Dose Intensity Analysis of High-Dose Carboplatin in Refractory Ovarian Carcinoma Relative to Age

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1 65 Dose Intensity Analysis of High-Dose Carboplatin in Refractory Ovarian Carcinoa Relative to Age Terri L. Cornelison, M.D., and Eddie Reed, M.D. Background. Cisplatin and carboplatin are essential to anageent of advanced-stage epithelial ovarian carcinoa. No published data exist regarding carboplatin dose intensity iportance in ovarian cancer, nor are there data for the effect of age on the ability to deliver dose-intensive carboplatin. Methods. Retrospective dose intensity analyses were perfored for 93 patients with advanced-stage refractory ovarian carcinoa, who received single-agent, high-dose carboplatin cheotherapy (8 g/2/35 days or 16 g/2/week). These patients had been treated on one of three high-dose carboplatin studies conducted in the Medicine Branch of the National Cancer Institute during the 198s. Eligibility criteria required age greater than or equal to 18 years, good end organ function, and good perforance status. Results. Patients 6 years of age or older coprised 33% of the cohort and patients 7 years of age or older coprised 8% of the cohort. Adinistered dose intensity of carboplatin did not differ aong age groups. Patients of age 5 39 years received a dose intensity of 136 f 28 g/2/week, those of age 4-59 years received 129 f 33, those of age 2 6 years received , and those of age 2 7 years received 129 f 19. Further, the adinistered carboplatin dose intensity did not differ aong clinical response groups. Dose intensity in coplete responders was 138 f 18 g/'/week; in partial responders, ; and in nonresponders, The age distribution of responders atched the age distribution of the cohort. Conclusions. These data deonstrate that elderly patients with good end organ function and good perforance status tolerate the sae level of dose-intensive platinu therapy as younger patients. Age alone should not be a deterinant for carboplatin dose odification in Presented at the Perspectives on Ovanan Cancer in Older-Aged Woen: Current Knowledge and Recoendahons for Research Working Conference, Bethesda, Maryland, Noveber 2-2 1, Fro the Mediane Branch, National Cancer Institute, Bethesda, Maryland Address for repnnts. Eddie Reed, M.D., Medicine Branch, National Cancer Institute, Building 1, Roo 12N226, 9 Rwkville Pike, Bethesda. MD 2892 Accepted for publication Septeber 16, the treatent of ovarian carcinoa. Cancer 1993; 71~65-5. Key words: dose intensity, high-dose carboplatin, ovarian carcinoa, age. Cisplatin and carboplatin are the ainstays of therapy in the anageent of advanced-stage epithelial ovarian carcinoa.'-4 Siilar activity spectrus have generated uch coparison of these two platinu coordination The collective clinical experience suggests that therapeutic equivalence is evident when carboplatin illigra doses are fourfold those of cisplatin illigra doses.4 At clinically equivalent doses, carboplatin has greater heatologic toxicity, but clinically insignificant nephrotoxicity, ototoxicity, and neurotoxicity copared to isp plat in.^,^ Carboplatin's reduced overall toxicity cobined with its equivalent clinical activity suggests that carboplatin ay be preferable to cisplatin in soe settings.' Dose intensity appears to be a ajor deterinant of clinical response to cisplatin. Levin and Hyiuk have shown the relative dose intensity (in illigras of edication, per squared eter of body surface area of the patient, per week of therapy [g/2/week]) of cisplatin to be directly related to disease response in initial and salvage therapies of ovarian carcinoa." This dose intensity effect appears to be independent of total cuulative dose, and represents a cisplatin dose intensity of 1-35 g/2/wk. 21s et al. have shown that high-dose cisplatin (2 g/2/cycle) offered a 32% response rate in refractory ovarian carcinoa," and that the coparable carboplatin dose (8 g/2/cycle) offered a 27% response rate in a siilar cohort of patients.'* No published data currently exist on the iportance of dose intensity in carboplatin therapy of ovarian carcinoa. Available data suggest that in general edical practice, age is an accepted factor in dose odifications and clinical response in ovarian carcinoa. Yancik et

2 Carboplatin Dose Intensity and Age/Cornelison and Reed 651 al., using data fro the National Cancer Institute Surveillance, Epideiology and End Results Progra, deonstrated an age relationship to the diagnosis and treatent of ovarian cancer.i3 They present data to suggest that older woen with ovarian carcinoa present with advanced disease ore frequently and that they are ore likely to be treated with less aggressive therapy than younger woen. For ethotrexate, an age effect on drug etabolis has been rep~rted,",'~ but no such data exist for carboplatin, although liited data exist for cisplatin.i6 In this paper, we retrospectively assess the effect of age on the ability to deliver dose-intensive carboplatin to patients with advanced-stage ovarian carcinoa. Materials and Methods Ninety-three patients are included in this analysis. Each patient received single-agent, high-dose carboplatin cheotherapy on either of three previously reported clinical trials. High-dose carboplatin alone was reported by Ozols et al. in High-dose carboplatin with diethyldithiocarbaate (DDTC) was reported by Rothenberg et al. in 1988." High-dose carboplatin with granulocyte-acrophage colony stiulating factor (GM-CSF) was reported in abstract for by Reed et al. in 199." There are inor differences in patient eligibility criteria between the three high-dose carboplatin studies; however, coon eleents exist. Eligibility criteria required that the patient have advanced-stage refractory ovarian carcinoa of epithelial histology, and have failed or relapsed fro at least one prior platinubased therapy. Borderline histologes were not eligible. Good end organ function was required to enter these studies as deonstrated by liver function studies less than or equal to twice the upper liit of noral, and a seru aeatinine of less than 1.5. Also required were a Kaofsky perforance status greater than or equal to 6, and age of greater than 17 years. There was no upper age liit. These cobined studies included in total 16 patients. Of these 16 patients, 13 had uneasureable disease or unavailable data, and were therefore excluded fro final statistical analysis. Of the reaining 93 patients, 19 received only one cycle of therapy for one of the following reasons: the patient's intolerance of cheotherapy side effects, clear evidence of progressive disease after the first cycle of therapy, or drug-related toxicity that was edically unacceptable in the view of the principal investigator. These 19 patients were included in the statistical analysis, however. Because the study was designed to adinister drug every 35 days, dose intensity was calculated fro the first day of the first dose of cheotherapy to 35 days after the last dose of cheotherapy for each individual. Therefore, a patient who received only one cycle of therapy was calculated to have received 8 g/2 divided by 35 days, or 16 g/2/week. All statistical analyses were perfored using the Cricket Graph Version 1.3 software package on a Macintosh SE coputer (Macintosh Inc. Palo Alto, CA). Response to therapy was defined as follows: coplete response (CR), total eradication of disease that lasts at least 1 onth and is confired by peritoneoscopy; partial response (PR), greater than 5% reduction in the su of the products of the perpendicular diaeters of all easurable lesions that lasts at least 1 onth; and no response (NR), failure to eet criteria for coplete or partial response. Results We first assessed ean dose intensity for each of the three carboplatin studies to deterine whether significant interstudy differences occurred that would reflect teporal changes in our objective to deliver aggressive cheotherapy. The respective ean dose intensity values for each study are: 13 -t 13 g/2/week for highdose carboplatin alone, 137 f 35 g/2/week for high-dose carboplatin with DDTC, and 129 _+ 26 g/ 2/week for high-dose carboplatin with GM-CSF. The dose intensity values were approxiately the sae across these three studies, which span an approxiate 6-year tie period. These three studies are cobined for all following analyses. In the general population, the edian age for ovarian cancer incidence is 61 years.13 In this cohort, 17% of the patients were 39 years of age or younger. Fifty percent of the patients were in the interediate age range of 4-59 years. Thirty-three percent of the patients were 6 years of age or greater. Of the group that was 6 years and older, seven patients (8% of the cohort) were 7 years of age or older. In the data presented below, the age group designated as 2 6 includes all individuals above that age, whereas the group designated as 2 7 is a subset of the 2 6 age group. Many factors ay affect the drug dosage a physician chooses to adinister to a patient. The focus in each of our carboplatin trials was to deliver the axiu dosage safely tolerated. In patients I 39 years of age, the dose intensity was 136 k 28 g/2/week; in patients 4-59 years of age, dose intensity was 129 f 33; in patients 2 6 years of age, dose intensity was 139? 24; and in patients 2 7 years of age, dose intensity was 129 _+ 19. Thus the actual adinistered dose intensity of carboplatin did not differ aong age groups, deonstrating that elderly patients (2 6 years

3 652 CANCER Suppleent Ianuary 15, 1993, Volue 71, No AUTHREESTUDIES HD-CBDCA CBDCA-DDTC CBDCA-CSF 3 > 8. 1, E EEE nu r Q= AGE 9 A2 = AOE Figure 1. (A) Patients studied are stratified by treatent group and substratified by age. Actual adinistered carboplatin dose intensities are copared. (B) Adinistered carboplatin dose intensity is shown for each patient studied. [ID-CBDCA: high-dose carboplatin (ref. 12); CBDCA-DDTC: high-dose carboplatin with diethyldithiocarbaate (ref. 17); CBDCA-CSF: high-dose carboplatin with granulocyte-acrophage colony-stiulating factor (ref. 18). of age) tolerated the sae level of dose-intensive carboplatin therapy as did patients who were literally half their age. This nonassociation between carboplatin dose intensity and age was aintained when the three highdose studies were assessed separately. Table 1 shows the adinistered carboplatin dose intensity by age group for each of the three studies. This inforation is graphically displayed in Figure 1A.. W li AGE Figure 2. Each patient's age is plotted against the nuber of cycles of therapy adinistered (A), and against the total cuulative carboplatin dose (B). To address if dose intensity and age were unrelated only when patients were allocated to our arbitrarily defined age groups, we produced a scattergra depicting dose intensity versus age for each individual patient (Fig. 1B). Linear regression was perfored and the correlation coefficient was.. Thus, elderly patients received the sae carboplatin dose intensity as younger patients when the data were analyzed for the entire 1 Table 1. Dose Intensity by Treatent Group and Patient Age Age (yr) Treatent group t 6 t 7 HD-CBDCA rt f rt 26. None entered* CBDCA-DDTC f rt f f 22.3 CBDCA-CSF rt rt rt rt 15.7 Studies cobined f rt f rt 18.9 HD-CBDCA: high-dose carboplatin; CBDCA-DDTC: high-dose carboplatin with diethyldithiocarbaate; CBDCA- CSF. high-dose carboplatin with granulocyte-anophage colony-stiulating factor. No patients in this age group were entered in this study.

4 Carboplatin Dose Intensity and AgelCornelison and Reed 653 n 6o fl I Cohort Responders Figure 3. Presented is the age distribution for the entire cohort (solid bars) and the age distribution for those individuals who were responders to therapy (hatched bars). These are juxtaposed for ease of coparison. cohort, or for each separate study, or for the individual patients. Elderly patients not only tolerated the sae carboplatin dose intensity, they also received the sae nuber of cycles and the sae total dose of therapy as younger patients. Figure 2A shows the nuber of cycles adinistered versus age for each patient studied, and Figure 2B shows the total dose of carboplatin versus age for each patient. The correlation coefficients are. and.1, respectively. The age distribution of responders atched the age distribution of the cohort. Figure 3 shows the age distribution of objective responders (CR plus PR) juxtaposed with the age distribution of the cohort. Fifteen percent of the responders were s 39 years of age; 52% were 4-59 years of age; 33% were 2 6 years of age; and 4% were 2 7 years of age. These data deonstrate that age had no effect on disease response in these studies. The carboplatin dose intensities for individual patients in our cohort ranged fro less than 5 to 16 g/2/week (see Fig. lb), with a edian dose intensity of 139 g/2/week. To ascertain the relationship between dose intensity and clinical response in this COhort, patients were stratified by disease response and carboplatin dose intensity was assessed. Dose intensity of carboplatin in coplete responders was 138 f 18 g/2/week; in partial responders, 121 & 19; and in nonresponders, 134 f 3. This pattern of equivalent dose intensity for each response group was conserved within each of the three carboplatin trials, as shown in Table 2. When the cohort was grouped first by clinical response, and then subgrouped by age, there was a odest trend toward an increase in dose intensity with increasing age in patients who responded to therapy (Fig. 4A). There also was a odest trend toward a decrease in dose intensity with increasing age in patients who did not respond to therapy (Fig. 4B). The ean dose intensity for responders was: age I 39 years, I16 g/ 2/week; age 4-59 years, 125; age 2 6 years, 133; and age 2 7 years, 154. The ean dose intensity for nonresponders was: age I 39 years, 143 g/2/week; age 4-59 years, 13; age 2 6 years, 134; and age 2 7 years, 125. Table 3 lists the dose intensity by age for each response group. Coplete responders were seen only in patients 4-69 years of age, even though overall response rates did not differ significantly between age groups. There were no coplete responders in patients I 39 or in patients 2 7 years of age. Dose-liiting toxicity for these carboplatin studies was cuulative yelosuppression and has been reported previo~sly.'~~''*'* In the carboplatin/gm-csf trial, yelosuppression was anifested priarily as throbocytopenia. Within the cohort that received 1 pg/kg/day of GM-CSF, the platelet nadir lasted 8-1 days during cycle one; up to 14 days during cycle two; and in soe patients, ore than 14 days during cycle three. This pattern of cuulative throbocytopenia was seen in all three trials, and occurred in patients of all age groups (data not shown). Discussion In this analysis of 93 patients with advanced-stage refractory ovarian carcinoa, the adinistered dose intensity of high-dose carboplatin (target dose, 16 g/ 2/week) did not differ aong age groups. For all pa- Table 2. Dose Intensity by Treatent Group and Clinical Response Clinical response Treatent group Coplete Partial No HD-CBDCA k f f 27.3 CBDCA-DDTC No patients* f & 37.3 CBDCA-CSF f k f 23.6 Studies cobined f f f 3. HD-CBDCA: high-dose carboplatin; CBDCA-DDTC: high-dose carboplatin with diethyldithiocarbaate; CBDCA. CSF: high-dose carboplatin with granulocyte-acrophage colony-stiulating factor. No patients in this study experienced a coplete response to therapy.

5 654 CANCER Suppleent Ianuary 25, 2993, Volue 71, No. 2 X I i3 E. 2 g loo - d c w6 w7 c w6 >7 NonResponders Figure 4. Mean dose intensity adinistered to each age group is shown for responders (A) and nonresponders (B). Responders are further stratified by coplete responders and partial responders. Nonresponders include all individuals not eeting the definition of objective response to therapy (see Methods). Detailed data are presented in Table 3. tients, the eligibility criteria of good Karnofsky perforance status and good end organ function were prerequisite for study entry. When data are analyzed by patient stratification for treatent protocol, for disease response, or for the total aount of therapy adinistered, elderly patients (2 6 years of age) consistently tolerated the sae level of dose intensity as younger patients. Thus, advanced age is not a contraindication to the adinistration of dose-intensive platinu therapy in this disease. Although our data suggest that age should not alter the delivery of dose-intensive carboplatin therapy, these data do not address the question of coorbid disease. The incidence of coorbid disease does increase Table 3. Dose Intensity by Age and Clinical Response with age, but the presence of a coorbid disease directly effects cheotherapy tolerance in younger patients as well as in elderly individuals. Balducci et al. reported that elderly patients are at increased risk for heatopoietic, ucosal, cardiac, and neurologic coplications fro aggressive cheotherapy." Begg and Carbone observed that the toxic reactions of elderly patients on Eastern Cooperative Oncology Group studies were siilar to those of nonelderly patients.2 Walsh et al. have suated that chronologic age is a weak predictor for toxicity or therapy response.21 Walsh et al. argue that it is not the increased age but coorbid characteristics accopanying longevity that ay negatively influence toxicity or response.21 Because our studies were liited to individuals without substantial coorbid disease, we believe that our findings support the assessent of Walsh et al. Further, we believe that our data reflect the effect of age as an isolated variable, on the ability to deliver carboplatin in a dose-intensive fashion. The observation in these studies that overall dose intensity did not differ aong response groups ay be the result of the sall dose range investigated. These studies were designed to adinister to the patient the highest dose intensity tolerable, up to 16 g/2/ week. If a wider range of adinistered dose intensities had been generated, differences relative to clinical response ay have been seen. On an average, carboplatin doses of 125 g/2/week were tolerated by patients in these clinical trials regardless of age. We therefore believe that 5 g/2/28 days should be considered as the target carboplatin dose for patients not participating in controlled clinical trials. Dose intensity analyses of cisplatin in ovarian cancer have been in the literature for soe tie"; however, no such published data currently exist for carboplatin. Because cisplatin and carboplatin have siilar olecular structures and siilar biocheical activit^,',^,^ it sees reasonable to extrapolate that dose intensity ay be iportant for carboplatin. This has to be considered as speculative at this juncture, however, and we are hopeful that our data will contribute to the database for such future analyses. In conclusion, for patients with advanced-stage refractory ovarian carcinoa, good perforance status Clinical resuonse Age (yr) Coplete Partial No 5 39 No patients* f f f k f f L f No patients (1 patient) f 16.9 No patient.. in thi> apt' group expenenced a coplete response to therapy

6 Carboplatin Dose Intensity and Age/Cornelison and Reed 655 and good end organ function are the priary deterinants for delivering dose-intensive carboplatin therapy. We believe that age alone should not be a deterinant for dose odification of carboplatin. References I Reed E, Kohn KW. Cisplatin and platinu analogues. in: Chabner BA, Collins JM, editors. Cancer cheotherapy: principles and practice. Philadelphia: JB Lippincott, Litteat CL, Reed E. Platinu copounds. In: Kaiser HE, editor. Progressive stages of alignant neoplastic growth. London: Alden Press, 1989: Mangioni C, Bolis G, Pecorelli S, Bragan K, Epis A, Favalli C, et al. Randoized trial in advanced ovarian cancer coparing cisplatin and carboplatin. J Natl Cancer Inst 1989; 81: Muggia FM. Overview of carboplatin: replacing, copleenting, and extending the therapeutic horizons of cisplatin. Sein OnCol 1989; 16 SUPPI 5~7-13. Harrap KR. Platinu analogues: criteria for selection in cancer cheotherapy I. In: Muggia FM, editor. Cancer treatent and research series. Boston: Martinus Nijhoff, Harrap KR. Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Trent Rev 1985; 12 Suppl A: Rose WC, Schurig JE. Preclinical antituor and toxicolo@c profile of carboplatin. Cancer Treat Rev 1985; 12 Suppl A1-19. Wiltshaw E. Ovarian trials at the Royal Marsden. Cancer Treat Rev 1985; 12 Suppl A Reed E. Cisplatin. In: Pinedo HM, Chabner BA, Long DL, editors. Cancer cheotherapy and biological response odifiers. vol. 11. Asterda: Elsevier Science Publishers, 199:9-6. Levin L, Hyiuk WM. Dose intensity analysis of cheotherapy regiens in ovarian carcinoa. J Clin Oncol 1987; 5: Ozols RF, Ostchega Y, Myers CE, Young RC. Cisplatin in hypertonic saline in refractory ovarian cancer. J Cfin Oncol 1985; 3: Ozols RF, Ostchega Y, Curt C, Young RC. High-dose carboplatin in refractory ovarian cancer patients. J Clin Oncol 1987; 5: Yancik R, Ries LG, Yates JW. Ovarian cancer in the elderly: an analysis of surveillance, epideiology, and end results progra data. A J Obstet Gynecol 1986; 154: Monjanel S, Rigault JP, Can JP, Carcassonne Y, Favre R, Baratier F. High dose ethotrexate: preliinary evaluation of a pharacokinetic approach. Cancer Cheother Pharacol 1979; 3: Hansen HH, Selawry OS, Holland JF, McCall CB. The variability of individual tolerance to ethotrexate in cancer patients. Br ] Cancer 1971; 25: Hrushesky WJM, Ship W, Kennedy BJ. Lack of age-dependent cisplatin nephrotoxicity. A Med 1984; 76: Rothenberg ML, Ostchega Y, Steinberg SM, Young RC, Hue1 s, Ozols RF. High dose carboplatin with diethyldithiocarbaate cheoprotection in treatent of woen with relapsed ovarian cancer. J Natl Cancer Inst 1988; 8: Reed E, Janik J, Bookan M, Rothenberg M, Sith J 11, 21s RF, et al. High dose carboplatin (HD-C) with rcm-csf (GM) in refractory ovarian cancer [abstract]. Proc A Soc Clin Oncol 199; 9: Balducci L, Parker M, Sexton W, Tantranond P. Pharacology of antineoplastic agents in the elderly patient. Sein Oncoll989; 16: Begg CB, Carbone PP. Clinical trials and drug toxicity in the elderly: the experience of the eastern cooperative oncology group. Cancer 1983; 52: Walsh SJ, Begg CB, Carbone PP. Cancer cheotherapy in the elderly. Sein Oncol 1989; 16:66-75.