcitabine with erlotinib or placebo:

Gemcitabine 1000 mg/m² per dose diluted with 0.9% NS to concentrations as low as 0.1 mg/mL, administered intravenously over 30 minutes once weekly
- Cycle 1: Gemcitabine was given on days 1, 8, 15, 22, 29, 36, and 43 during the initial 8-week cycle (total dosage = 7000 mg/m²)
- Subsequent cycles: Gemcitabine was given on days 1, 8, and 15 every 4 weeks (total dosage/4-week cycle = 3000 mg/m²)
- Erlotinib 100 mg/day or 150 mg/day orally, continually or placebo orally, continually
- Most patients received erlotinib 100 mg/day, orally
In the control arm of gemcitabine, the median survival was 5.91 months and 1-year overall survival was 17%. One-year survival was also greater with erlotinib plus gemcitabine (23% vs. 17%; P = 0.023). Patients who developed a skin rash following therapy with erlotinib had the best outcome and longest survival. The median survival for patients without a rash was 5.3 months (1-year survival = 16%) compared to 10.5 months (1-year survival 43%) for those who had a grade 2 + rash with treatment

Therapy of Patients with "Good" Performance Status

nab-Paclitaxel + gemcitabine: MPACT was a large, international study performed at community and academic centers. nab-Paclitaxel + gemcitabine was superior to gemcitabine monotherapy across all efficacy endpoints, had an acceptable toxicity profile. nab-Paclitaxel + gemcitabine is a new option for the treatment of metastatic pancreatic cancer that will now be studied in the adjuvant and locally advanced setting
FOLFIRINOX: As compared with gemcitabine, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin] was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and a good performance status [younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels]

Abbruzzese J. JAMA 2008;299:1066–1067

Conroy T et al. N Engl J Med 2011;364:1817–1825

Moore MJ et al. J Clin Oncol 2007;25:1960–1966

Philip PA. Lancet Oncol 2008;9:7–8

Russo S et al. Semin Oncol 2007;34:327–334

Sultana A et al. J Clin Oncol 2007;25:2607–2615

Ujiki MB, Talamonti MS. Semin Oncol 2007;34:311–320

Von Hoff DD et al. J Clin Oncol 2011;29:4548–4554

Von Hoff et al. J Clin Oncol 31, 2013(Suppl; abstr 4005)

Survival

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Survival

1-Year survival for all stages

19%

5-Year survival for all stages

5-Year survival in resected patients

25%

Jemal A et al. CA Cancer J Clin 2009;59:225–249

Katz MH. CA Cancer J Clin 2008;58:111–125

Li D et al. Lancet 2004;363:1049–1057

ADJUVANT THERAPY REGIMEN: GEMCITABINE + RADIATION THERAPY (RTOG 97-04)

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Adjuvant Therapy Regimen: Gemcitabine + Radiation Therapy (RTOG 97-04)

Regine WF et al. JAMA 2008;299:1019–1026

Pre-chemoradiation:

Gemcitabine 1000 mg/m² per dose diluted with 0.9% sodium chloride injection (0.9% NS) to concentrations as low as 0.1 mg/mL administer intravenously over 30 minutes once weekly for 3 consecutive weeks (total dosage/3-week course = 3000 mg/m²), followed 1–2 weeks later by

Chemoradiation therapy:

Radiation therapy for a total dose of 5040 cGy (28 fractions 5 days/week with a boost of 540 cGy) with

Fluorouracil 250 mg/m² per day in 25–1000 mL 0.9% NS or D5W administer by continuous intravenous infusion over 24 hours throughout radiation therapy, followed 3–5 weeks later by

Post-chemoradiation:

Gemcitabine 1000 mg/m² per dose diluted with 0.9% NS to concentrations as low as 0.1 mg/mL administer intravenously over 30 minutes once weekly for 3 consecutive weeks every 4 weeks for a total of 12 weeks (total dosage/4-week cycle = 3000 mg/m²)

Supportive Care

Emetogenic potential: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 451 patients (388 with pancreatic head tumors) with resected pancreatic adenocarcinoma who were randomized and 221 who received the study arm of gemcitabine and fluorouracil/RT. The control group received fluorouracil and fluorouracil/RT. The margin positive rate following surgery (R1) was 34%. In patients with pancreatic head tumors there was an increase in survival, but this did not reach statistical significance (P = 0.5)

Toxicity (N = 221 Treated with Gemcitabine and Concurrent Chemoradiation)

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Toxicity (N = 221 Treated with Gemcitabine and Concurrent Chemoradiation)

Grade 3/4 Toxicity

Percentage (%)

Grade 3/4 hematologic

Grade 4 hematologic

Diarrhea

Stomatitis/mucositis

Nausea/vomiting

Comment: Grade 3/4 hematologic toxicity was higher in the gemcitabine arm than in the fluorouracil arm (58% vs. 9%, respectively). However, there was no difference in the incidence of febrile neutropenia or infection

There was no difference in the ability to deliver chemotherapy (90% vs. 87%) or radiation therapy between the gemcitabine and fluorouracil groups (88% vs. 86%, respectively)

Treatment Modifications

Modifications for gemcitabine: see single-agent gemcitabine dosing

Burris HA et al. J Clin Oncol 1997;15:2403–2413

Concurrent chemoradiation dose modifications:

The following guidelines may be considered as Regine et al. did not specify modifications (Talamonti MS et al. J Clin Oncol 2000;18:3384–3389)

Hold radiation therapy for grade 3/4 GI or grade 4 hematologic toxicity, and resume after toxicity resolves
Dose reduce fluorouracil by 25% for grade 3 hematologic toxicity
Hold fluorouracil in the case of grade 4 hematologic toxicity, grade 3/4 GI tract and other nonhematologic toxicity. Resume fluorouracil at a 25% reduced dose after toxicity resolves
Hold fluorouracil for grade 2/3 hand-foot syndrome until symptoms resolve and resume with a 25% dose reduction

Efficacy

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Efficacy

Pancreatic Head Tumors (N = 388)

Gemcitabine + Fluorouracil Arm

Fluorouracil Arm

Median survival

20.5 months

16.9 months

3-Year survival

31%

22%

Therapy Monitoring

Every week: CBC with differential
During the period of RT, monitor patients for toxicity every week
Before each cycle of chemotherapy: H&P, CBC, complete chemistry panel including electrolytes, liver function tests, and magnesium; CA19-9 level if initially elevated

Surveillance

H&P every 3–6 months for 2–3 years and then annually
At every visit, H&P, CBC, complete chemistry panel including electrolytes, liver function tests, and magnesium; CA19-9 level if initially elevated
CT scans for surveillance every 6 months for 2–3 years then annually

METASTATIC DISEASE REGIMEN: GEMCITABINE

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Metastatic Disease Regimen: Gemcitabine

Burris HA et al. J Clin Oncol 1997;15:2403–2413

Gemcitabine 1000 mg/m² per dose; administer by intravenous infusion in 50–250 mL 0.9% sodium chloride injection over 30 minutes on days 1, 8, and 15, every 28 days (total dosage/cycle = 3000 mg/m²)

In the referenced trial, for the first cycle, patients received gemcitabine 1000 mg/m² once weekly for up to 7 weeks. Thereafter, gemcitabine was administered once weekly for 3 consecutive weeks out of every 4 weeks
Single-agent gemcitabine given at the dose of 1500 mg/m² at the rate of 10 mg/min over 150 minutes is an alternative regimen

Tempero M et al. J Clin Oncol 2003;15:3402–3408

Supportive Care Antiemetic prophylaxis

Emetogenic potential with gemcitabine: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Persistent rash or flulike symptoms after gemcitabine:

Consider Dexamethasone 10 mg orally or intravenously before starting gemcitabine

Patient Population Studied

Study of 63 patients with locally advanced or metastatic pancreatic cancer not amenable to curative surgical resection treated with single-agent gemcitabine. Patients who had received previous chemotherapy were not eligible

Efficacy (N = 63)

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Efficacy (N = 63)

Median survival

5.65 months

Survival rate at 12 months

18%

Clinical benefit response^✫

23.8%

^✫Clinical benefit response (CBR) is a composite measurement of pain, performance status, and weight that was sustained more than 4 weeks in at least 1 parameter without the worsening in any other parameter. The median time to achieve CBR in gemcitabine-treated patients was 7 weeks and duration of benefit was 18 weeks

Note: In this pivotal phase III clinical trial, gemcitabine was compared in a randomized fashion with fluorouracil (600 mg/m² per week). The median survival in the fluorouracil arm was 4.41 months, survival rate at 12 months was 2%, and clinical benefit response was 4.8%

Therapy Monitoring

Every week: CBC with differential
Before each cycle: CBC with differential, serum electrolytes, creatinine, mineral panel, and LFT
Response assessment: CT scans every 2 months and CA19-9 monthly

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

WBC <1000/mm³ to 500/mm³ or platelets <99,000/mm³ to 50,000/mm³ on day of treatment

Reduce gemcitabine dosages by 25%

G ≥3 nonhematologic adverse event during the previous treatment cycle

WBC <500/mm³ or platelet <50,000/mm³ on day of treatment

Delay chemotherapy for up to 2 weeks

Treatment delay >2 weeks for recovery from hematologic adverse event

Discontinue treatment

Adverse Events (N = 63)

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Adverse Events (N = 63)

WHO Grade (%)

Grade I

Grade II

Grade III

Grade IV

WBC

Platelets

Hemoglobin

Bilirubin

Alkaline phosphatase

Aspartate transaminase

1.6

BUN

Creatinine

Diarrhea

Constipation

Pain

Fever

Infection

Pulmonary

Hair

Proteinuria

Hematuria

12.7

Nausea/vomiting

METASTATIC DISEASE REGIMEN: GEMCITABINE + ERLOTINIB

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Metastatic Disease Regimen: Gemcitabine + Erlotinib

Moore MJ et al. J Clin Oncol 2007;25:1960–1966

In the referenced trial, for the first cycle, patients received gemcitabine 1000 mg/m² once weekly for 7 consecutive weeks during an 8-week cycle. Thereafter, gemcitabine was administered once weekly for 3 consecutive weeks out of every 4 weeks

Erlotinib was administered orally 100 mg/day (n = 262) or 150 mg/day (n = 23), continually, until progression or intolerable toxicity

Supportive Care Antiemetic prophylaxis

Emetogenic potential is: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially, then 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea free interval is treated as a new episode
If diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize patient for IV hydration

Persistent or severe diarrhea (G ≥3):

Interrupt erlotinib treatment until symptoms resolve, then consider resuming at a decreased dose

Adverse Events for Gemcitabine and Erlotinib

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Adverse Events for Gemcitabine and Erlotinib

Grade 3/4 Toxicity

Percentage (%)

Diarrhea

Fatigue

Any infection

Rash

Consider regimen for patients with ECOG performance status 0–2 and total bilirubin ≤ ULN or ≤1.8 mg/dL (≤30.8 μmol/L); ALT and AST ≤5× ULN

Therapy Monitoring

Every week: CBC with differential
Before each cycle: CBC, complete chemistry panel including electrolytes, liver function tests, and magnesium; CA19-9 level if initially elevated
Response assessment: Every 8 weeks with CT scans or earlier if clinically indicated; CA19-9 monthly

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

WBC <1000/mm³ to 500/mm³ or platelets <99,000/mm³ to 50,000/mm³ on day of treatment

Reduce gemcitabine dosages by 50%

WBC <500/mm³ or platelet <50,000/mm³ on day of treatment

Delay gemcitabine for up to 2 weeks

Patients with grade 4 granulocytopenia, thrombocytopenia, or nonhematologic toxicity during the previous treatment cycle

Reduce gemcitabine dosages by 25%

Erlotinib dose modifications

Dose reductions should be made in 50-mg decrements
Pulmonary symptoms: If acute onset (or worsening) of pulmonary symptoms (eg, dyspnea, cough, fever), interrupt treatment and evaluate for drug-induced interstitial lung disease; discontinue permanently with development of interstitial lung disease
Severe skin reaction: Reduce dose or temporarily interrupt treatment

Patient Population Studied

A total of 569 patients were randomly assigned to receive erlotinib/placebo with gemcitabine. Locally advanced unresectable patients comprised 24% of the population. The majority received erlotinib at the dose of 100 mg/day

Efficacy (N = 569)

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Efficacy (N = 569)

Variable

Gemcitabine + Erlotinib N = 285

Gemcitabine + Placebo N = 284

Median survival

6.24 months

5.91 months

1-Year survival

23%

17%

Of patients receiving gemcitabine+ erlotinib, 16% had at least 1 dose reduction compared to 5% in the control group

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN: GEMCITABINE + nab-PACLITAXEL

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Advanced or Metastatic Pancreatic Cancer Regimen: Gemcitabine + nab-Paclitaxel

Von Hoff DD et al. J Clin Oncol 2011;29:4548–4554

Von Hoff DD et al. J Clin Oncol 2013;31(Suppl; abstr 4005)

Paclitaxel protein-bound particles for injectable suspension (nab-paclitaxel) 125 mg/m² per dose intravenously once weekly for 3 doses on days 1, 8, and 15 every 28 days (total dosage/cycle = 375 mg/m²), followed by

Gemcitabine HCl 1000 mg/m² per dose intravenously in 50–250 mL 0.9% sodium chloride injection for 3 doses on days 1, 8, and 15 every 28 days (total dosage/cycle = 3000 mg/m²), followed by:

Supportive Care Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

(Filgrastim may be given according to institutional guidelines for the treatment of neutropenic fever or infections associated with neutropenia and for the prevention of febrile neutropenia in patients with an ANC <500/mm³. Patients not experiencing resolution of neutropenia within 21 days, despite uninterrupted filgrastim should discontinue therapy)

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

(Prophylaxis Against Sepsis: At the first occurrence of fever ≥38.5°C [101.3°F] [regardless of ANC], institution of ciprofloxacin (500 mg orally, twice daily)—or amoxicillin/clavulanate [Augmentin, 500 mg orally, 2–3 times daily] in patients with allergy to fluoroquinolones—should be initiated. On their first visit, patients should be provided with enough ciprofloxacin [or the alternative antibiotic] for use at home, and they should be instructed to begin taking it when they first record a temperature of ≥38.5°C [101.3°F] [or if they feel they are developing a fever and a thermometer is not available]. They should also immediately contact their physician for guidance on where to go for blood counts to be evaluated for sepsis as soon as possible. Hospitalization or evaluation in the emergency room may be required depending on the clinical presentation)

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Note

Interstitial Pneumonitis

Monitor patients carefully for signs and symptoms of pneumonitis (ie, episodes of transient or repeated dyspnea with unproductive persistent cough or fever) and, if observed, perform immediate clinical evaluation and timely institution of appropriate management (emphasizing the need for corticosteroids if an infectious process has been ruled out, as well as appropriate ventilation and oxygen support when required)

Treatment Modifications

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Treatment Modifications

Dose Adjustments on Day 1 of Each Treatment Cycle for Hematologic Toxicity

ANC

Platelets

Timing

≥1500/mm³

AND

≥100,000/mm³

Treat on time

<1500/mm³

<100,000/mm³

Delay by 1 week intervals until recovery

Dose Levels

nab-Paclitaxel (mg/m²)

Gemcitabine HCl (mg/m²)

Starting dose

125

1000

Dose level −1

100

800

Dose level −2

600

Dose Adjustments within a Treatment Cycle for Hematologic Toxicity

Day 8

Day 15

Blood Counts

nab-Paclitaxel

Gemcitabine

Blood Counts

nab-Paclitaxel

Gemcitabine

ANC >1000/mm³ and platelets ≥75,000/mm³

100%

ANC >1000/mm³ and platelets ≥75,000/mm³

100%

ANC 500–1000/mm³ or platelets 50,000–74,999/mm³

Full dose (treat on time) and administer filgrastim^✫

ANC <500/mm³ or platelets <50,000/mm³

Hold and administer filgrastim^✫

ANC 500–1000/mm³ or platelets 50,000–74,999/mm³

Decrease dose by 1 level (treat on time)

ANC >1000/mm³ and platelets ≥75,000/mm³

Return to previous dose level (treat on time) and administer filgrastim^✫

ANC 500–1000/mm³ or platelets 50,000–74,999/mm³

Same dose as day 8 (treat on time) and administer filgrastim^✫

ANC <500/mm³ or platelets <50,000/mm³

Hold and administer filgrastim^✫

ANC <500/mm³ or platelets <50,000/mm³

Hold

ANC >1000/mm³ and platelets ≥75,000/mm³

Decrease day 8 dose by 1 level (treat on time) and administer filgrastim^✫

ANC 500–1000/mm³ or platelets 50,000–74,999/mm³

Decrease day 8 dose by 1 level (treat on time) and administer filgrastim^✫

ANC <500/mm³ or platelets <50,000/mm³

Hold and administer filgrastim^✫

^✫Febrile patients (regardless of ANC) should have chemotherapy treatment interrupted. A full sepsis diagnostic work-up should be performed while continuing broad-spectrum antibiotics. If cultures are positive, guide antibiotic therapy by the sensitivity profile of the isolated organism. Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, should discontinue therapy. Febrile neutropenic patients can also receive filgrastim, in addition to antibiotic treatment, to hasten resolution of their febrile neutropenia

Dose Adjustments on Day 1 of Each Treatment Cycle for Nonhematologic Toxicity and/or Dose Hold with Previous Cycle

Toxicity/Dose Held

nab-Paclitaxel + Gemcitabine Dose This Cycle

G0/1/2 toxicity

Same as day 1 previous cycle (except for G2 cutaneous toxicity where doses of gemcitabine and nab-paclitaxel should be reduced to next lower dose level)

G3 toxicity^✫

Decrease nab-paclitaxel and gemcitabine to next lower dose level^✫

G ≥3 peripheral neuropathy

Hold nab-paclitaxel treatment but continue gemcitabine administration if indicated. Resume nab–paclitaxel treatment at next lower dose level after the peripheral neuropathy improves to G ≤1

G4 toxicity

Hold therapy^†

Dose held in 2 previous consecutive cycles

Decrease gemcitabine to next lower dose level and continue throughout the rest of treatment

^✫Except for cutaneous toxicity: If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced

^†The decision as to which drug should be modified depends upon the type of nonhematologic toxicity seen and which course is medically most sound in the judgment of the physician

Dose Adjustments within a Treatment Cycle for Nonhematologic Toxicity

CTC Grade

Percent of Day 1 nab-Paclitaxel + Gemcitabine Dose

G1/2, G3 nausea/vomiting and alopecia

100%^✫

G3 (except G3 nausea/vomiting and alopecia)

Hold either 1 or both drugs until resolution to G ≤1. Then resume treatment at the next lower dose level

G ≥3 peripheral neuropathy

Hold nab-paclitaxel treatment but continue gemcitabine administration if indicated. Resume nab–paclitaxel treatment at next lower dose level after the peripheral neuropathy improves to G ≤1

Hold therapy^†

^✫Except for cutaneous toxicity: If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced

^†The decision as to which drug should be modified depends upon the type of nonhematologic toxicity seen and which course is medically most sound in the judgment of the physician

Patient Population Studied

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Patient Population Studied

Patients with histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma (PDA) who had not previously received treatment for metastatic disease. Prior adjuvant treatment with fluorouracil or gemcitabine administered as a radiation sensitizer during and up to 4 weeks after radiation therapy was allowed. If a patient received adjuvant therapy, tumor recurrence must have occurred >6 months after the last treatment. Patients had an ECOG PS of 0 or 1. Twenty, 44, and 3 patients received 100, 125, and 150 mg/m² nab-paclitaxel, respectively

Characteristic

nab-Paclitaxel (mg/m²)

100 (n = 20)

125 (n = 44)

150 (n = 3)

No.

Age, years

Median

Range

30–86

28–78

53–72

Female sex

ECOG

Site of metastatic disease

Abdomen/peritoneal

Liver

Liver only

Lung

Lung only

Other

Number of metastatic sites

≥3

—

CA19-9 baseline levels, number

—

Normal^✫

Elevated

CA19-9 baseline, units/mL

Median

1,148

881

181

Range

14–180,062

1–96,990

23–339

Previous treatment

Prior chemotherapy (no prior adjuvant)

Prior adjuvant therapy

With gemcitabine

—

With capecitabine

—

With fluorouracil

—

With docetaxel

—

With erlotinib

Time since last dose adjuvant therapy, months

Median

Range

9–81

1–23

ECOG, Eastern Cooperative Oncology Group; nab-paclitaxel, paclitaxel protein-bound particles for injectable suspension (albumin bound)

^✫Upper limit for normal range was <37 units/mL. Approximately 10–15% of patients with pancreatic cancer lack Lewis antigens and thus lack the ability to secrete CA19-9

MPACT Trial

A total of 861 patients with metastatic pancreatic ductal adenocarcinoma (PDA) and a Karnofsky performance status (KPS) ≥70 were randomized at 151 community and academic centers 1:1 to receive nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² days 1, 8, and 15 every 4 weeks or gemcitabine alone 1000 mg/m² weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The median age was 63 years (range: 27–88 years). KPS was 100 (16%), 90 (44%), 80 (32%), and 70 (7%). Patients had advanced disease with liver metastases (84%), ≥3 metastatic sites (46%), and CA19-9 ≥59 × upper limit of normal (46%)

Efficacy

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Efficacy

Response Result

Gemcitabine 1000 mg/m² + nab-Paclitaxel 125 mg/m² (n = 44)

Gemcitabine 1000 mg/m² + nab-Paclitaxel 100, 125, or 150 mg/m² (n = 67)

Number

Complete response

Partial response

Stable disease^✫

Progressive disease

Disease control rate^†

Median OS of patients who received nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² (n = 44)

12.2 months

Median OS according to metabolic response compared to baseline (EORTC criteria for absence of [¹⁸F]fluorodeoxyglucose uptake) (cohorts 1 + 2^‡)

Metabolic Response

P Value

Incomplete

Complete

10.2 months

20.1 months

0.01

Median OS correlated with SPARC (all cohorts^§)

Average z-Score

P Value

≥0, High SPARC

<0, Low SPARC

17.8 months

8.1 months

0.0431

EORTC, European Organization for Research and Treatment of Cancer; OS, overall survival; SPARC, secreted protein acidic and rich in cysteine

^✫Stable disease was defined as ≥16 weeks

^†Disease control rate defined as percentage of patients with complete and partial response and stable disease ≥16 weeks

^‡Cohort 1 = gemcitabine 1000 mg/m² + nab-paclitaxel 100 mg/m²; Cohort 2 = gemcitabine 1000 mg/m² + nab-paclitaxel 125 mg/m²

^§Three cohorts. All received gemcitabine 1000 mg/m². The nab-paclitaxel dosages were 100, 125, or 150 mg/m²

Efficacy: MPACT

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Efficacy: MPACT

nab-Paclitaxel + Gemcitabine

Gemcitabine Monotherapy

Hazard Ratios/p Values

Median overall survival (OS)

8.5 months

6.7 months

HR 0.72; 95% CI, 0.617–0.835 p = 0.000015

Overall survival, 6 months

67%

55%

Overall survival, 12 months

35%

22%

Overall survival, 24 months

Median progression-free survival (PFS)

5.5 months

3.7 months

HR 0.69; 95% CI, 0.581–0.821 p = 0.000024

ORR (RECIST v1.0 criteria)

23%

p = 1.1 × 10−¹⁰

Metabolic response by PET (N = 257/861 patients)

63%

38%

p = 0.000051

ORR by CT scans in PET-evaluable patients

31%

11%

p = 0.0001

CA19-9 response (≥90% decrease)

31%

14%

p <0.0001

CA19-9 response (≥20% decrease)

61%

44%

p <0.0001

Median duration of treatment

3.9 months

2.8 months

—

Von Hoff et al. J Clin Oncol 2013;31(Suppl; abstr 4005)

Toxicity

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Toxicity

Adverse Events

Gemcitabine 1000 mg/m² + nab-Paclitaxel 100 mg/m² (n = 20)

Gemcitabine 1000 mg/m² + nab-Paclitaxel 125 mg/m² (n = 44)

No.

Nonhematologic Events

Diarrhea

Fatigue

Nausea

Sensory neuropathy

Vomiting

Hematologic Events

Anemia

Leukopenia

Neutropenia

Febrile Neutropenia

Thrombocytopenia

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Toxicity: MPACT

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Toxicity: MPACT

G ≥3 neutropenia

38%

27%

Febrile neutropenia

G ≥3 fatigue

17%

G ≥3 diarrhea

G ≥3 peripheral neuropathy^✫

17%

^✫Improved to grade ≤1 in median 29 days, and 44% of patients resumed nab-Paclitaxel treatment

Von Hoff et al. J Clin Oncol 2013;31(Suppl; abstr 4005)

Treatment Monitoring

Days 1, 8, and 15: CBC with differential

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN: OXALIPLATIN + IRINOTECAN + FLUOROURACIL + LEUCOVORIN (FOLFIRINOX)

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Advanced or Metastatic Pancreatic Cancer Regimen: Oxaliplatin + Irinotecan + Fluorouracil + Leucovorin (FOLFIRINOX)

Conroy T et al. N Engl J Med 2011;364:1817–1825

Oxaliplatin 85 mg/m² intravenously in 250 mL 5% dextrose injection (D5W) over 2 hours on day 1, every 2 weeks (total dosage/cycle = 85 mg/m²)

Note: Oxaliplatin must not be mixed with sodium chloride injection

Either: (racemic) Leucovorin calcium 400 mg/m² or levoleucovorin calcium 200 mg/m² intravenously in 25–500 mL D5W or 0.9% sodium chloride injection over 2 hours on day 1, every 2 weeks (total dosage/cycle for racemic leucovorin = 400 mg/m², for levoleucovorin = 200 mg/m²), followed 30 minutes after administration begins by:

Irinotecan 180 mg/m² intravenously over 90 minutes in 500 mL D5W on day 1, 30 minutes after leucovorin (or levoleucovorin) administration begins, every 2 weeks (total dosage/cycle = 180 mg/m²), followed by:

(bolus) Fluorouracil 400 mg/m² by intravenous injection over 1–2 minutes after leucovorin (or levoleucovorin) and irinotecan administration are completed on day 1, every 2 weeks, followed by:

Fluorouracil 2400 mg/m² by continuous intravenous infusion over 46 hours in 100–1000 mL 0.9% NS or D5W, starting on day 1 every 2 weeks (total dosage/cycle = 2800 mg/m²)

Important note: This regimen is difficult for patients. Thus, FOLFIRINOX is a first-line option for patients with metastatic pancreatic cancer who are younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels

Notes:

Patients must be instructed in the use of loperamide as treatment for diarrhea, and must have a supply of this drug upon starting FOLFIRINOX
Filgrastim is not recommended as primary prophylaxis, but it could be considered for high-risk patients
The dose of leucovorin is not modified for toxicity, but is omitted if fluorouracil is omitted. Once a fluorouracil dose is decreased, it is not re-escalated

Supportive Care Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Acute cholinergic syndrome

Atropine sulfate 0.25–1 mg subcutaneously or intravenously if abdominal cramping or diarrhea develop during or within 1 hour after irinotecan administration

If symptoms are severe, add as primary prophylaxis at least 30 minutes before irinotecan during subsequent cycles
For irinotecan, acute cholinergic syndrome may be characterized by: abdominal cramping, diarrhea, diaphoresis, hypotension, flushing, bradycardia, rhinitis, increased salivation, meiosis, and lacrimation

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Treatment Modifications

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Treatment Modifications

Event

Delay of Cycle

Dosage Reductions

Irinotecan

Oxaliplatin

Fluorouracil

First occurrence of ANC <1500/mm³ on day 1

Hold treatment up to 2 weeks until granulocytes ≥1500/mm³

In case of nonrecovery >2 weeks delay, stop treatment

Reduce dosage to 150 mg/m²

Do not reduce dosage

Delete bolus fluorouracil

Second occurrence of ANC <1500/mm³ on day 1

Maintain the dosage at 150 mg/m²

Reduce the dosage to 60 mg/m²

Continue without bolus fluorouracil

Third occurrence of ANC <1500/mm³ on day 1

Discontinue treatment

First occurrence of platelets <75,000/mm³ on day 1

Hold treatment up to 2 weeks until platelets ≥75,000/mm³. In case of nonrecovery >2 weeks delay, stop treatment

Do not reduce dosage

Reduce the dosage to 60 mg/m²

Reduce both bolus and CI by 25% of original dosages

Second occurrence of platelets <75,000/mm³ on day 1

Reduce the dosage to 150 mg/m²

Maintain the dosage at 60 mg/m²

Continue both bolus and CI at 75% of original dosages

Third occurrence of platelets <75,000/mm³ on day 1

Discontinue treatment

First occurrence febrile neutropenia or G4 neutropenia >7 days or infection with concomitant G3/4 neutropenia

Reduce the dosage to 150 mg/m²

Do not reduce dosage

Delete bolus fluorouracil

Second occurrence febrile neutropenia or G4 neutropenia >7 days or infection with concomitant G3/4 neutropenia

Maintain the dosage at 150 mg/m²

Reduce the dosage to 60 mg/m²

Continue without bolus fluorouracil

Note: Consider the use of filgrastim for recurrent G3/4 neutropenia despite a first-dose reduction or after febrile neutropenia

Third occurrence febrile neutropenia or G4 neutropenia >7 days or infection with concomitant G3/4 neutropenia

Discontinue treatment

First occurrence G3/4 thrombocytopenia

Do not reduce dosage

Reduce the dosage to 60 mg/m²

Reduce both bolus and CI fluorouracil by 25% of the original dosages

Second occurrence G3/4 thrombocytopenia

Reduce the dosage to 150 mg/m²

Maintain the dosage at 60 mg/m²

Continue with bolus fluorouracil at 75% of the original dosage and reduce CI by an additional 25–50% of the original dosage

Third occurrence G3/4 thrombocytopenia

Discontinue treatment

First occurrence G3/4 diarrhea, or diarrhea + fever and/or diarrhea + G3/4 neutropenia

Reduce the dosage to 150 mg/m². Do not retreat with irinotecan until recovered from diarrhea without loperamide for at least 24 hours

Do not reduce dosage

Delete bolus fluorouracil

Second occurrence G3/4 diarrhea, or diarrhea + fever and/or diarrhea + G3/4 neutropenia

Maintain the dosage at 150 mg/m². Do not retreat with irinotecan until recovered from diarrhea without loperamide for at least 24 hours

Reduce the dosage to 60 mg/m²

Continue without bolus fluorouracil and reduce the CI by 25% of the original dosage

Third occurrence G3/4 diarrhea or diarrhea + fever and/or diarrhea + G3/4 neutropenia

Discontinue treatment

Diarrhea ≥48 hours despite high doses of loperamide

No systematic reduction of the irinotecan, oxaliplatin, or fluorouracil doses after complete recovery, unless G3/4 diarrhea, or diarrhea + fever, and/or concomitant neutropenia G3/4

G3/4 mucositis or "hand-foot" syndrome

Do not reduce dosage

Reduce both bolus and CI fluorouracil by 25% of the original dosages

Angina pectoris or of myocardial infarction

Do not reduce dosage

Discontinue fluorouracil

Any toxicity G ≥2, except anemia and alopecia

Consider reducing the dosage to 150 mg/m²

Consider reducing the dosage to 60 mg/m²

Consider reducing both bolus and CI fluorouracil by 25% of the original dosages

Total bilirubin ≥1.5× ULN

Do not administer

Do not reduce dosage

CI, continuous infusion; ULN, upper limit of normal of laboratory value

Efficacy

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Efficacy

Objective Responses in the Intention-to-Treat Population

Variable

FOLFIRINOX^✫ (N = 171)

Gemcitabine (N = 171)

P Value

Response—Number (%)

Complete response

1 (0.6)

Partial response

53 (31.0)

16 (9.4)

Stable disease

66 (38.6)

71 (41.5)

Progressive disease

26 (15.2)

59 (34.5)

Could not be evaluated

25 (14.6)

Rate of objective response^†

<0.001

No. (%)

54 (31.6)

16 (9.4)

95% CI

24.7–39.1

5.4–14.7

Rate of disease control^‡

<0.001

No. (%)

120 (70.2)

87 (50.9)

95% CI

62.7–76.9

43.1–58.6

Response duration—months

0.57

Median

5.9

3.9

95% CI

4.9–7.1

3.1–7.1

Variable

FOLFIRINOX^✫ (N = 171)

Gemcitabine (N = 171)

HR [95% CI] P Value

Progression-free survival

6.4 months 95% CI, 5.5–7.2

3.3 months 95% CI, 2.2–3.6

0.47 [0.37–0.59] p <0.001

6-Month PFS rate

52.8%

17.2%

—

12-Month PFS rate

12.1%

3.5%

—

18-Month PFS rate

3.3%

—

Overall survival^§

11.1 months

6.8 months

0.57 [0.45–0.73] p <0.001

6-Month OS rate

75.9%

57.6%

—

12-Month OS rate

48.4%

20.6%

—

18-Month OS rate

18.6%

6.0%

—

95% CI, 95% confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival

^✫FOLFIRINOX = oxaliplatin + irinotecan + fluorouracil + leucovorin

^†Defined as percentage of patients who had a complete response or partial response

^‡Defined as the percentage of patients who had a complete response, partial response, or stable disease

^§Synchronous metastases, albumin level <3.5 g/dL (<35 g/L), hepatic metastases, and age >65 years were identified as independent adverse prognostic factors for overall survival

Patient Population Studied

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Patient Population Studied

Patients with histologically and cytologically confirmed metastatic pancreatic adenocarcinoma not previously treated with chemotherapy. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and adequate bone marrow, liver function (total bilirubin ≤1.5 times the upper limit of normal range), and renal function. Exclusion criteria included an age ≥76 years and previous radiotherapy for measurable lesions

Patient Characteristics

Age (years)

Median

Range

25–76

Sex—number (%)

Male

106 (62.0)

Female

65 (38.0)

ECOG performance status score—number (%)

64 (37.4)

106 (61.9)

(0.6)

Pancreatic tumor location—number (%)

Head

67 (39.2)

Body

53 (31.0)

Tail

45 (26.3)

Multicentric

6 (3.5)

Biliary stent—number (%)

Yes

27 (15.8)

144 (84.2)

Number of metastatic sites involved

Median

Range

1–6

Number of measurable metastatic sites—number of patients/total number (%)

Liver

149/170 (87.6)

Pancreas

90/170 (52.9)

Lymph node

49/170 (28.8)

Lung

33/170 (19.4)

Peritoneal

33/170 (19.4)

Other

18/170 (10.6)

Toxicity

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Toxicity

Most Common G3/4 Adverse Events^✫

Event

FOLFIRINOX (N = 171)

Gemcitabine (N = 171)

P Value

Number of Patients/Total Number (%)

Hematologic

Neutropenia

75/164 (45.7)

35/167 (21.0)

<0.001

Febrile neutropenia

9/166 (5.4)

2/169 (1.2)

0.03

Thrombocytopenia

15/165 (9.1)

6/168 (3.6)

0.04

Anemia

13/166 (7.8)

10/168 (6.0)

NS^†

Nonhematologic

Fatigue

39/165 (23.6)

30/169 (17.8)

NS^†

Vomiting

24/166 (14.5)

14/169 (8.3)

NS^†

Diarrhea

21/165 (12.7)

3/169 (1.8)

<0.001

Sensory neuropathy

15/166 (9.0)

0/169

<0.001

↑ Alanine aminotransferase

12/165 (7.3)

35/168 (20.8)

<0.001

Thromboembolism

11/166 (6.6)

7/169 (4.1)

NS^†

^✫Events listed are those that occurred in more than 5% of patients in either group

^†NS denotes not significant

Note: Despite the higher incidence of adverse events associated with the FOLFIRINOX regimen, a significant increase in the time to definitive deterioration of the quality of life was observed in the FOLFIRINOX group as compared with the gemcitabine group

Treatment Monitoring

At start of every cycle: medical history, complete physical examination, CBC with differential and serum electrolytes and LFTs
Weekly: CBC with differential

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN—SECOND LINE: OXALIPLATIN + FOLINIC ACID (LEUCOVORIN) + FLUOROURACIL (OFF) + BSC (BEST SUPPORTIVE CARE)

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Advanced or Metastatic Pancreatic Cancer Regimen—Second Line: Oxaliplatin + Folinic Acid (Leucovorin) + Fluorouracil (OFF) + BSC (Best Supportive Care)

Pelzer U et al. Eur J Cancer 2011;47:1676–1681

Days 1, 8, 15, and 22 during 6-week cycles:

Leucovorin calcium 200 mg/m² per dose intravenously in 25–100 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 30 minutes for 4 doses on days 1, 8, 15, and 22, every 6 weeks (total dosage/6-week cycle = 800 mg/m²), followed by:

Fluorouracil 2000 mg/m² per dose by continuous intravenous infusion in 100–1000 mL 0.9% NS or D5W over 24 hours for 4 doses on days 1, 8, 15, and 22, every 6 weeks (total dosage/6-week cycle = 8000 mg/m²)

Days 8 and 22 during 6-week cycles:

Oxaliplatin 85 mg/m² per dose administer intravenously in 250 mL D5W over 2–4 hours for 2 doses prior to leucovorin and fluorouracil on days 8 and 22 (total dosage/6-week cycle = 170 mg/m²)

Note: Oxaliplatin must not be mixed with sodium chloride injection. If leucovorin or fluorouracil are diluted in solutions containing sodium chloride injection and administered through the same tubing or vascular access device as oxaliplatin, the fluid pathway should be flushed with D5W before administering oxaliplatin

Best supportive care (BSC) according to current palliative care guidelines includes:

Adequate pain management
Therapy of infection
Biliary stent intervention if needed
Social support and on-demand psychooncologic intervention
Nutrition consultation/intervention

Supportive Care Antiemetic prophylaxis

Emetogenic potential on days with fluorouracil and leucovorin is LOW

Emetogenic potential on days with oxaliplatin is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil)

Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Dose Modifications

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Dose Modifications

Fluorouracil and Oxaliplatin

Any G2/3/4 nonhematologic toxicity

Delay start of next cycle until the severity of all toxicities are G ≤1

ANC >1500/mm³ or platelet count >100,000/mm³

Delay start of next cycle until ANC >1500/mm³ and platelet count >100,000/mm³

G3/4 Nonneurologic

Reduce fluorouracil and oxaliplatin dosages by 20%

G3/4 ANC

Reduce oxaliplatin dosage by 20%

Persistent (≥14 days) paresthesias

Reduce oxaliplatin dosage by 20%

Temporary (7–14 days) painful paresthesias

Temporary (7–14 days) functional impairment

Persistent (≥14 days) painful paresthesias

Discontinue oxaliplatin

Persistent (≥14 days) functional impairment

Adapted in part from de Gramont A et al. J Clin Oncol 2000;18:2938–2947

Efficacy

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Efficacy

OFF

Best Supportive Care

Statistics

Median survival with therapy

4.82 months (95% CI: 4.29–5.35)

2.30 months (95% CI: 1.76–2.83)

HR 0.45

(95% CI: 0.24–0.83)

p = 0.008

Median survival since diagnosis

9.09 months (95% CI: 6.97–11.21)

7.90 months (95% CI: 4.95–10.84)

HR 0.50 (95% CI: 0.27–0.95)

p = 0.031

Treatment Monitoring

At start of every cycle: Medical history, complete physical examination, CBC with differential and serum electrolytes and LFTs
Weekly: CBC with differential

Patient Population Studied

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Patient Population Studied

Patients with histologically confirmed advanced pancreatic cancer whose disease had progressed during first-line gemcitabine therapy. Patients had a Karnofsky performance status (KPS) >60% and good hepatic function, defined as AST (aspartate aminotransferase) and ALT (alanine aminotransferase) <2.5× the upper normal limit (UNL), or, in case of liver metastasis <5× UNL

Total number of patients

Sex, male-to-female ratio

14/9

Median age (range)

60 (38–76)

Karnofsky Performance Status 70–80%

Karnofsky Performance Status 90–100%

Gemcitabine first-line therapy

23/23

PFS on gemcitabine <3 months

PFS on gemcitabine 3–6 months

PFS on gemcitabine >6 months

M0/M1 disease

6/17

Toxicity

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Toxicity

Toxicity (NCI CTC 2.0)

(Number of Patients)

Hemoglobin

Leucopenia

Thrombocytopenia

Diarrhea

Nausea/emesis

Paresthesia

Mean (range) cumulative doses administered:

Oxaliplatin 281 mg (0–850 mg)

Folinic acid 1591 mg (200–8000 mg)

Fluorouracil 15, 630 mg (2000–20,000 mg)

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Chapter 29: Pancreatic Cancer

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INTRODUCTION

Expert Opinion

ADJUVANT THERAPY REGIMEN: GEMCITABINE + RADIATION THERAPY (RTOG 97-04)

METASTATIC DISEASE REGIMEN: GEMCITABINE

METASTATIC DISEASE REGIMEN: GEMCITABINE + ERLOTINIB

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN: GEMCITABINE + nab-PACLITAXEL

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN: OXALIPLATIN + IRINOTECAN + FLUOROURACIL + LEUCOVORIN (FOLFIRINOX)

ADVANCED OR METASTATIC PANCREATIC CANCER REGIMEN—SECOND LINE: OXALIPLATIN + FOLINIC ACID (LEUCOVORIN) + FLUOROURACIL (OFF) + BSC (BEST SUPPORTIVE CARE)

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