Originally published as JCO Early Release 10.1200/JCO.2004.03.129 on December 9 2003

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Phase I Trial Using a Time-to-Event Continual Reassessment Strategy for Dose Escalation of Cisplatin Combined With Gemcitabine and Radiation Therapy in Pancreatic Cancer

From the Departments of Internal Medicine and Radiation Oncology, University of Michigan, Ann Arbor, MI

Address reprint requests to Mark M. Zalupski, MD, University of Michigan Medical Center, 1500 E Medical Center Dr, CCGC 3-219, Ann Arbor, MI 48109-0934; e-mail: Zalupski{at}umich.edu.

	ABSTRACT

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PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer.

PATIENTS AND METHODS: Nineteen patients were treated. Gemcitabine 1,000 mg/m² was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m², escalated to a targeted dose of 50 mg/m² using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest.

RESULTS: Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m² cisplatin dose level. Patients treated at 30 and 40 mg/m² cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis.

CONCLUSION: Cisplatin at doses up to 40 mg/m² may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

	INTRODUCTION

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Multimodality therapy improves outcome in patients with pancreatic cancer. Following surgical resection, patients treated with chemotherapy and radiation therapy (RT) have improved survival as compared to surgery alone [1-3]. A Gastrointestinal Tumor Study Group trial demonstrated superiority of RT and fluorouracil as compared to RT alone, supporting combined-modality therapy in unresectable disease [4]. The benefit of local therapy is also suggested by the finding that some patients initially presenting with unresectable disease are resected following radiation and chemotherapy [5,6]. However, systemic failure remains a crucial problem for patients with pancreatic cancer. Thus, the common goals of improving local control with or without surgery and developing more effective systemic treatment are applicable to all stages of this disease.

To address the difficulties of local and systemic disease control, we have attempted to develop an approach that permits simultaneous maximum local and systemic therapy. Gemcitabine was initially approved for use in pancreatic cancer based on phase II and III trial data demonstrating clinical benefit [7-9]. Laboratory studies demonstrating that gemcitabine is a potent radiosensitizer led to a variety of trials combining radiation and gemcitabine [10-12]. In vitro data suggested that the optimal radiosensitization occurred when a cytotoxic concentration of gemcitabine was used [13]. Based on this combination of laboratory and clinical observations, we conducted a phase I trial of full dose gemcitabine (1,000 mg/m²/wk) with radiation dose escalation for patients with locally advanced pancreatic cancer (one-third of whom had small volume metastatic disease) [14]. We were able to safely deliver 36 Gy in 2.4 Gy fractions by using conformal treatment delivered to the tumor only, without prophylactic nodal radiation. This treatment, followed by additional gemcitabine, produced an objective response rate of 30% and a median survival of 11.6 months. Approximately two thirds of the failures were distant, suggesting the need to improve systemic disease control while maintaining or lowering the local failure rate.

In an effort to improve systemic therapy, agents have been combined with gemcitabine. Several trials have suggested improved response rates and clinical benefit with the addition of cisplatin to gemcitabine [15-17]. In addition, preclinical studies suggested that the combination of gemcitabine and cisplatin produced synergistic cytotoxicity without loss of radiosensitization [18]. Taken together, these studies suggested it would be reasonable to attempt to add cisplatin to the combination gemcitabine and radiation. We hoped the use of highly conformal radiation would permit the full dose of cisplatin and gemcitabine that had been tolerable when the drugs were given alone.

Delayed-onset toxicities are a particular challenge for phase I trials of combined-modality therapy. Conventional dose-escalation designs that treat many patients at subtherapeutic doses waste time, are often inaccurate at determining true toxicity rates, and rarely allow estimation of clinical response at doses to be used in phase II studies. These designs also have the disadvantage of periodic closures and lengthy accrual time, and often lose momentum because of the episodic nature of accrual. Standard phase I/II designs have no provisions for orderly dose adjustment if too many or too few toxicities are observed in the phase II stage. The publication of the Time-to-Event Continual Reassessment Method (TITE-CRM) for planning dose-escalation trials presented an opportunity to test a trial design and management paradigm that promised to allow the execution of dose-escalation trials without the need to close accrual periodically, while treating more patients at therapeutic doses and resulting in statistically justified estimates of toxicity and response rates [19].

Based on these clinical, biologic, and statistical considerations, we conducted a phase I trial of escalating cisplatin with full-dose gemcitabine and radiation to the primary tumor. The goal of the trial was to begin to test the hypothesis that systemic control of pancreatic cancer could be improved, without an intolerable increase in toxicity, by adding cisplatin to an established protocol of radiation plus gemcitabine.

	PATIENTS AND METHODS

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Eligibility
Patients with unresectable pancreatic carcinoma with or without distant metastases were eligible for the trial. Determination of unresectability was based on helical computed tomography (CT) scan, endoscopic ultrasound, and surgical consultation. Pathologic confirmation was necessary before study entry. Pretreatment evaluation included a complete history and physical examination, baseline assessment of organ function, chest x-ray and CT scan of the abdomen. Eligibility criteria included age greater than 18 years, Zubrod performance status of 2, estimated life expectancy of at least 12 weeks, and adequate organ function defined as: absolute neutrophil count (ANC) 1,500/cm³, platelets 100,000/cm³, serum creatinine < 1.5 mg/dL, bilirubin < 3 mg/dL, and AST < 5 times upper limit of normal. Patients with a prior history of abdominal irradiation or chemotherapy for pancreatic cancer were ineligible. The institutional review board of the University of Michigan Medical School (Ann Arbor, MI) approved the trial. Written informed consent was obtained from all patients before initiation of therapy.

Treatment
Protocol treatment consisted of two 28-day cycles of chemotherapy, with radiation given during the first cycle of chemotherapy. Radiation and gemcitabine doses were held constant, while a dose level of cisplatin was assigned based on the TITE-CRM algorithm (described in Trial Design, below). RT (36 Gy) was given daily in 2.4 Gy fractions, five times weekly, beginning on day 1 of the first cycle as described previously [14]. Briefly, the planning target volume was gross tumor volume defined on a contrast-enhanced CT scan obtained at end expiration using 3-mm slices, with 1-cm expansion to account for occult invasion (0.5 cm) and set-up uncertainty (0.5 cm). We did not routinely expand the planning target volume for ventilatory motion. Radiographically uninvolved lymph nodes were not included. A three-field plan using static intensity modulation was typically used, with an anterior inferior oblique (angled from the foot toward the head to avoid the kidneys) and lateral fields. The planned target volume received the isocenter dose (36 Gy) ± 5%. If greater than one-half of one kidney received more than 18 Gy, then no more than 10% of the other kidney was permitted to receive greater than 18 Gy. Spinal cord dose was limited to less than 30 Gy. Gemcitabine was given at a dose of 1000 mg/m² as a 30 minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Cisplatin was given intravenously 1 to 2 hours after gemcitabine in 250 mL of 0.9% saline over 30 minutes on days 1 and 15 of a chemotherapy cycle. After combination treatment with chemotherapy and radiation, a second cycle of gemcitabine and cisplatin was given. The protocol therapy intended to administer 6 g/m² of gemcitabine and 120 to 200 mg/m² cisplatin dependent on assigned dose level over 42 days. The dose of each drug received was calculated as a percentage of dose intended by the following formula; % drug received = (total received/total intended) x (42 days/d required to complete two cycles). Following two cycles of therapy as described above, additional chemotherapy could be delivered at the discretion of the treating physician.

Dose Adjustments for Toxicity
Full doses of gemcitabine and cisplatin were delivered for ANC 1,000/mm³ and platelets 75,000/mm³; a 30% dose reduction for both drugs was given when ANC 500/mm³ and less than 1,000/mm³ and/or platelets > 51,000/mm³ and < 75,000/mm³. Treatment was delayed for ANC < 500/mm³, platelets 50,000/mm³, or grade 3 nonhematologic toxicity. If both drugs were held at any point during cycle 1 for toxicity, radiation was also held. Treatment resumed when toxicity resolved to grade 1, with cisplatin and gemcitabine doses reduced by 30%. A 1-week break was maintained between completion of cycle 1 and initiation of cycle 2. If chemotherapy was held during the second cycle, doses were dropped. Dose adjustment not associated with the observation of a dose-limiting toxicity (DLT) did not affect subsequent patients' dose assignments.

Trial Design
The cisplatin dose was assigned using the TITE-CRM to establish the rate of DLT, while maximizing the number of patients treated at doses likely to be efficacious and maintaining the trial open to enrollment [19,20]. Dose levels and prior estimates of the probability of DLT, based on previous experience with radiochemotherapy involving gemcitabine, are presented in Table 1 [14]. The goal of the trial was to determine the dose of cisplatin associated with a 20% probability of DLT (a target rate of 0.20). The initial dose level of cisplatin was 30 mg/m². When a patient was eligible for enrollment, the probability of DLT was estimated for each dose, based on the trial experience up to that time and the prior expectations of toxicity. In the TITE-CRM paradigm, patients who had enrolled in the trial but had not experienced DLT were included in the probability calculation with a weight equal to the proportion of the 9-week acute toxicity observation period they had completed; patients who experienced toxicity or completed the observation period without toxicity were assigned full weight. Each new patient was assigned to the currently estimated target dose, defined as the dose having an estimated probability of toxicity closest to but not greater than the target rate, subject to the restriction that two patients must have completed therapy at the lower dose before the first patient was assigned to a higher dose. The prior distribution of the dose-toxicity model was chosen to control the expected number of toxicities in the trial under a variety of scenarios about the true relationship between dose and toxicity [20].

Statistical Estimation
At the end of the trial, the posterior distribution of the dose-toxicity parameter, , and DLT at each dose, was calculated by means of Bayesian Analysis Using Gibbs Sampling software (MRC Biostatistics Unit, Cambridge, UK) using the logistic dose-toxicity model and exponential prior distribution on that were employed to conduct the trial. A burn-in of 40,000 iterations was followed by an estimation phase of 80,000 iterations, retaining every tenth value. Ninety-five percent posterior intervals for the toxicity probabilities were calculated from the sampled values. Survival was calculated from the date of treatment initiation to the date of death or last follow-up. Survival curves were calculated by the product-limit (Kaplan-Meier) method using SAS PROC LIFETEST software (SAS Institute, Cary, NC). Confidence intervals for binomial proportions were calculated by exact procedures available in SAS PROC FREQ software.

	RESULTS

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Between April 2000 and July 2001, 19 patients were registered to the study. The median age of study participants was 62 years (range, 45 to 77 years). There were 11 men and eight women. Five subjects had a baseline performance status of 0, while the rest had a performance status of 1. Sixteen patients had elevated baseline CA 19-9 (median value in all 19 patients, 275 U/mL; range, 3 to 73,000 U/mL). Each patient had locally unresectable disease, and four patients had metastatic disease to the liver at the time of protocol entry. No patient had received prior therapy for pancreatic cancer. Patient 8 suffered a major cerebrovascular accident on day 2 and was not considered assessable for toxicity or response.

The assigned cisplatin dose levels of the 18 assessable patients are listed in Table 2. As a result of the cohort restriction, four patients were assigned at both the 30 mg/m² and 40 mg/m² dose levels, even though no DLTs were observed and the estimated target dose was higher than the assigned dose. After Patient 12 (treated at 50 mg/m²) experienced DLT, the estimate of , and therefore the target dose, began to decrease, but not sufficiently to move the target dose to 40 mg/m². The DLT of patient 13 was dated March 30, 2001, but was not officially established until after Patients 17 and 18 were enrolled. At that time, based on two toxicities out of seven patients enrolled at 50 mg/m², the estimated target dose was still 50 mg/m². Patient 17 was enrolled at 40 mg/m², because of concerns about a potential DLT in Patient 16. Patient 18 was enrolled at the current estimated target dose of 50 mg/m², as additional time had passed and the DLT of patient 16 had not yet been established.

Toxicity
Two patients experienced death during or shortly following protocol therapy (patient 8 on day 13 and patient 2 on day 63), but both were judged to be secondary to the hypercoaguable state associated with pancreatic cancer, and neither death was classified as related to therapy. The four DLTs, all of which occurred at the cisplatin 50 mg/m² dose level, were: duodenal ulcer; diarrhea resulting in dehydration; and grade 3 anorexia and nausea leading to a two-level decline in performance status (two patients). The estimated probabilities of toxicity for each dose employing the dose-toxicity model used to conduct the trial are presented in Table 1. The final estimate of the dose-toxicity parameter was 0.99 (95% CI, 0.75 to 1.30).

Toxicities not considered dose-limiting included one patient who experienced transient (< 1 week) grade 4 neutropenia, four patients who experienced grade 3 neutropenia, and six patients who experienced grade 3 thrombocytopenia. The mean weight loss, compared to the patient weight before start of therapy, was 5.7% (± 0.9%) at day 28 and 6.8% (± 1.3%) at week 9. Late toxicity developed in two patients. One patient treated at the initial dose level of cisplatin developed symptoms of partial gastric outlet obstruction approximately 22 weeks from protocol initiation. He underwent a Whipple resection and pathologic examination revealed extensive ulceration of the proximal duodenum and ampulla. A second patient treated with 50 mg/m² of cisplatin developed thrombosis of the superior mesenteric artery and vein 13 weeks after protocol initiation that ultimately proved fatal. The relationship to therapy is unknown.

Response and Survival
Three patients experienced an objective partial response (17%; 95% CI, 4% to 41%), while 15 patients maintained stable disease at the time of initial response evaluation. No complete responses were achieved. Whipple resection became possible in two patients. Of the 15 assessable patients with an initial elevated serum CA 19-9, 11 achieved a 50% reduction in that serum marker following protocol therapy (73%; 95% CI, 45% to 92%). The two resected patients (one partial response) had declines of 85% and 86% in CA 19-9, the two additional responders had a 30% decline and a normal CA 19-9 throughout.

The median progression-free interval for all 19 registered patients was 5.8 months (95% CI, 2.9 to 10.6). In the three assessable patients with metastatic disease at study entry, each progressed distantly. Of the 15 patients without metastasis, initial failure was local in five, in regional unirradiated lymph nodes in one, distant in three, and simultaneous local and distant in one. Three patients had global deterioration without recognition of pattern of recurrence and two resected patients remain clinically free of disease. The median progression-free interval for the 15 patients without metastasis was 6.8 months (95% CI, 4.6 to 12.2). Sixteen of 19 patients have died. With a minimum follow-up in living patients of 20 months, the median survival for all 19 patients was 10.7 months (95% CI, 5.4 to 18.2; Fig 1). The median survival of the 15 patients without metastasis was 12.9 months (95% CI, 7.4 to 21.2).

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curve in all patients (N = 19) and in those without metastasis at registration (n = 15).

	DISCUSSION

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Our second hypothesis was that the addition of cisplatin to full-dose gemcitabine with radiation might decrease systemic failure without sacrificing local control. Acknowledging the small number of patients in both studies, the rate of distant progression was only 39% (95% CI, 16% to 61%) in the current study which is substantially less than the 68% (95% CI, 52% to 83%) distant progression rate in our previous trial using radiation and gemcitabine alone [14]. In further support of this hypothesis, local control was not significantly different from our previous trial. Local control was preserved even though the median percent dose gemcitabine received was somewhat lower than our previous phase I trial (85% v 96%) [14]. Additionally, the fraction of patients resected in this trial was not obviously different than those we have treated with RT and gemcitabine [22]. It is possible that radiosensitizing effects of cisplatin, though not observed in our in vitro studies, may have contributed to local control [18,23-25]. If these observations are supported through additional studies, combination chemotherapy in pancreatic cancer may be anticipated to be particularly valuable in the adjuvant or neoadjuvant setting.

This trial is the first phase I trial conducted at any institution using the TITE-CRM paradigm. This method of conducting a phase I trial is suited to situations in which the observation period is long compared to the mean patient inter-arrival time, since it allows the continual recruitment of patients. This trial was designed to recruit 18 patients (one patient nonassessable for toxicity was replaced, for a total of 19), which, in retrospect, is too few to take full advantage of the potential for usefully narrow confidence intervals around estimates of the DLT proportions at each dose and the response rate at the target dose. This is demonstrated by the wide posterior intervals in Table 1. Had the trial accrued more patients, most would have likely been treated at 40 mg/m², so that the estimate of toxicity at that dose would be much improved. In their current state, the data suggest a steep increase in toxicity between 40 mg/m² and 50 mg/m², but more patients treated at 40 mg/m² are required to truly determine if this is true. Because the estimated value of was so close to 1, resulting in posterior toxicity probability estimates close to our prior estimates, we were concerned that the estimation of the dose-toxicity parameter was being dominated by an overly informative prior distribution, so we repeated the estimation based on a noninformative prior. The estimate of was almost identical, confirming our belief that the sample size of 18 was too small. Based on this experience, we believe that TITE-CRM trials must accrue at least 24 patients, and preferably 30 to 36, especially if the trial is designed with cohort restrictions on dose estimation.

Some researchers have expressed concern that TITE-CRM trials may expose patients to excess risk. Based on our simulations, we do not believe this to be the case [20]. The 50% toxicity rate of the top dose is similar to that observed in a standard 3/6 design when one toxicity has been observed in the first three patients. This trial did demonstrate, however, that if the risk is to be controlled, evaluations of toxicity must be possible in a timely fashion. The declaration of DLT in patient 16 occurred with documentation of gastric ulceration following endoscopy. Although the toxicity was suspected, the delay in the final assessment occurred as the procedure was arranged and the results communicated. Based on this experience, we recommend that the DLT criteria for TITE-CRM trials must be assessable at the end of the observation period. Conversely, this set of events also demonstrates a strength of the TITE-CRM paradigm. During the observation period, we were able to reduce the dose of patient 17, because of our uncertainty concerning the status of patient 16, without violating the decision rule associated with the determination of the target dose. This would not have been possible in the standard 3/6 phase I dose-escalation design. These findings suggest that the TITE-CRM is not only a feasible design for phase I combined modality trials, but offers distinct advantages with respect to accrual, flexibility, and statistical inference, compared to the standard phase I dose-escalation trial design.

In conclusion, we believe continued investigation of full-dose gemcitabine with RT is warranted in pancreatic cancer. Based on an apparent increased efficacy of gemcitabine infused at a fixed dose rate of 10 mg/m²/min, it may be reasonable to consider varying the dose rate of gemcitabine in combination with radiation ± cisplatin [26]. Alternatively, it may be worthwhile adding other chemotherapeutic agents, such as oxaliplatin or a growth factor receptor antagonist in patients who overexpress these receptors. In contrast to 10 years ago, the development of new agents that have both radiosensitizing and systemic activity in patients with advanced pancreatic cancer supports increased exploration of innovative chemoradiotherapy approaches.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by Eli Lilly and Co, Indianapolis, IN.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted March 21, 2003; accepted August 29, 2003.

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