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© 2003 American Society for Clinical Oncology Role of Docetaxel in the Treatment of Newly Diagnosed Advanced Ovarian CancerFrom the Cancer Research UK West of Scotland Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary, Glasgow, Scotland, United Kingdom. Address reprint requests to Paul A. Vasey, Cancer Research UK West of Scotland Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary, Glasgow, Scotland, United Kingdom; email: p.vasey{at}beatson.gla.ac.uk.
Docetaxel is currently licensed for use in a variety of malignancies, including breast cancer and lung cancer, and is the preferred taxane in breast cancer treatment. In ovarian cancer, the taxane of choice has historically been paclitaxel; however, there is now substantial evidence that docetaxel also may be the preferred taxane in this disease. Docetaxel has many preclinical advantages over paclitaxel and has been shown to be effective in both platinum- and paclitaxel-resistant disease. Phase I and II studies have shown docetaxel plus carboplatin to be feasible, and the combination is associated with a tolerable adverse-effect profile. The Scottish Randomized Trial in Ovarian Cancer (SCOTROC) trial randomly assigned 1,077 patients with International Federation of Gynecology and Obstetrics stage Ic to IV disease to six cycles of docetaxel plus carboplatin (DC) or paclitaxel plus carboplatin (PC) as primary chemotherapy. Progression-free survival is not statistically different, and to date, no differences are apparent in overall survival. Toxicity differences were evident. There was more myelosuppression with DC but no additional mortality. More neuropathy was present with PC, with more patients stopping paclitaxel because of this toxicity during chemotherapy. Quality-of-life analyses highlighted important differences, all favoring the DC treatment arm. Additional SCOTROC studies using docetaxel are ongoing. These data indicate that docetaxel and carboplatin represent a reasonable first-line option for patients with newly diagnosed epithelial ovarian cancer.
ALTHOUGH OVARIAN cancer remains the most lethal of the gynecologic malignancies, progress is evident, with an improvement in survival rates during the last 30 years. In the 1960s, the 5-year survival rate was 30%, whereas the most recent figures for the United States indicate that more than half of all patients now survive 5 years.1 Despite this, most patients with advanced disease experience relapse after achieving complete clinical response, and in most of these patients, the disease is incurable.2 Randomized trials have established paclitaxel (Taxol, Bristol-Myers Squibb, New York, NY) in combination with platinum as the standard initial chemotherapy.3–6 However, there are emerging data indicating that docetaxel (Taxotere, Aventis Oncology, Bridgewater, NJ) should be considered as a standard of care.
Docetaxel was obtained by semisynthesis from a noncytotoxic precursor,7 the needles of the European yew tree (Taxus baccata). Like paclitaxel, docetaxel is a mitotic spindle poison, simultaneously promoting microtubule assembly and stabilization in addition to the inhibition of tubulin disassembly, thereby arresting the replication of rapidly dividing cells.8 However, docetaxel has demonstrated more pronounced effects on tubule binding sites and proteins and has several potential pharmacologic and mechanistic advantages compared with paclitaxel (Table 1  ).
Preclinical data for docetaxel have previously been comprehensively reviewed by Bissery et al.9 Docetaxel has a greater affinity for tubulin and is more potent (up to five-fold) in vitro than paclitaxel with regard to tubulin polymerization and inhibition of depolymerization. In established tumor cells, the antitumor activity of docetaxel was greater than that of other recognized agents, including cisplatin, cyclophosphamide, doxorubicin, and etoposide. In a direct comparison with paclitaxel in a large number of freshly explanted tumors (including breast, ovarian, lung, and colorectal tumors), docetaxel was found to have at least equivalent cytotoxicity and incomplete cross-resistance. Docetaxel also had a longer residence time, accumulated at higher concentrations within cells, and demonstrated a superior therapeutic index.
Phase 1 studies in the early 1990s were aimed at deriving the optimal dose and schedule for subsequent clinical development, but because paclitaxel had demonstrated activity against breast and ovarian cancer, half of the patients recruited into these early studies had one of these tumor types. Seven studies were performed using intravenous doses of 5 to 130 mg/m2 and infusion schedules of 1 to 24 hours.10–16 The dose-limiting toxicity in all trials was neutropenia, and the established maximum-tolerated dose was 115 mg/m2. Docetaxel demonstrated linear pharmacokinetics between 20 and 115 mg/m2.16 The recommended dose for further development was 100 mg/m2 administered for 1 hour every 3 weeks. These early studies also confirmed that incomplete cross-resistance with paclitaxel was present with activity for docetaxel in paclitaxel-resistant metastatic breast cancer.17
During the 1990s, four trials of docetaxel 100 mg/m2 were performed in platinum-pretreated, taxane-naive patients (Table 2 ). In the United States, these consisted of two single-institution studies,18,19 whereas two multicenter trials were performed in Europe.20,21 In the first study, from Memorial-Sloan Kettering hospital (New York, NY), a response rate of 35% in 23 assessable platinum-resistant patients was observed, with a response duration of 3 to 9 months. Only 5 of 25 patients received prophylactic corticosteroids, and the incidence of clinically important fluid retention was 12%. In contrast, in the study from the M.D. Anderson Cancer Center (Houston, TX),19 59 platinum-resistant patients were all premedicated with dexamethasone in addition to diphenhydramine, and grade 3 to 4 fluid retention was observed in only 5% of patients. A response rate of 40% was reported, with three complete responses and 19 partial responses. In both of these studies, hematologic toxicity was high (grade 3 to 4 neutropenia in 95% of patients), in contrast with low levels of neurosensory toxicity.
In Europe, two European Organization for Research on the Treatment of Cancer (EORTC) trials consisted of patients with mixed potential platinum sensitivity.20,21 Response rates of 24% to 26% among 196 assessable patients were reported. A meta-analysis of patients from all four trials was performed by Kaye et al22 and revealed an overall response rate of 30% (95% confidence interval, 24% to 36%), which did not appear to be dependent on the platinum-free interval. Patients with a platinum-free interval of fewer than 4 months had a response rate of 28%, compared with 31% for those patients with a platinum-free interval of more than 4 months. Overall, the most commonly reported clinically important toxicity in these trials was myelosuppression. Also noteworthy were the incidences of hypersensitivity, diarrhea, and fluid retention; however, although the incidence of this last toxicity was generally high, it subsequently was found to be considerably lessened if premedication with corticosteroids was used. In all studies, significant neurotoxicity rarely was reported. In the study by Francis et al,18 11 patients not responding to docetaxel subsequently were treated with paclitaxel without any evidence of clinical benefit. However, there are clinical data that indicate that patients resistant to paclitaxel may respond to treatment with docetaxel. Vershraegen et al23 assessed the activity of docetaxel in 32 patients with strictly defined paclitaxel-resistant ovarian cancer. In their study, a response rate of 23% was reported, confirming the preclinical data of non–cross-resistance between the two taxanes. In addition, the Gynecologic Oncology Group has collated a database of patients with similarly defined resistance to paclitaxel and has also observed that approximately one fourth of such patients can have an objective response to docetaxel treatment (Rose, personal communication). In Japan, docetaxel was given at a dose of 70 mg/m2 to patients previously treated with platinum.24 In phase I studies, doses of 70 to 90 mg/m2 every 3 weeks as 1-hour infusions were described as the maximum-tolerated doses, without corticosteroid premedication. Phase II studies in platinum-resistant patients not only showed a low rate of significant fluid retention (1 of 60 patients)25,26 and satisfactory tolerability but also indicated that antitumor activity was maintained despite the dose reduction (overall response rate, 24% to 28%).
In 1994, the Scottish Gynaecological Cancer Trials Group (SGCTG) performed a feasibility study of cisplatin plus docetaxel in 100 chemotherapy-naive patients with stage Ic to IV ovarian cancer.27 Cisplatin plus docetaxel was given 3 weekly for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg twice daily). Patients were initially treated with 75 mg/m2 of both agents, and after a preliminary toxicity analysis, the dose of docetaxel was increased to 85 mg/m2. An additional planned interim toxicity analysis demonstrated problems at the higher dose. There were five treatment-related deaths in this higher-dose cohort, of which three were the result of sepsis associated with neutropenia and two were the result of gastrointestinal hemorrhage thought to be secondary to the prolonged course of dexamethasone. Because of this, the remaining patients were treated with 75 mg/m2, and those already undergoing treatment continued at their current dose, but with prophylactic antibiotics. Overall, 16 patients stopped treatment early because of toxic effects: six for neurotoxicity, three for nephrotoxicity, two for neutropenia, and one each for hypersensitivity, diarrhea and vomiting, dermatologic toxicity, clinical deterioration, and patient’s wishes. This resulted in only 66 of 100 patients being able to complete six full cycles of protocol therapy. Furthermore, grade 3 to 4 neutropenia was seen in more than 75% of patients. In addition, patients receiving the higher dose of docetaxel had more severe neutropenia and more lethargy. However, despite the use of 75 mg/m2 of cisplatin, National Cancer Institute common toxicity criteria (NCI-CTC) neurotoxicity at higher than grade 1 occurred in only 23 patients. Despite an overall response rate of 69% (complete response, 38%; partial response, 31%; CA-125 response, 73%), the problems of completing planned therapy affected patient survival. Median progression-free survival for the group as a whole was 12 months, which is unacceptably low for chemotherapy-naive ovarian cancer patients. The conclusion of this study was that although cisplatin and docetaxel can each be administered at doses of 75 mg/m2 every 3 weeks and their utility is not limited by fluid retention (the main study end point), the additional toxic effects caused primarily by cisplatin were not likely to be acceptable. Docetaxel 85 mg/m2 in combination with cisplatin certainly seemed to add significantly more hematologic toxicity for the patient and increased the risk of premature death.
The SGCTG performed an additional dose-finding study of carboplatin plus docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics stage Ic to IV epithelial ovarian cancer.28 Again, this regimen was given once every 3 weeks for six planned cycles, but with a shorter 3-day prophylactic dexamethasone regimen (8 mg twice daily starting the day before treatment). One hundred thirty-nine eligible patients were treated at five dose levels of docetaxel and carboplatin ranging from 60 to 85 mg/m2 and area under the concentration-time curve (AUC) 5 to 7. This combination was much better tolerated. One hundred ten patients (79%) completed six cycles; 17 (12%) discontinued the protocol because of adverse effects. Again, hematologic toxic effects were predominant, with 104 patients (75%) experiencing NCI-CTC grade 4 neutropenia. Only five patients (4%) had grade 4 neutropenia plus fever. There were two treatment-related deaths. Significant nonhematologic toxic effects were uncommon, and overall the combination was well tolerated. No patients experienced grade 4 nausea or vomiting, and only 6% (nausea) and 4% (vomiting) of patients experienced grade 3 toxicity. Severe diarrhea was observed in only four patients. The incidence of significant neurotoxicity was especially low and was reported in 36 patients (26%) during the study. This was defined in 28 patients (20%) as grade 1, in only seven patients as grade 2 (4.6%), and in only one patient as grade 3 (0.7%). No patients stopped therapy because of neurotoxic effects, and no neuromotor toxicity was reported at greater than grade 1. Hypersensitivity reactions to docetaxel were observed in 11 patients (8%), and four reactions (3%) were severe; a severe reaction occurred in one patient during the first or second cycle. Five patients were withdrawn from protocol therapy and continued treatment with single-agent carboplatin. All other patients were re-treated, with slight schedule modification and additional dexamethasone premedication. Fluid retention was not a significant clinical problem. Increased weight gain or mild peripheral edema that did not require diuretic therapy was reported for 15 patients (11%). The dose-limiting toxicities for higher-dose cohorts were myelosuppression and diarrhea. The overall response rate was 66%; 75% of patients had a CA-125 response. Only 6% progressed with chemotherapy and stopped treatment before the planned six cycles. Progression-free survival for the group as a whole was 16.6 months. In the United States, a single-dose cohort study of 50 patients was performed using carboplatin AUC 6 plus docetaxel 60 mg/m2.29 Most patients were chemotherapy naive, although three were previously treated (but had a treatment-free interval of 3 to 10.5 years). Routine premedication consisted of a 5-day dexamethasone regimen. In this study, grade 4 neutropenia was noted in 64% patients, of whom 16% developed associated fevers. Other nonhematologic toxic effects included hypersensitivity reactions in 34% of patients, although all were successfully rechallenged and no patient withdrew from treatment because of this effect. Neuropathy was again uncommon and occurred in only three of 50 patients, and the drug combination was generally well tolerated. Objective responses occurred in 34 (81%) of 42 assessable patients, and a progression-free survival of more than 16 months was projected. Other studies have added to the clinical experience with this doublet by demonstrating high levels of efficacy (89% response rate)30 and also documenting the absence of significant pharmacokinetic interactions between the two drugs.31
The Scottish Randomized Trial in Ovarian Cancer compared paclitaxel 175 mg/m2 administered for 3 hours or docetaxel 75 mg/m2 administered for 1 hour in combination with carboplatin (dosed to AUC 5 with glomerular filtration rate for dose calculation performed by the chromium-51 EDTA isotopic method), given for six cycles every 21 days (Fig 1 ). The primary end point was progression-free survival, and the study had an 80% power to detect superiority in either arm of 25% or to detect equivalence within the same limit. In 17 months, 1,077 patients from 12 countries and 83 cancer centers were entered onto the trial. Different but standardized premedications were used before treatment: the standard intravenous triple cocktail of antihistamines and corticosteroids for paclitaxel and the now standard 3-day oral dexamethasone regimen for docetaxel. It was planned that patients would receive a total of six treatment cycles.
First results that focused primarily on toxicity were presented in 2001,32 and early survival data were presented in 2002.33 Patients were well balanced for known prognostic factors. Median age was 59 years, and most patients had an Eastern Cooperative Oncology Group performance status of 0 to 1 (87%), had advanced-stage disease (80%), and were considered to have undergone optimal cytoreduction (63%). The main differences in toxicity between the two regimens related to neurotoxicity and myelosuppression (Table 3 ), with more neurotoxicity seen in the paclitaxel plus carboplatin combination and more myelosuppression seen in the docetaxel plus carboplatin combination (P < .001). There was a marked difference in the incidence of clinically important (NCI-CTC grade ≥ 2) neurotoxicity, with the results strongly in favor of docetaxel plus carboplatin (11% v 30%; P < .001; Table 4). This was confirmed by two other methods of assessing neurotoxicity: a published neurotoxicity scoring system,34 and individual patient answers to an EORTC quality-of-life questionnaire (QLQ-OV28) developed during the trial.35 All three methods of neurotoxicity assessments confirmed a statistically significant advantage for the docetaxel plus carboplatin combination, and in addition, more patients (32 v four patients) discontinued protocol therapy prematurely because of neurotoxicity.
Myelogenous toxicity was greater for docetaxel plus carboplatin, with a 94% incidence of grade 3 to 4 neutropenia versus 82% (P < .001) for paclitaxel plus carboplatin. All patients had weekly complete blood cell counts measured during treatment, which probably explains the higher-than-expected level of neutropenia for the paclitaxel plus carboplatin combination. There was also more febrile neutropenia and prolonged neutropenia for docetaxel, but importantly, there were no excess toxic deaths (two patients v one patient), and in general, neutropenia was managed safely in the community setting. In addition, there was no difference in median dose-intensity between paclitaxel plus carboplatin and docetaxel plus carboplatin (98% v 98%, respectively), and treatment delivery (percentage of patients completing six cycles, 79% v 84%, respectively) was similar. There were differences in other nonhematologic toxic effects, such as more arthralgia, myalgia, and alopecia for paclitaxel plus carboplatin compared with more diarrhea, hypersensitivity, and edema for docetaxel plus carboplatin, but the overall incidence of grade 3 or 4 toxic effects was less than 8% for both arms. For the preliminary survival presentation in 2002, the median follow-up was 23 months, with a maximum survival of 26 months. There were no differences in progression-free survival between paclitaxel- or docetaxel-based chemotherapy (15.4 v 15.1 months), and overall survival at 2 years was estimated at 69.8% and 65.4%, respectively. It was noted, however, that there were not enough events in the overall survival analysis to promote confidence about these curves, and the data required another 12 months to mature. Longer-term data for neurotoxicity using both NCI-CTC grading and a standardized neurotoxicity scoring system demonstrated that paclitaxel plus carboplatin continued to be significantly more neurotoxic after completion of chemotherapy, at least to 14 months after randomization. Furthermore, quality-of-life scales using the validated EORTC questionnaire QLQ-OV2835 confirmed these differences in neurotoxicity from the patients’ perspective, with statistically significant differences being apparent up to 22 months from randomization. Other positive benefits in quality-of-life scales were demonstrated for aches and pains, weakness, hair loss, body image, insomnia, gastrointestinal symptoms, and general pain. All of these differences favored the docetaxel plus carboplatin arm of the study. The SCOTROC data on the different toxicity profiles in conjunction with a better quality-of-life profile strongly indicate that not only is docetaxel a viable alternative to paclitaxel in combination first-line therapy, but it could even be considered the taxane of choice. The main toxicity differences, neurotoxicity and myelosuppression, are both important and need careful management. However, in the SCOTROC trial, myelosuppression was transient, was not associated with increased mortality, and was managed by dose reductions and oral antibiotics. In addition, lowering the dose of docetaxel to 60 mg/m2 is extremely unlikely to adversely affect efficacy and should decrease the bone marrow suppression, according to the Cleveland Clinic (Cleveland, OH) data.29 Furthermore, no more patients stopped chemotherapy early because of myelosuppression from docetaxel plus carboplatin, and the levels of grade 3 to 4 myelosuppression seen in patients undergoing treatment were high for both arms (74% v 89%). However, neurotoxicity emerged as the most important determinant of tolerance on this protocol. Of the patients who stopped chemotherapy early, more had NCI-CTC grade 2 to 3 toxicity that lasted longer with paclitaxel plus carboplatin. When the new QLQ-OV28 results and a shorter infusion time (meaning less time spent in clinic) are considered, it is hard to argue against docetaxel plus carboplatin being the superior combination. The caveat regarding immature overall survival data has been raised, but it is considered unlikely, with the existing tight confidence intervals in progression-free survival curves, that a significant divergence in overall survival will appear. Median overall survival data will be available in 2003.
Additional studies with carboplatin plus docetaxel combinations are ongoing and planned by the SGCTG. The SCOTROC 2 program was designed to examine the feasibility of sequential chemotherapy scheduling as the first-line chemotherapy for patients with epithelial ovarian cancer (Fig 2 ). Patients enrolled in the arms of these studies were randomly assigned to assess the feasibility of delivering a planned eight cycles of treatment in comparable groups of patients between studies, with similar control arms. Random assignment of treatment to patients ensures that the feasibility of each regimen is assessed in similar groups of patients. In addition, it provides an unbiased basis for making informal comparisons of the relative merits of the combinations. In SCOTROC 2A, it was planned that all patients would receive cycles of carboplatin AUC 7 every 3 weeks (if possible) followed by four cycles of either (a) docetaxel 100 mg/m2 every 3 weeks; (b) docetaxel 75 mg/m2 on day 8 followed by gemcitabine 1,250 mg/m2 on days 1 and 8 every 3 weeks or (c) docetaxel 25 mg/m2 followed by gemcitabine 800 mg/m2, both drugs given on days 1, 8, and 15 every 3 weeks. In SCOTROC 2B, all patients were randomly assigned to receive four cycles of either docetaxel 100 mg/m2 every 3 weeks, or docetaxel 60 mg/m2 and irinotecan 200 mg/m2 every 3 weeks, after administration of carboplatin.
After completion of this study, one of these three treatment arms is expected to be considered as the new study arm for a randomized trial against the best arm of the SCOTROC trial. Additional similar studies involving paclitaxel in combination with carboplatin and gemcitabine are also ongoing.
OSI-774 (Tarceva, Genentech, San Francisco, CA) is an orally active, potent, and selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. The preliminary results of OSI-774 treatment in cancer patients indicate that this agent may be active in a wide variety of tumors in which EGFR is overexpressed or in which signaling through this receptor is important for tumor cell growth and survival (for comprehensive reviews of the development of EGFR as a target for cancer therapy and recent updates, see Mendelsohn36 and Ciardiello37). Activity of OSI-774 as monotherapy has been demonstrated in patients with ovarian cancer, although no formal analysis of the relationship between EGFR status at baseline and patient outcomes or adverse events has been completed thus far.38 Herein, 34 patients with advanced ovarian carcinoma who were refractory to at least two prior chemotherapy regimens were treated with continuous dosing of OSI-774. Thirty of the enrolled patients underwent follow-up imaging studies at 8 weeks. All imaging studies were reviewed for confirmation by a third-party reading center. Three patients had objective partial responses at week 8, with two of the responses ongoing at 4 and 5 months after therapy was instituted with OSI-774 (response rate, 15 patients [8.8%]). Three patients had stable disease for more than 2 months, and an additional 12 patients had stable disease when assessed at 2 months. The adverse event profile in 124 patients with head and neck cancer in a phase II study was dominated by an acneform rash (74%; 11% grade 3) and diarrhea (3% grade 3).39 Patients in each of these studies received 150-mg daily doses of OSI-774. Dose reduction was allowed if intolerance was evident. Diarrhea was treated with loperamide therapy, dose reduction, or both. Rash was treated with a variety of agents, including oral and topical antibiotics, corticosteroids, and other agents. Significant levels of myelosuppression were not observed in monotherapy phase I and II trials. The SGCTG is undertaking a feasibility study to examine the combination of OSI-774 plus docetaxel and carboplatin in patients with untreated ovarian cancer, fallopian tube cancer, and primary peritoneal cancers. The potential increased hematologic toxic effects observed in an ongoing study with docetaxel plus OSI-774 in a heavily pretreated patient population require a careful evaluation for safety in this untreated patient group (data on file, Roche Pharmaceuticals, Basel, Switzerland). There are no currently available data on pharmacokinetic interactions between carboplatin plus docetaxel and OSI-774, and therefore, this will be investigated as part of the study. It may be relevant that the combination of another EGFR tyrosine kinase inhibitor, ZD1839 (IRESSA, AstraZeneca, London, UK), with carboplatin plus paclitaxel in previously untreated lung cancer patients did not demonstrate any significant drug-drug interactions or influence cytotoxic pharmacokinetics.40 However, this small pilot study demonstrated an increase in the systemic exposure of ZD1839 without any obvious increase in clinical toxicity. The primary objectives of this study are to determine the safety, tolerability, and maximum-tolerated dose of daily OSI-774 in combination with cycles of docetaxel 75 mg/m2 plus carboplatin AUC 5 given every 21 days. Secondary objectives include a pharmacokinetic evaluation of the effect of OSI-774 on the disposition and clearance of carboplatin and docetaxel and of the effect of carboplatin and docetaxel on the disposition and clearance of OSI-774. Documentation of the clinical and radiologic response rate to this combination, in addition to CA-125 response, also will be recorded. Provided this feasibility study is successful in determining a safe dose of OSI-774 in combination with docetaxel plus carboplatin, the SGCTG plans to perform a prospective randomized study using this novel combination both as first-line therapy and as maintenance of disease-free status. The design of this study will be important to try to maximize the potential benefits of such receptor-mediated blockades in addition to chemotherapy in ovarian cancer patients. There are a number of unanswered scientific questions regarding the optimal way to affect this pathway, and additional laboratory studies should be performed in parallel to evaluate which patients may or may not benefit from this approach. The disappointing results of the study evaluating chemotherapy plus ZD1839 combinations in the treatment of non–small-cell lung cancer require careful consideration for the conduct of future trials in this field.41 In conclusion, the docetaxel and carboplatin doublet can now be considered a reasonable first-line option for patients with newly diagnosed epithelial ovarian cancer. This doublet should not be limited to patients thought to be at a higher risk of neuropathy (eg, insulin-dependent diabetic patients and alcoholic patients) because such patients were specifically excluded in the SCOTROC study. Furthermore, there are no robust clinical predictive factors that can accurately determine in advance which patients will develop significant neurological symptoms and signs from carboplatin plus paclitaxel chemotherapy. Furthermore, initial, upfront dose modification of docetaxel for patients at risk of myelosuppression may not appear to adversely affect efficacy, but data on these lower doses are limited to phase II, noncomparative studies. In general, dose reductions for myelosuppressive problems should be initiated after the fact, and it should be noted that in the SCOTROC trial, mortality was not significantly worse with docetaxel 75 mg/m2 plus carboplatin compared with paclitaxel plus carboplatin; therefore, this is the dosing schedule that should be used. Future clinical trial work involving docetaxel combinations is continuing, with the use of novel sequential schedules and the integration of biologic agents into the combination and maintenance therapy.
DR. CANNISTRA: Regarding the first SCOTROC trial [Am Soc Clin Oncol 20: 2001 (abstr 804)], how exactly were those patients managed in terms of prophylactic antibiotics, use of growth factors, hospitalization, and so on? What impact does the difference in neutropenia have both medically and financially? DR. VASEY: The recommendation was that all patients be admitted and treated appropriately with intravenous antibiotics, which happened in most but not all patients. Some patients who came to the clinic with a borderline temperature and grade 4 neutropenia were managed in the community. Prophylactic G-CSF was not recommended, but it was used in a small number of patients. Of course, physicians were able to use G-CSF and antibiotics as they felt appropriate in terms of managing patients’ episodes of fever. DR. BAST: Why is docetaxel less neurotoxic than paclitaxel? DR. VASEY: This is not really understood. They may have slightly different binding sites on the axon. They certainly produce structurally different tubulin polymers [Proc AACR 33:3055, 1992], so they may be acting as slightly different agents. DR. ROWINSKY: If you look at the pharmacological data, you will see that these agents do not do anything qualitatively different [Philadelphia, Pa: Cancer Chemotherapy; 2001]. We ran several xenografts side by side with equally toxic doses of paclitaxel and docetaxel to get a better handle on exactly what these agents do at equitoxic doses. I think we will see that both paclitaxel and docetaxel induce some superiority in a variety of tumor types and xenografts [unpublished data]. We’re trying to figure that out now with genomic and proteonomic studies. Quantitatively, there are differences in cells with regard to potency on a micromolar per micromolar basis. So, on a quantitative basis, docetaxel undoubtedly is a superior or more potent inducer of microtubule polymerization [Biochemistry 32:2747, 1993]. Paclitaxel more indiscriminately hits a variety of different types of microtubules [Philadelphia, Pa: Cancer Chemotherapy; 2001]. However, no one has looked in the nerve cell, which is the problem. DR. BOOKMAN: I agree that our quality-of-life tools are imprecise. One area of imprecision might revolve around what day the instrument was applied; usually, it’s on the day of treatment. At the time of the study, patients getting docetaxel were more likely to have steroids at higher doses for a longer period around their treatment day than patients getting paclitaxel. Most patients, while taking steroids, report a higher quality of life. I’m wondering if that’s part of the explanation for that effect. DR. VASEY: These patients’ questionnaires were only sent to them if they were not able to fill them out at the clinical prior to treatment, so there may be a small variation in time points, and we are currently analyzing this. Remember these patients only had 3 days of steroids, and even in the paclitaxel arm, they have an IV dose of steroids and an antiemetic dose of steroids. I think the differences quantitatively are probably not going to be responsible for that. DR. ROWINSKY: But the timing could be. DR. CANNISTRA: It absolutely could be, and this raises another issue. When you mail these questionnaires, I could easily envision patients not filling them out at a time when they’re feeling poorly and waiting a few days later until they feel better. So it might be more accurate to require that quality of life questionnaires be filled out on a fixed schedule as opposed to letting the patient decide. DR. RUSTIN: As far as alopecia is concerned, how many patients used a cold cap in that study? DR. VASEY: Virtually nobody used a cold cap. DR. CANNISTRA: SCOTROC clearly showed less neuropathy with the use of docetaxel and no convincing difference in overall survival [Proc Am Soc Clin Oncol 21:804, 2002]. However, there’s more grade 4 neutropenia with the docetaxel-containing arm, at a docetaxel dose of 75 mg/m2. I’m still troubled by the fact that we don’t really understand the dose response curve of docetaxel, specifically regarding whether 60 mg/m2 might be just as effective as 75 mg/m2, but might be associated with more tolerable myelosuppression. I consider docetaxel and carboplatin a very reasonable first-line regimen, but I tend to reserve it for patients who might be at high risk of neuropathy. For instance, a patient with preexisting neuropathy might be a good candidate, although admittedly it’s difficult to predict who will or will not develop neuropathy with these regimens. Should the docetaxel and carboplatin combination be more widely used in first line treatment? DR. McGUIRE: I think it should be a standard of care. If there’s no difference in outcome, I’d rather deal with the hematologic toxicity than the neurotoxicity. DR. ROSE: There’s a lack of evidence to suggest that paclitaxel is a dose-dependent drug. For example, in breast cancer, people are often using 225 or 250. We wouldn’t even consider that in ovarian cancer. We consider 175 mg/m2 the maximum dose. But some, ICON-3, for example, may suggest that the role of taxane is less important than we once believed. If platinum is our primary agent and we’re going to add a taxane, adding docetaxel at a dose of 60 mg/m2, which is much more acceptable in terms of toxicity, is reasonable. If a patient starts to develop neuropathy, I switch them to docetaxel at 60 mg/m2. Surprisingly, many patients who have preexisting neuropathy have resolution of that neuropathy while receiving a taxane regimen simply substituting docetaxel for paclitaxel. DR. CANNISTRA: What has been your practice with respect to the role of docetaxel in first-line therapy? DR. ROSE: I haven’t made that switch totally in my own practice, but I can see it coming relatively soon because I have seen the tolerance of the therapy. At a dose of 60 mg/m2, it’s very tolerable. In the SCOTROC 1 trial [Am Soc Clin Oncol 20: 2001 (abstr 804)], there was less neurotoxicity but there was significantly more hematologic toxicity. Nobody dies of neurotoxicity. There are fatalities related to neutropenic sepsis. If one looks at a toxicity as potentially life-threatening or bothersome, I would accept a bothersome one over a life-threatening one. DR. CANNISTRA: However, before we assume that using a docetaxel dose of 60 mg/m2 in the first-line setting is comparable to 75 mg/m2, shouldn’t an equivalency study be performed? DR. ROWINSKY: Another question is who are the patients who are most susceptible to severe neurotoxicity and can we dissect that out. Certainly, the data are there. It would be interesting to go back into some of the cooperative group databanks and try to understand which factors truly predispose patients to neurotoxicity. I would bet that we would see diabetics and patients who have a history of alcohol use or factors that predispose patients to diminished drug clearance. DR. ROSE: I’ve been impressed that the people who develop neurotoxicity do not have these preexisting criteria in my own practice. The people who I see with neurotoxicity are not necessarily diabetics or have other preexisting problems. You cannot predict this patient population.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) interval debulking surgery permitted within 4 weeks of cycle 3 or after cycle 6.
