J O U R N A L O F G E R I A T R I C O N C O L O G Y 2 ( 2 0 1 1 ) 1 4 2 – 1 4 6

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Clinical Trials

Phase I clinical trials in patients ≥80☆

Himabindu Gaddipati, Pingfu Fu, Afshin Dowlati⁎

Division of Hematology/Oncology, Case Western Reserve University and University Hospitals Case Medical Center and the DevelopmentalTherapeutics Program, Case Comprehensive Cancer Center, Cleveland, OH, USA

A R T I C L E I N F O

☆ This study was supported by grant U01-C⁎ Corresponding author at: University Hospitals

E-mail address: afshin.dowlati@case.edu

1879-4068/$ – see front matter © 2011 Elsevidoi:10.1016/j.jgo.2011.01.001

A B S T R A C T

Article history:Received 2 November 2010Received in revised form 13 January2011Accepted 18 January 2011Available online 15 February 2011

Objective: Phase I clinical trials play a crucial role in development of therapeutics for cancerpatients. During phase I clinical trials, common toxicities are delineated, dose-limitingtoxicities (DLT) are determined and a dose for phase II studies is recommended. However,reviews of the phase I population indicate a younger group of participantswith amedian ageof 50–55 years. No data exists on the performance of octogenarians on phase I trials.Concerns for enrollment of this patient population relate to the presence of co-morbiditiesand possibly altered pharmacokinetics in the setting of unknown potential toxicities.Materials and Methods: We present herein the largest review of octogenarians on phase Itrials. Twenty-two octogenarian patients with a median age of 83 were enrolled on phase Iclinical trials.Results: More than 50% of them were chemotherapy naïve, most likely indicative of the factthat treating physicians believed standard therapy to be potentially toxic to this population.These 22 patients were otherwise matched in terms of performance status and otherparameters to a control group of participants (<80 years). This includes a similar number ofcycles administered. Patients (≥80 years) had a 3-fold higher rate of achieving DLT (p=0.06)compared to the control group enrolled at the same dose level. The toxicities observedinclude cardiovascular, gastrointestinal and infectious complications. Three patients wereenrolled on molecular targeted treatments with no significant toxicities.Conclusions: We conclude that enrollment of patients of ages ≥80 years on phase I trials ofchemotherapy agents is most likely associated with higher risk of DLT.

© 2011 Elsevier Ltd. All rights reserved.

1. Introduction

The goal of phase I oncology trials is to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD)for an experimental agent or regimen and to recommend aphase II dose for subsequent testing. Standard eligibilitycriteria include locally advanced or metastatic cancer, whichis refractory to standard treatment regimens or where nostandard therapy exists. Patients in general must have a good

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Eastern Cooperative Oncology Group (ECOG) performancestatus (PS) of 0, 1 or 2.

As the patient population in the United States is aging, alarger proportion of people will become candidates for clinicaltrials.1 Although oncologists have more readily embraced theconcept of treatment for advanced malignancies in elderlypatients, there is still some reluctance because of the concernfor undue toxicity in this patient population.2 In a survey ofAmerican oncologists, 80% of the respondents agreed with

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.

Table 1 – Patient characteristics.

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published data, showing that patients have better outcomeswhen they receive treatment on clinical trials, but 50%indicated that they declare patients unsuitable for clinicaltrials on the basis of age alone.3 Additionally elderly patientsare often disproportionately excluded because of a higherincidence of co-morbidities. When the enrollment of patients(≥70 years old) in 164 Southwest Oncology Group (SWOG)treatment trials between 1993 and 1996 was evaluated, asignificant discrepancy was found between the rates ofenrollment (13%) versus those in the US population withcancer (47%). These figures indicated that patients who were70 years of age or older accounted for much of the shortfall inenrollment.4

Over the past few decades, the median life expectancy inthe United States has increased.5 By 2030, the number ofpersons in the United States over the age of 65 years will havedoubled, and the number of persons over the age of 85 yearswill have quadrupled. Therefore, the definition of who is an“elderly patient” will continue to evolve. Generally patientsaged greater than 80 years have multiple co-morbidities and asuboptimal performance status, so there is a disproportion-ately higher rate of exclusion from clinical trials. However, dueto the increasing proportion of patients within this cohort, thequandary of how aggressive one should be is becoming morecommonplace. This dilemma is more pronounced in thephase I trial setting, as the therapeutic dose and associateddrug toxicity is yet to be established.

So far there have been no studies that have addressed thetolerability and toxicity of patients enrolled in phase I trials inthis age group. From our observations as a comprehensivecancer center with 17 years of experience conducting phase Iclinical trials, we hypothesized that patients with agesof ≥80 years may experience an excess in dose-limitingtoxicity. We thus conducted a retrospective review andcompared the degree of adverse events and other importantparameters in two groups of patients: patients≥80 years andtheir younger counterparts (with ages less than 80) who wereenrolled on the same phase I trials.

Characteristic n (%)

Total no. of patients 22Age (years)Median 83Mean 83.5

SexMale 12 (55%)Female 10 (44%)

ECOG PS0 5 (23%)1 15 (67%)2 0Unknown 2

No. of prior treatments0 13 (59%)1 5 (23%)2 1 (4.5%)3 3 (13.5%)

Type of trialsHematologic 3 (20%)Gynecologic 4 (27%)Solid tumor 8 (53%)Organ dysfunction 4 (27%)

2. Materials and Methods

This was a retrospective review conducted after receivinginstitutional review board approval. We reviewed patientrecords from phase I trials conducted at our institutionbetween 1994 and 2009. Out of 1195 patients who wereenrolled on phase I studies during this time period, 31 patientswere aged 80 years or above and deemed to be eligible for thisstudy (2.6%). Eligibility was defined by patients aged 80 yearsor greater who had been enrolled in phase I trials for cytotoxicor targeted systemic anti-cancer agents. Out of the 31 elderlypatients who were potentially evaluable, analysis was con-ducted on 22 patients. Six patientswere excluded from the twostudies because theywere treatedwith photodynamic therapyand topical chemotherapy, respectively, for cutaneous malig-nancies. Therewas insufficient information available from thearchived records on three patients. The following data wasobtained: age, gender, performance status, number of priorchemotherapy treatments, length of time on study, reason fortermination of treatment, nature of dose-limiting adverse

events, total number of cycles administered, dose level inwhich the patient was enrolled and MTD for the respectivestudy. Dose-limiting toxicity was defined as per the respectivestudy protocols.

The 22 patients were enrolled in 15 different trials,6–19 3 ofwhich were for targeted agents. This information wascompared to the 123 patients who were enrolled on thesame studies and at the same dose levels as the patients whowere ≥80 years. Thus elderly patients' adverse event and DLTdata were matched with younger patients who were enrolledat the same dose level on the same trials. For the patientsenrolled in organ dysfunction trials, comparisons were madefor patients enrolled on the same dose level within theindividual treatment cohorts (mild, moderate and severelevels of organ dysfunction).

Elderly patients (age≥80 years) and patients with ages of<80 years who were treated at the same dose level as theelderly patients in the phase I trials were compared in terms ofDLT rate, number of treatment cycles, performance status (PS)and number of prior therapies. The difference of DLT ratebetween two age groupswas examined by chi-square test. Thedifference in number of treatment cycles, PS and number ofprior therapies between two age groups was examined byWilcoxon signed rank sum test. All statistical analyses weredone using SAS (SAS Institute, Cary, NC), and a p-value of lessthan 0.05 is considered to be statistically significant.

3. Results

A total of 22 patients aged 80 years or older participated in 15phase I clinical trials at the Ireland Cancer Center of UniversityHospitals Case Medical Center from 1994 to 2009. Table 1shows the data on patient characteristics in regards to age,performance status, number of prior therapies and trial

Table 3 – Comparison of DLT rate.

Without DLT (%) With DLT (%) p

Age≥80 years 18 (81.8) 4 (18.2) 0.067Age<80 years 115 (93.5) 8 (6.5)

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characteristics. The median patient age was 83 years old (55%were males and 45% were females). Ninety percent of thepatients had a performance status of 0–1. The majority of thepatients (59%) were treatment naïve, whereas only 13% ofpatients had three prior treatments. None of the patients weretreated with more than three prior regimens.

Four of the 22 (18%) elderly patients developed dose-limiting toxicities (DLT) in cycle 1 of treatment. These adverseeventswere atrial fibrillation, gastric perforation, sepsis due toprolonged neutropenia and intractable nausea/vomiting. Thesignificant grades 3 and 4 adverse events are summarized inTable 2. In contrast only 8 patients out of 123 (6.5%) under theage of 80 experienced DLTs (Table 3). This difference reachedborderline statistical significance (p=0.067). The mean num-ber of treatment cycles administered in the elderly populationin comparison to the younger individuals was equivalent (3.39vs. 3.16, p=0.88). Table 4 shows the differences between thestudy and control groups for number of treatments, baselinePS and number of prior therapies before study participation.There were no differences amongst the groups for either ofthese characteristics.

Three patients (14%) of the 22 were enrolled on trials oftargeted agents. None of them experienced significant toxic-ity, and they were all removed from the study because ofdisease progression. They were on study for an average of47 days compared to 94 days for the patients who were ontrials with cytotoxic agents. There were no treatment-relateddeaths in the elderly population.

4. Discussion

In a large retrospective review of 460 phase I trials, 11,935patients were assessed for toxicity and response to therapy.20

The overall incidence of grade 4 toxicity was 14.4%. Patients on

Table 2 – Listing of grades 3 and 4 adverse events inelderly patients.

Toxicity Adverseevents

Grade Dose-limitingtoxicity

Atrial fibrillation 1 4 YDiarrhea 2 3

3Thrombocytopenia 1 4Hematuria 1 4Hypotension,weakness

1 3

Sepsis 1 3 YNeutropenia withoutinfection

1 4

Intractable nausea/vomiting

1 4 Y

Perforated gastric ulcer 1 4 YAllergic reaction 1 3Pulmonary embolus 1 3Stomatitis 1 3None 10 –

cytotoxic regimens had a severe adverse event rate of 17.4%,while the rate was only 4.8% for all other non-chemotherapytrials.20 In comparison the overall toxicity rate amongst theelderly patients in our study was 18%.

The results of our study serve to highlight the potentialrisk for toxicity in the elderly patient group (≥80 years) onphase I trials. There was an increase in the number of DLTsin this patient population when compared to the youngerpatients enrolled on the same studies that trended towardstatistical significance (p=0.067), despite the fact that theelderly patients were equivalent to the younger cohort interms of the performance status at enrollment, number ofprior therapies, dose level and median number of cyclesreceived. The analysis showed no statistically significantdifference for these variables. A significant proportion of theelderly patients (59%) were treatment naïve, which mayexplain their relatively good performance status atenrollment.

These results are in contrast to those recently reported byLoConte et al., who published a retrospective review of 242patients with a mean age of 57. A multivariate logisticregressionmodel was used to incorporate variables pertainingto socioeconomic status, demographics, co-morbidities, ECOGperformance status and laboratory values to help predicttoxicity. They concluded that age and co-morbidity did notpredict for the development of DLT in phase I chemotherapytrials. However there were only seven patients (3%) who wereover 75 years and no patients over the age of 80.21 Therefore,the sample of patients in this age range was likely insufficientto make the comparison for this cohort of patients valid.

Another retrospective study was conducted at JohnsHopkins Oncology Center, where clinical and pharmacokineticdata for 344 patients enrolled in 13 phase I clinical trials fornine different drugs were examined. Patients were stratifiedaccording to age; however, only 1.5%were ≥75 years old. Therewas no significant difference between the younger (<65 years)

Table 4 – The comparison of mean number of treatmentcycles, performance status and prior therapies betweenelderly patients (≥ 80 years) and younger patients (<80 years).

Mean Std p

Number of treatment cyclesAge≥80 years 3.39 2.38 0.88Age<80 years 3.16 1.17Performance statusAge≥80 years 0.75 0.44 0.18Age<80 years 0.4 0.5Number of prior therapiesAge≥80 years 0.73 1.08 0.26Age<80 years 1.38 1.19

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and older patients (≥65 years) with regards to dose, drugclearance and toxicity, but the ≥80 years age group was againunderrepresented.1

Our data is the most comprehensive representation of thisunique minority of patients, so far. However, this is still arelatively small sample size, and the study was also limited bythe fact that it is a retrospective review. Over time, there hasbeen an increased tendency at our institution to includeelderly patients in phase I trials. This is reflected by theobservation that only two patients were enrolled in year 1999and the rest were after 2000. This tendency to raise the age barfor enrollment parallels the rise in the number of trials withmolecularly targeted agents/biologic therapies. It is presumedthat trials of molecularly targeted agents have more favorabletoxicity profiles and, in some cases, treatment convenience inthe setting of oral agents.20

Since enrollment of patients aged ≥80 in phase I clinicaltrials is very limited at present, larger prospective studieswould be required to validate these findings. Additionalinformation pertaining to socioeconomic, co-morbidity, labo-ratory data and, most importantly, pharmacokinetic datashould be incorporated into the analysis. It is important tohighlight that patients enrolled on phase I trials are a selectedgroup of patients and it is likely that those greater than the ageof 80 are even more highly selected. Patients greater than80 years may be good candidates for phase I trials withmolecularly targeted agents, immunomodulators, etc., giventhe generally lower adverse event rate.

In conclusion, our analysis of phase I trials enrolled at asingle institution notes that only 2.6% of those enrolled wereover the age of 80. A higher rate of DLTwas seen in this patientpopulation despite the fact that the majority of patients weretreatment naïve with no prior chemotherapy history.

Conflict of Interest

None of the authors have conflict of interests pertaining to thecurrent project.

Authors Contributions

Afshin Dowlati: Conception and design, data collection,analysis and interpretation of data and manuscript writing.

Pingfu Fu: Data analysis and manuscript writing.Himabindu Gaddipati: Conception and design, data collec-

tion, analysis and interpretation of data and manuscriptwriting.

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