Novel High-dose Chemotherapy Regimens for the Treatment of Advanced Cancer: Part I
Special Feature
Novel High-dose Chemotherapy Regimens for the Treatment of Advanced Cancer: Part I
By Daniel M. Sullivan, MD, and James S. Partyka, PharmD
Since hryniuk and colleagues published their retrospective analyses both in metastatic breast cancer and in the adjuvant breast cancer setting,1,2 the application of dose intensive cytotoxic regimens in the autologous setting remains an area of great scientific interest. Maximizing the dose intensity of chemotherapy, defined as the amount of chemotherapy delivered per unit time, has become an area of investigation for the treatment of various malignant disorders. There are several common approaches to optimizing dose intensity in treating the cancer patient, and these include: supportive care measures (e.g., antiemetic administration), target drug delivery systems (e.g., regional perfusion of chemotherapy), growth factors to overcome chemotherapy-induced myelosuppression (e.g., G-CSF, GM-CSF), and high-dose chemotherapy followed by stem cell rescue.
Blood and marrow transplantation (BMT) utilizing hematopoietic stem cell support has allowed further dose escalation of cytotoxic agents that exhibit myelosuppression as their dose-limiting toxicity. The ultimate goal of maximizing dose intensity in the cancer patient is to prolong disease-free survival. Table 1 lists the common indications for high-dose therapy followed by stem cell rescue. Over the past decade, recent advances in technology and improved supportive care measures have resulted in a dramatic reduction in treatment-related mortality; a mortality rate of 3-5% is now the standard of care for autologous stem cell transplantation. However, there are still numerous scientific questions that remain unanswered regarding the role of BMT in the treatment of various malignancies. What are the optimal doses, combinations, and sequencing of agents to be utilized in the high-dose setting? Which patients benefit the most from BMT as compared to standard therapy? Is their quality of life improved? Is BMT a cost-effective strategy in the treatment of cancer?
Currently, several large, randomized, controlled clinical trials (RCTs) are ongoing to study the role of high-dose chemotherapy in comparison to standard-dose chemotherapy. One area of controversy is in defining the role of high-dose therapy in the treatment of metastatic and high-risk adjuvant breast cancer. Phase II trials in this patient population have demonstrated prolonged disease-free survival following high-dose chemotherapy as compared to historical controls. These clinical trials are difficult to interpret because of potential selection bias (i.e., patients selected for BMT may have had an overall better prognosis as compared to those patients receiving standard dose therapy). Recently, several RCTs in breast cancer patients comparing high-dose therapy to standard therapy have been published with conflicting results.3-7 Several of these studies have been difficult to interpret due to small sample sizes, short patient follow-up, and imbalances of risk factors between treatment arms. The question of whether or not high-dose therapy has a role in breast cancer still remains unanswered.
Table 1- Common indications for high-dose therapy with stem cell rescue |
Type of BMT / Malignancy |
Autologous |
• Acute and chronic myelogenous leukemia |
• Acute lymphocytic leukemia |
• Hodgkin’s disease |
• Non-Hodgkin’s lymphoma |
• Multiple myeloma |
• Breast cancer |
• Ewing’s sarcoma |
• Small cell lung cancer |
• Ovarian cancer |
• Testicular cancer |
Allogeneic/Syngeneic |
• Acute and chronic myelogenous leukemia |
• Acute and chronic lymphocytic leukemia |
• Aplastic anemia |
• Hodgkin’s disease |
• Non-Hodgkin’s lymphoma |
• Myeloproliferative disorders |
• Myelodysplastic syndrome |
• Multiple myeloma |
Developing Novel High-Dose Chemotherapy Regimens Utilizing Topoisomerase Inhibitors
A dynamic area of scientific interest is in the development of novel high-dose regimens to treat both solid tumors (e.g., breast cancer, ovarian cancer, germ cell tumors), as well as hematologic malignancies. One of our areas of research includes the selection, sequencing, and dosing of chemotherapeutic agents to be used in the high-dose setting. Chemotherapeutic agents that appear to be ideal in the setting of high-dose therapy have the following properties: 1) dose-limiting toxicity of myelosuppression; 2) steep dose response; 3) minimal non-overlapping toxicities; and 4) additive to synergistic activity. Typically, alkylating agents (e.g., cyclophosphamide, melphalan, and busulfan) have been the cornerstones of several high-dose preparative regimens, since they typically can be escalated 4-10 times higher than their standard doses and may exhibit additive to synergistic activity when used in combination with other agents.
At our institution, the H. Lee Moffitt Cancer Center in Tampa, we have been actively investigating the role of high-dose topotecan followed by stem cell rescue. (See Table 2.) Several in vitro models suggest that the timing of administration of the combination of topoisomerase (topo) I and II inhibitors are critical in determining the optimal cytotoxic effect of these drugs. Topotecan’s unique mechanism of action, the S-phase specific inhibition of DNA topoisomerase I, makes it an ideal agent to be combined with etoposide (a DNA topoisomerase II inhibitor) and ifosfamide (an oxazaphosphorine ring alkylating agent). Our trials have focused on the determination of the appropriate dosing and sequencing of this combination of agents and determining the role alterations of topoisomerases may have in the drug resistance of human malignancies. As with any antineoplastic agent, cells may have either an intrinsic or acquired resistance to the toxic effect of the drug. Drug resistance to topotecan (and other camptothecin analogs) has been studied solely in in vitro models and found to involve either the down-regulation of cellular topoisomerase I content or point mutations which result in an inactive enzyme. In vitro and in vivo data suggest that the optimal sequencing and timing of administration of these classes of antitumor agents is as follows: a DNA-damaging agent, followed by a topoisomerase I inhibitor followed by a topoisomerase II inhibitor.
Table 2-High-dose preparative regimens under investigation at the H. Lee Moffitt Cancer Center | ||||
Protocol | Regimen (total dose) | Sequencing | ||
A phase I/II study of intensive-dose topotecan, ifosfamide/mesna and etoposide (TIME) followed by autologous stem cell rescue in refractory metastatic breast cancer, refractory lymphoma, and other refractory malignancies. | TIME1 | Ifosfamide | ||
Tropotecan | 10 to 64+ mg/m2 | Topotecan | ||
Ifosofamide/Mesna | 10 g/m2 | Etoposide | ||
Eoptoside | 1500 mg/m2 | |||
A study of intensive-dose melphalan, topotecan and VP-16 phosphate (MTV) followed by autologous stem cell rescue in patients with multiple myeloma. | MTV1 | Melphalan | ||
Melphalan | 150 mg/m2 | Topotecan | ||
Topotecan | 10 to 27+ mg/m2 | Etoposide | ||
VP-16 phosphate* | 2400 mg/m2 | |||
A phase I/II study of intensive-dose etoposide, topotecan, and carboplatin (ETC) followed by autologous stem cell rescue in chemosensitive ovarian cancer patients with either minimal residual disease or at first relapse. | ETC1 | Carboplatin | ||
Etoposide | 2400 mg/m2 | Topotecan | ||
Topotecan | 30+ mg/m2 | Etoposide | ||
Carboplatin | 1200 mg/m2 | |||
* Etoposide equivalent dose provided by Bristol-Myers Squibb 1 Supported in part by a grant from SmithKline Beecham Pharmaceuticals |
In Vitro Sequencing of DNA-Damaging Agents, Topo I and Topo II Inhibitors
Several human cell lines, xenografts, and short-term human tumor cultures have been exposed to combinations of DNA-damaging agents and topo inhibitors to determine the optimal timing and sequencing of these agents. The combination of a DNA-damaging agent (cis-platinum [CDDP], melphalan, 4-HC, BCNU, Ara-C, or ionizing radiation) with a topo I inhibitor (CPT, CPT-11, SN-38 [the active metabolite of CPT-11], TPT, or 9-amino-CPT) has generally resulted in synergistic in vitro cytotoxicity when the drugs are given either simultaneously or in the order of DNA-damaging agent ® topo I inhibitor.8-22 The reverse order of CPT-11 ® CDDP demonstrated no enhanced xenograft cytotoxicity,23 while the simultaneous exposure of human tumor cell lines to CDDP and a topo II poison (VP-16) resulted in minimal synergistic activity,15 additive cytotoxicity,14 and antagonistic cell kill.11 Several studies suggest that the molecular basis for the observed synergism results from the involvement of topo I in the repair of CDDP-induced DNA damage,12,16 or radiation-induced DNA damage.18,19,24 Therefore, the inhibition of this repair by a topo I inhibitor would potentiate cell kill by the DNA-damaging drug. The observation that augmenting topo IIa levels by transfection in EMT6 mouse cells results in resistance to CDDP and melphalan indirectly suggests that topo II may also have a role in DNA damage repair.25 The role of DNA topoisomerases in DNA repair and DNA damage tolerance has recently been reviewed.26
Combinations of topo I inhibitors and topo II inhibitors have also been studied in vitro.9,20,21,23,27-32 Antagonistic cytotoxic effects have been demonstrated by many studies in which topo I and II inhibitors were either given simultaneously or in the order topo II inhibitor ® topo I inhibitor. Recently, however, three studies have shown synergistic cytotoxic effects when topo I inhibitors (CPT, CPT-11, TPT) were given simultaneously with topo II inhibitors (VP-16, doxorubicin).20,21,32 The sequential treatment with a topo I inhibitor followed by a topo II inhibitor has resulted in synergistic cell kill in several cell lines and xenografts. This may be due to an up-regulation of cellular topo IIa in response to topo I inhibitor exposure.23,31
In Vivo Sequencing of DNA-Damaging Agents, Topo I and Topo II Inhibitors
Several recent Phase I and II clinical studies have combined DNA-damaging agents with topo inhibitors in specific sequences, including CDDP ® TPT,33-37 CDDP ® CPT-11,38-40 CPT-11 ® CDDP,41,42 cyclophosphamide ® TPT,43,44 VP-16 ® CPT-11,45-49 CPT ® VP-16,50 CPT-11 ® VP-16,48 CPT-11 ® RT,51 TPT ® VP-16,52-58 and Ara-C ® TPT.8 It is difficult to determine if these protocols actually maximized tumor cell kill (or optimized toxicity of normal tissue), since patients were rarely randomized to the opposite sequence of drug administration. In one study, the same patient alternated both drug sequences (CDDP ® TPT and TPT ® CDDP), and significantly worse hematologic toxicity was seen when the topo I inhibitor was given second.34 A second study randomized patients to both sequences of CPT-11 and VP-16 and concluded that the toxicities were equivalent in both arms.48 In general, protocols which sequenced agents as DNA-damaging drug ® topo I inhibitor, or as topo I inhibitor ® topo II inhibitor reported more toxicity and higher response rates, suggesting synergistic activity. Neither the fractionated administration (every week or 2 weeks) of CDDP ® CPT-1139,40 nor the continuous infusion of TPT for 14 d after CDDP36 appear to offer any advantage.
Another approach to determine if a specific drug treatment sequence is optimal is to correlate drug levels with topo levels, as well as toxicity and response with both drug levels and topo I and II levels/activity. Very few investigators have examined patient samples for changes in topoisomerase levels. DNA topo I protein levels in peripheral blood lymphocytes (PBL) were found to increase by greater than 50% in five of 13 patients after a 30-minute cyclophosphamide infusion, and decrease significantly in 18 of 33 chemotherapy cycles during days 3-5 of a TPT infusion.43 A progressive decrease in patient PBL "free" topo I (non DNA-complexed) content has also been reported during a 21-day continuous infusion of TPT.59 A CPT-induced decrease in topo I has also been seen in cell lines.60,61 In a phase I dose-escalation study of continuous infusion TPT (d1-3) ® bolus VP-16 (d7-9), the investigators obtained serial biopsies from six patients and four patients for topo I and II protein analyses, respectively.57 Topo I levels decreased by 10-68% in three of six patients at the end of the 72-hour TPT infusion and returned to normal or increased in all six patients just prior to VP-16 administration. In a Phase I study of 33 patients given CPT (po for 14 d) followed by VP-16 (IV on d 20), steady-state plasma levels of CPT and peripheral blood mononuclear cell (PBMN) protein levels of topo I and IIa (in 11 patients) were measured.50 Although the investigators found a 30-fold variation in steady-state drug levels, there was a correlation between CPT levels and the decrease in topo I protein levels in PBMN (P = 0.035). The variation in topo IIa protein expression was high, with topo IIa levels actually decreased on the day of VP-16 administration (d 20). Finally, in a Phase I study of TPT (5 d CI) ® VP-16 (IV d 6-8) in adult leukemia, topo IIa protein levels were found to increase 1.5- to 3.0-fold in peripheral blasts during days 2-4 of TPT infusion, and to be unchanged or decreased on day 5 in eight of 9 patient bone marrow blasts.58 This study suggests that VP-16 should be given after three days of TPT, when topo IIa levels are maximal.
In summary, the in vitro and in vivo data suggest that the optimal sequencing and timing of administration of the classes of antitumor agents discussed above is DNA-damaging agent ® topo I inhibitor ® topo II inhibitor. The major shortcoming of the clinical trials has been a lack of correlative laboratory studies to determine if the sequencing and timing of the three classes of agents are optimal. Only by assessing topo I and IIa levels, activity, and subcellular distribution in sequential tumor biopsies, and correlating these with toxicity, response, and serum drug levels of TPT and VP-16 in sufficient numbers of patients, will we be able to determine if there is a scientific justification for this specific sequence of administration of antitumor agents. (Dr. Sullivan is Associate Professor of Medicine and Biochemistry & Molecular Biology, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Division of Blood and Marrow Transplantation; and Dr. Partyka is Assistant Professor of Medicine, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Division of Blood and Marrow Transplantation.)
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