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Prince et al. 325
excessive to be used in such a setting. To this end, we modified the protocol by substituting
ifosfamide with cyclophosphamide (4 g/m 2
/cycle). In this cohort, tolerable
grade 3 mucositis in two patients was the only major toxicity observed.
Thiotepa toxicity. Standard doses of thiotepa are 10-30 mg/m 2
but can be
escalated beyond 170 mg/m 2
when supported by autologous stem cells. 38,39
The
MTD is 900-1,125 mg/m 2
when administered alone, and doses of 350-550 mg/m 2
have been used as part of combination high-dose chemotherapy regimens, although
the MTD in these latter regimens has not been formally determined. Toxicities
include stomatitis, enterocolitis (at doses >720 mg/m 2
), dermatitis, hepatotoxicity,
interstitial pneumonitis, with severe neurotoxicity being the major dose-limiting
toxicity. The latter toxicity is manifested by inappropriate behavior, forgetfulness,
confusion, and somnolence at an incidence >15% when doses exceed 900
mg/m 2
. 38,40
The above dose-finding studies were performed after single doses of
thiotepa; however, limited information is known about the cumulative toxic effects
of repetitive administration of high-dose thiotepa, i.e., cumulative doses >900
mg/m 2
. Thus in our phase I study, we planned for careful dose-escalation of
thiotepa. Indeed, there was an additional concern that the neurotoxicity would be
increased because of the combination with ifosfamide.
The major thiotepa-related toxicities observed in our phase I study were
mucositis, interstitial pneumonitis, and skin rash. Importantly, although the
maximum cumulative dose of thiotepa in this study was 1050 mg/m 2
, the typical
neurologic toxicity of a dementia-like syndrome was not observed. However,
formal neuropsychiatric testing was not performed, and subtle defects may not
have been detected. Reversible grade 2 interstitial pneumonitis and skin rash were
also observed and probably related to thiotepa. 40
Paclitaxel toxicity. We selected paclitaxel in combination with the two
alkylating agents because we anticipated that a number of patients in this
prospective study would previously had received considerable prior anthracycline
therapy or would have recently failed an anthracycline, and paclitaxel had little
known additive toxicity with the selected alkylating agents. Other investigators
have escalated the dose of paclitaxel in their high-dose regimens, 41
^ with the
maximum dose of paclitaxel delivered being 550 mg/m 2
when combined with
carboplatin. 42
We elected not to escalate the dose of paclitaxel beyond the conventional-dose
range, as it allowed us to focus on the dose-escalation of the alkylating
agents. Indeed, there is little evidence that there is a meaningful dose-response
relationship for paclitaxel above the dose of 175 mg/m 2
. 45
In our phase I study, only
grade 2 paclitaxel-associated peripheral neuropathy was observed. Not
surprisingly, as the doses of paclitaxel were not above those in the conventionaldose
range, no unexpected toxicity was observed.