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Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma

From the Departments of Radiochemotherapy, Radiology, and Surgery, and Unit of Epidemiology and Medical Statistics, San Raffaele H. Scientific Institution, Milan, Italy.

Address reprint requests to Michele Reni, MD, Department of Radiochemotherapy, San Raffaele H. Scientific Institute, Via Olgettina 60, 20132 Milan, Italy; email: reni.michele{at}hsr.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma.

PATIENTS AND METHODS: Patients 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m² each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m² on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m²/d as a protracted venous infusion.

RESULTS: Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients.

CONCLUSION: PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PANCREATIC adenocarcinoma is one of the most lethal forms of cancer, with a mortality rate of 65% within 6 months of diagnosis and nearly 90% within the first year. Another hallmark of the disease is advanced stage diagnosis, with more than 80% of patients having unresectable or metastatic disease at diagnosis and a median survival time of 4 months from diagnosis.^1,2 The use of chemotherapy (CHT) with this type of cancer has proved frustrating and discouraging over the last 20 years. Although many agents and combination schedules have been evaluated in phase II and III trials, they continue to produce disappointing results, with reproducible objective response rates of 0% to 20% and median survival times of less than 5 or 6 months.³ Multidrug CHT regimens have not produced results that were any more effective than single-agent therapies.^4-6

Cisplatin has been reported to produce a 15% to 21% response rate when used as a single agent in patients with metastatic pancreatic adenocarcinoma.⁷ Epirubicin also seems to have some effect, yielding response rates between 11% and 20%.^8-10 Gemcitabine has shown a very favorable toxicity profile and has shown activity in the disease. Response rates were 6% to 15%,^11-14 and the treatment reduced the symptoms caused by cancer in approximately one fourth of cases.¹⁵ In colorectal cancer, protracted venous infusion (PVI) fluorouracil (FU) had a higher objective response rate than a bolus regimen (30% v 7%) and caused fewer side effects.¹⁶ This strategy was also used in pancreatic cancer, with a response rate of 21%.¹⁷ The combination of PVI FU and cisplatin, with or without epirubicin, was found to be synergistic in vitro and in various clinical settings, with a response rate of 16% to 35% in pancreatic cancer.^18-20

This phase II trial was performed to determine the antitumor activity of the cisplatin, epirubicin, PVI FU, and gemcitabine (PEF-G) regimen in patients with unresectable or metastatic pancreatic adenocarcinoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Patients aged 18 to 70 years with histologically or cytologically confirmed diagnosis of stage IVA (T4N0M0 or T4N1M0)²¹ or metastatic pancreatic ductal adenocarcinoma were eligible for the study. Inclusion criteria were the following: Eastern Cooperative Oncology Group performance status (PS) 2 or Karnofsky PS 50; at least one bidimensionally measurable indicator lesion that had not been previously irradiated; no prior CHT; adequate bone marrow (absolute neutrophil count [ANC] 1,500 cells per cubic millimeter, platelet count 100,000 cells per cubic millimeter, and hemoglobin 10 g/dL); kidney function (serum creatinine 1.5 mg/dL) and liver function (serum total bilirubin 2 mg/dL and serum transaminases three times the upper limit of normal). Patients with prior malignancy were ineligible for the study, with the exception of those who had had basal-cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer for which the patient had been disease free for at least 5 years. Patients with ampullary tumors or other histologic variants of pancreatic carcinoma were ineligible for the study. Eligibility criteria for clinical benefit (CB) assessment were either pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or a Karnofsky PS between 50 and 70. The protocol was reviewed and approved by an institutional review board. All participating patients were required to give written informed consent.

Treatment Plan
Eligible patients were treated with the PEF-G regimen: cisplatin was diluted in 250 mL of 0.9% saline and administered, after hydration of the patient with 500 mL of 0.9% saline with 16 mEq of MgSO₄ and the administration of 250 mL of 20% mannitol, at a dose of 40 mg/m² over 1 hour by IV infusion on day 1. Epirubicin was reconstituted for IV bolus by diluting the total dose in 0.9% saline and was administered at a dose of 40 mg/m² on day 1. Gemcitabine was diluted in 500 mL of 0.9% saline and administered at a dose of 600 mg/m² over 1 hour by IV infusion on days 1 and 8. FU was administered with a protracted infusion schedule at a dose of 200 mg/m²/d for the duration of CHT by use of an indwelling single-lumen implanted central venous catheter. This regimen was repeated every 28 days for a maximum of six cycles or until there was evidence either of unacceptable side effects or of progressive disease (PD). In stage IVA patients, the treatment was interrupted after four cycles if no objective response or CB or a CA 19-9 reduction less than 50% of the basal value was observed. At the end of treatment, IVA patients were sent to surgery when operable. All stage IVA patients, whether resected or not, received radiotherapy (RT) with 56 to 60 Gy to the pancreatic region associated with weekly gemcitabine (150 mg/m²).

Dose adjustments were made according to the greatest degree of toxicity. Treatment was delayed if the ANC was not 1,500 cells per cubic millimeter or if the platelet count was not 100,000 cells per cubic millimeter on day 29 (the first day of the next cycle). If recovery was not evident within 2 weeks, the patient was discontinued from the study. The dose of cisplatin and epirubicin was not modified for thrombocytopenia or neutropenia. The dose of gemcitabine was increased by 50 mg/m² in the subsequent course when no grade 3 or 4 World Health Organization (WHO) toxicity was observed, or it was lowered by 100 mg/m² when grade 4 thrombocytopenia was observed. Gemcitabine was omitted on day 8 when ANC was less than 1,000 cells per cubic millimeter or the platelet count was less than 75,000 cells per cubic millimeter; it was halved if ANC was between 1,000 and 1,500 or if the platelet count was between 75,000 and 100,000. If the patient had grade 4 neutropenia or thrombocytopenia, FU infusion was withheld until recovery to the grade 3 level. If the patient had grade 3 nonhematologic toxicity, the treatment was withheld until recovery to the grade 2 level.

Study Evaluations
Pretreatment evaluations consisted of complete medical history, PS assessment, hematologic and biochemical profiles, CA 19-9 assessment, spiral computed tomography scan of the abdomen and the chest, and color Doppler ultrasonography to assess vascular infiltration. Seven IVA patients (39%) were submitted to explorative laparotomy. Complete blood, platelet, and differential counts were performed weekly, whereas biochemistry profile and CA 19-9 assessment were performed at the end of every cycle. Imaging studies were repeated every two treatment cycles to assess objective response. At the end of CHT, CA 19-9 assessment was performed every 40 to 50 days, and imaging studies were repeated every 2 to 3 months, when an increase of CA 19-9 was observed, or when PD was suspected.

Toxicity and Response Criteria
Toxicity was graded by the National Cancer Institute common toxicity criteria.²² The standard WHO response criteria were used to define the antitumor effects that were observed. A complete response (CR) was defined as the disappearance of all measurable and assessable disease in all disease sites. A partial response (PR) was defined as a 50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions, with no new lesions or progression of assessable disease. PD was defined as a 25% increase of the product of the perpendicular diameters of all measurable lesions, the appearance of any new lesions, or the reappearance of any lesion that had previously disappeared. Stable disease (SD) was defined as disease that did not meet the criteria for CR, PR, or PD. CR, PR, and SD had to be confirmed by two observations performed not less than 4 weeks apart. The duration of CR was defined as the time between the first documentation of complete disease resolution and the first documented observation of PD. The duration of PR was defined as the time between the initiation of treatment and the time of PD. The time to progression was defined as the interval between the initiation of treatment and the occurrence of PD. Survival was measured from the initiation of treatment to the date of death or to the last follow-up assessment. CB was assessed on the basis of two primary measures—pain and PS—and a secondary measure, body weight change. Each patient was classified as either positive, stable, or negative for each of the primary CB measures (pain and PS). Patients were considered to have a positive response for CB if they had a positive response for at least one primary parameter without being negative for any of the others. This improvement had to be sustained for at least 4 weeks. PS was considered positive if a 20-point increase in Karnofsky score was observed. Pain intensity was not formally measured with standardized scales and was considered reduced on the basis of patients’ subjective reports of pain improvement associated with a 50% reduction of analgesic consumption (within the same analgesic level), or on the basis of a reduction of the analgesic consumption score, which was evaluated according to the six-point scale proposed by Carmichael et al.¹⁴ If both primary measures were stable, the secondary measure of weight change (7% increase in dry body weight) was used to determine CB.

Statistical Analysis
The end point of this phase II trial was the overall response to the PEF-G regimen. The maximum response rate considered of low interest, on the basis of the experience reported in the literature, was 15%. The minimum response rate considered of interest, because of the demanding design of the regimen, was 45%. The sample size was calculated with a type I error of 5% and a test power of 90%. The target enrollment was estimated to be 44 patients. For the analyses of tumor response, the intent-to-treat (ITT) and assessable populations were defined. The ITT group included all eligible patients, independent of therapy administered. The assessable group included all patients who had received at least two cycles of PEF-G and had had at least one imaging tumor assessment. All patients could be evaluated for toxicity. Survival time was calculated with the Kaplan-Meier method.²³

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Between April 1997 and April 1999, 50 patients from a single institution were entered onto this study. One patient was ineligible because of inadequate hepatic function (transaminases > three times the upper limit of normal). The characteristics of the 49 eligible patients are listed in Table 1. None of the patients had received prior external-beam irradiation, whereas three patients had received electron-beam intraoperative RT.

Response and Survival
Response data are listed in Table 2. There was one CR and 24 PRs for an objective response rate of 58% in 43 assessable patients and of 51% in the ITT population. Fourteen patients had SD, seven of whom had a tumor reduction between 25% and 50%. CR occurred after four cycles of PEF-G in a 30-year-old woman with nodal recurrence, 8 months after pancreatoduodenectomy (two lesions of 6 and 5 cm maximum diameter). Her treatment was consolidated with two additional cycles and 45-Gy local irradiation. Her CR status was maintained at the time of this report (27 months from CR). The objective response rate was 65% in 26 assessable metastatic patients and 47% in 17 assessable IVA patients. The objective response rates in the ITT population were 55% and 44%, respectively. Among the 16 metastatic patients with PR, four had had prior surgery, and their disease was confined to the liver; the liver and lung; the lymph nodes; and the lymph nodes, liver, and muscle. In the other 12 cases, in addition to the pancreas, the involved sites were the liver (five cases); the liver and lymph nodes (four cases); the liver and lung (one patient); the liver, lung, and lymph nodes (one patient); and the lymph nodes (one patient). Fourteen patients (58%) showed PR after two cycles, and 10 patients (six with stage IVA disease and four with pancreatic disease associated with metastatic disease) showed PR after four cycles.

The median response duration was 8.5 months (11.5 months for IVA and 7.5 months for metastatic patients). The median time to tumor progression was 7.5 months (10.5 months for IVA and 7 months for metastatic patients; Fig 1). The median survival was 11 months (18.5 months in IVA and 9.5 months in metastatic patients) in the assessable population and 10 months in the ITT population (18 months in IVA and 9 months in metastatic patients; Fig 2). No difference in survival was observed between IVA patients with surgical or radiologic staging (median survival, 17 and 15.5 months, respectively). If the three IVA patients submitted to surgery after CHT are excluded, the median response duration for the five other stage IVA patients with PR was 11 months, the median time to tumor progression for the 15 stage IVA patients without surgery was 11 months, and their median survival was 18.5 months. Forty-four patients were deceased and five were alive at 22 to 34 months (median, 23.5 months). The 1-year survival of the ITT population was 39% ± 7% (Fig 2).

View larger version (11K): [in this window] [in a new window]   Fig 1. Time to tumor progression for whole population (dashed line), stage IVA patients (wavy line), and metastatic patients (solid line), based on the ITT principle.

View larger version (13K): [in this window] [in a new window]   Fig 2. Overall survival for whole population (dashed line), stage IVA patients (wavy line), and metastatic patients (solid line), based on the ITT principle.

Fifteen patients were not assessable for CB because of a PS more than 70 and no reported pain at the time of enrollment. Thus, CB was assessable in 28 patients. Twelve of 16 patients (75%) who had pain at entry were classified as positive in the pain category, whereas four patients were stable. Both pain and PS were improved in eight responders, whereas PS was more than 70 in the other four responders and was stable in three of four nonresponders. The last nonresponder had improved PS. Seventeen of 23 patients (74%) with PS 70 at entry had an improved PS. One patient with no reported pain and PS more than 70 at entry had a dry body weight improved by 12%. In summary, the CB response was considered positive in 22 of 28 patients (78%).

Safety and Toxicity
All 49 eligible patients were assessed for toxicity ( Table 3). The most common toxicity was hematologic. Grade 3 or 4 neutropenia occurred in 85% of patients and in 51% of cycles. No febrile neutropenia was observed. Growth factors were not routinely performed, but their use was allowed according to the attending physician’s discretion. They were used in 7% of cycles for a median duration of 3 days (range, 2 to 6 days). In patients who did not receive growth factors, grade 4 neutropenia lasted for a median of 3 days (range, 1 to 6 days). One patient had developed grade 3 pneumonia, which was associated with grade 2 neutropenia, during the fourth cycle of PEF-G while receiving gemcitabine at a dose of 650 mg/m². Grade 3 or 4 thrombocytopenia was observed in 59% of patients and in 28% of cycles but was not complicated by hemorrhage or hospitalization for platelet transfusion. Grade 3 anemia was observed in 10% of patients and in 7% of cycles. No grade 4 anemia was observed. Grade 3 nonhematologic toxicity consisted mainly of stomatitis (12% of patients and 5% of cycles), diarrhea (6% of patients and 2% of cycles), and vomiting (6% of patients and 2% of cycles). No grade 4 nonhematologic toxicity was observed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

This trial, by using a new combination CHT, supports the hope that some improvements in response rates may be achievable and that CHT could positively affect patients with pancreatic carcinoma. However, these findings should be considered cautiously because of the difficulty in accurately measuring tumor areas in pancreatic cancer patients. In fact, the evaluation of objective responses, even with newer imaging techniques, is considered rather unreliable because of the vigorous desmoplastic reaction, including inflammation and fibrosis within and around the tumor. Fibrotic tissues are unlikely to immediately regress with cytotoxic therapy, whereas inflammatory tissue could shrink because of factors other than actual effectiveness of the therapy, thus leading, respectively, to the under- or overstatement of tumor regression. Therefore, the use of locally advanced pancreatic cancer as the sole indicator of response in phase II trials may yield misleading results; metastatic disease would likely be a more appropriate method of tumor-response assessment because of the small quantity of the desmoplastic component. The objective response rate achieved by the PEF-G regimen was higher in metastatic disease with respect to locally advanced cancer (55% v 44% in the ITT analysis). Notably, approximately 40% of responses developed as late as the fourth course, perhaps suggesting delayed resolution of fibrosis. In effect, all of these patients had a pancreatic mass, which constituted a part of or the totality of the measurable disease.

Patients with good PS are likely to better tolerate and profit from CHT. In our study group, 92% of cases had PS 1. This was probably related to the fact that the PEF-G regimen was delivered on an outpatient basis, which likely excluded patients with poor PS. Nevertheless, this unusually high response rate was observed in this subset of patients.

Subjective responses, particularly pain reduction, may frequently occur in patients manifesting less than an objective response. Even patients with radiologic SD may sometimes experience a significant reduction in pain, likely because even an undetectably small reduction of tumor pressure on the celiac plexus is enough to produce symptomatic improvement. Because of this observation and the lack of consistent response rates and survival improvement after CHT, an increasing number of trials consider CB to be the main response criterion and study end point. However, the definition of CB has differed between trials and seems to be an even less appropriate end point. CB is subject to the same pitfalls as objective responses, because it is unclear whether the benefit is caused by a reduction of cancer-related or inflammation-related symptoms. Measurement of pain intensity can also be subjective, even though standardized scales are used. It is unclear whether reported relief of pain is the result of a physical improvement or reflects a placebo effect. Even the Karnofsky score is subject to the experience of the investigator. The CB response rate reported seems to be consistently 16% to 22% higher than the objective response rate: series reporting a 5% to 28% objective response rate showed a 24% to 50% CB response rate.^12,13,34 Consistent with these findings, PEF-G achieved a 78% rate of CB responses in the subset of assessable patients in whom the objective responses were 50%, thus amplifying the antitumor effect by 28%. Furthermore, this criterion does not correlate with a clinically relevant prolongation of survival: a 20% improvement of CB corresponded to approximately 1 month of survival prolongation.^12,15 Therefore, tumor shrinkage, as reflected in the objective response rate, should continue to be the major end point of phase II studies while CB and QL provide useful, but complementary, information.

The very high rate of durable objective responses and of CB responses obtained with the PEF-G regimen are encouraging and deserve confirmation. In this lethal and rapid disease, survival time is both less equivocal and more clinically relevant, because the prolongation of survival is the only criterion for correctly estimating the benefit obtained. A median time to progression of 7.5 months, a median survival of 10 to 11 months, and a 1-year actuarial survival of 39% have been observed in our study. Overall survival, time to progression, and response duration in our stage IVA patients have been influenced by the administration of radiation with CHT. Notwithstanding this limit, the outcome of this subset of patients remains of interest when compared with other similar series of stage IVA patients submitted to concomitant radiochemotherapy ( Table 4).^35-38 The very favorable PS profile of our patient population may be influential in the results and should be kept in mind when interpreting these data. Gemcitabine in combination with cisplatin,³⁹ epirubicin,⁴⁰ or FU^41-45 has been extensively used in recent trials, yielding response rates between 5% and 21%, median time to progression of 2.4 to 7.4 months, median overall survival of 4.3 to 10.3 months, and 1-year survival rates ranging from 9% to 39.5%. Gemcitabine was delivered as a standard 30-minute infusion^39-44 or at a fixed dose-rate.⁴⁵ FU was infused with a bolus,^43-45 24-hour infusion,⁴² or PVI,⁴¹ with⁴² or without^41,43-45 biochemical modulation by leucovorin. Metastatic disease ranged from 46% to 100%, the liver was involved in 65% to 87% of cases, median age was 56 to 66 years, and the number of patients enrolled varied from 26 to 66. In these patient populations, a PS of 0 or 1 was observed in 59% to 97.5% of cases—less than 80% of patients in a single series.³⁹ However, tumor grade, which is one of the main prognostic factors in pancreatic ductal adenocarcinoma,⁴⁶ has not been reported in most series.^{35,36,38,39,41,43,45} The interpretation of differences among phase II studies is troublesome because of different statistical power and because the effect on survival of a number of known and unknown prognostic parameters may be of the same or greater order of magnitude than the treatment effect. Actually, the estimate of the survival effect is beyond the limits of a phase II trial. Accordingly, we have planned a phase III randomized multicenter study to compare the PEF-G regimen with gemcitabine alone, to assess whether or not this regimen can improve the outcome of pancreatic cancer.

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Submitted December 11, 2000; accepted February 21, 2001.

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