TACaxane/Platinum Regimens in Advanced NSCLC Raise Efficacy, Toxicity Questions

ASCO LOS ANGELES--Five studies presented at the American Societyof Clinical Oncology (ASCO) meeting raise questions as to whetherplatinum/taxane combinations are better in non-small-cell lungcancer (NSCLC) than standard platinum/etoposide (VePesid) regimens,and if so, which platinum and which taxane used in combinationare best with respect to efficacy, toxicity, and cost?

"In the 1990s and for ever more, no discussion of clinicaltrials results can be considered adequate without addressing cost,including consumption of supportive care medical resources,"Ron Natale, MD, of the University of Southern California NorrisCancer Center, said in his discussion of the five trials.

The studies all involved use of a platinum--either cisplatin (Platinol)or carboplatin (Paraplatin)--combined with 96-hour, 24-hour, or3-hour infusions of paclitaxel (Taxol), or with docetaxel (Taxotere).He noted that supportive care measures seemed to be profoundlydifferent with different taxane regimens.

Three-Hour Paclitaxel Favored?

"There appears to be a difference in the rate of severe granulocytopeniaand febrile neutropenia favoring the 3-hour Taxol regimens,"Dr. Natale said. Growth factor support is not required with 3-hourpaclitaxel infusion, he added. Furthermore, serotonin antagonistsfor nausea and vomiting, which are almost always required withcisplatin plus docetaxel or 24-hour paclitaxel, are rarely requiredwith carboplatin plus 3-hour paclitaxel.

All of the platinum/taxane regimens require steroid support, "butsteroids are cheap; hospitalization is not," Dr. Natale said.In his own study of carboplatin plus 3-hour paclitaxel, therewere only four hospitalizations for management of chemotherapy-relatedtoxicity out of 206 courses of outpatient therapy.

Dr. Natale noted that "no firm conclusions can be drawn fromthis type of comparison" and looked to three comparativetrials to help resolve the issues.

He cited ECOG trial E-5592, recently closed to accrual, whichcompares standard platinum/etoposide with cisplatin/paclitaxel(135 mg/m² given over 24 hours, or 250 mg/m² over 24hours with growth factor support). "It will be the firsthead-to-head comparison of what may be a new treatment regimenfor NSCLC," he said.

A multi-institutional phase III randomized trial of cisplatin/etoposidevs carboplatin/3-hour paclitaxel, developed by Dr. Natale andDr. Chandra Bellani of the University of Pittsburgh, and sponsoredby Bristol-Myers Squibb, has just been initiated. Endpoints willbe survival, toxicity, quality of life, and pharmaco-economics,he said.

A SWOG trial, still in the planning stage, will use the USC-Norrisregimen of carboplatin/3-hour paclitaxel vs cis-platin/vinorelbine(Navelbine).

Summary of the Trials

Fox Chase Cancer Center (24-hour paclitaxel/high-dose carboplatin).In this phase II study, Dr. Corey J. Langer and colleagues useda 24-hour paclitaxel infusion--135 mg/m² in the first cycle,escalated (with addition of growth factor) by 40 mg/m² percycle, to a maximum of 215 mg/m². Carboplatin was dosed toyield a targeted area under the curve (AUC) of 7.5. The regimenwas repeated at 3-week intervals for six cycles.

Paclitaxel was boosted to 215 mg/m² in 65% of patients, and,for phase III testing, the researchers recommend that dose, alongwith G-CSF (Neupogen), or 135 mg/m² without G-CSF, Dr. Langersaid. These doses are comparable to those used in the just completedECOG trial, which, he said, may answer questions of paclitaxeldose intensity.

Granulocytopenia was cycle specific, with grade 3 or 4 neutropeniaoccurring in 57% of patients during the first cycle, but decliningto 35% during cycle 2 when growth factor was added, and to 22%or less during cycles 3 to 6.

The response rate in 53 patients, 50 of whom had stage IV disease,was 62%: five complete responses and 28 partial responses, witha median duration of 6 months. Median survival was 12.5 months,and 1-year survival, 54%.

USC/Norris Cancer Center (3-hour paclitaxel/carboplatin).The researchers gave escalating doses of paclitaxel (in sequentialcohorts) by 3-hour outpatient infusion every 3 weeks, plus fixed-dosecarboplatin to reach an AUC of 6, for a maximum of six cyclesor four cycles plus radiation therapy.

Dr. D. Vafai reported that 75% of the patients received the fullpaclitaxel dose and 70% the full carboplatin dose in all cycles."Severe thrombocytopenia was unexpectedly rare," hesaid. Only one of 206 courses was associated with grade 3 thrombocyto-penia,and only one patient required hospitalization for treatment offebrile neutropenia.

Nonhematologic dose-limiting toxi-cities included grade 3 arthralgia,myalgia and cumulative sensory neuropathy.

Of 44 patients with measurable disease, 27 (61%) responded, witha slight trend toward higher response rates with increasing paclitaxeldose levels. Median survival of 51 patients is 10 months, againwith a trend toward better survival with higher dose, Dr. Vafaisaid.

The researchers concluded that the maximum tolerated dose of paclitaxelgiven as a 3-hour infusion in this combination is 225 mg/m²,which they were able to give without growth factors.

NCI-Navy Medical Oncology Branch (96-hour paclitaxel/cisplatin)--Inthis phase I study, presented by Dr. M.S. Georgiadis, the researcherschose to deliver paclitaxel as a 4-day continuous infusion. "Wewanted to determine if longer exposure increases not only myelosuppressionbut also cytotoxicity to cancer tumor cells," he said.

The study achieved a response rate of more than 50% in 34 patients(28 with stage III or IV NSCLC and six with extensive-stage SCLC).For phase II studies without growth factors, the researchers recommenda paclitaxel dose of 120 mg/m² given over 4 days, plus cisplatinat 80 mg/m². "Toxicity is mainly hematologic, but neuropathyemerges late during therapy," Dr. Georgiadis said. Furtherdose escalation will continue with addition of growth factors,he added.

Australia (docetaxel/cisplatin)--Preliminary analysis ofthe response rate and toxicity of the first phase II trial ofcis-platin/docetaxel in advanced NSCLC suggests that the scheduleused "would be difficult to take to phase III evaluation,"said Dr. J.R. Zalcberg, of the Heidelberg Repatriation Hospital,Melbourne.

Docetaxel, 75 mg/m², was given over 1 hour, followed immediatelyby cisplatin, 75 mg/m². Growth factor was not used.

The response rate (32%) was similar to that seen with docetaxelalone, but the combination was relatively toxic, even in goodperformance status patients, Dr. Zalcberg said. More than 70%of the 47 patients had grade 4 neutropenia, and more than 80%had grade 3 or 4 neutropenia. Approximately half of these patienthad febrile neutropenia, and there were two deaths from infection.Almost 45% had grade 3 or 4 GI toxicity.

Ochsner Cancer Institute (docetaxel/cisplatin). John T.Cole, MD, reported a 50% response rate and a median survival of11 months in 25 patients treated with docetaxel, ranging from75 to 85 mg/m², and cisplatin, 75 to 100 mg/m².

"The goal was to escalate both these agents to a dose of100 mg/m²," Dr. Cole said, but the maximum tolerateddose of docetaxel in this combination was reached at 85 mg/m²,and the schedule recommended for further study is docetaxel, 75mg/m², with cisplatin, 75 to 100 mg/m².

Docetaxel was given over 1 hour once every 3 weeks and cisplatinover 30 minutes together with mannitol on days 1 and 22 and thenevery 6 weeks, "a different schedule than that presentedby Dr. Zalcberg," Dr. Cole said.

As expected, neutropenia was the primary toxicity. At dose level3 (docetaxel, 85 mg/m², and cisplatin, 100 mg/m²), 83%of patients experienced grade 4 neutropenia. Dr. Cole suggestedthat this might be amenable to prophylactic antibiotics and growthfactors. Edema and pleural effusions were rare with dexa-methasoneprophylaxis, even in patients who completed 1 year of treatment.