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Sequential administration of docetaxel followed by cisplatin-vindesine: a pilot study in patients with locally advanced or meta

Bulletin du Cancer. Volume 92, Numéro 1, 10001-6, Janvier 2005, Electronic journal of oncology

Summary

Auteur(s) : Olivier Rixe, Michel Gatineau, Eric Jauffret, Jean-Philippe Spano, Brigitte Orcel, Jean-Michel Vannetzel, Jocelyne Berille, Jean-Philippe Derenne, David Khayat , Service d’oncologie, hôpital Pitié-Salpêtrière, 47 boulevard de l’Hôpital, 75013 Paris, France, Service de pneumologie et réanimation respiratoire, hôpital Pitié Salpêtrière, Paris, France, Clinique Hartmann, Neuilly sur Seine, France, Aventis Pharma, Antony Cedex, France.

Illustrations

ARTICLE

Auteur(s) :, Olivier Rixe¹, Michel Gatineau², Eric Jauffret¹, Jean-Philippe Spano¹, Brigitte Orcel², Jean-Michel Vannetzel³, Jocelyne Berille⁴, Jean-Philippe Derenne², David Khayat¹

¹Service d’oncologie, hôpital Pitié-Salpêtrière, 47 boulevard de l’Hôpital, 75013 Paris, France
²Service de pneumologie et réanimation respiratoire, hôpital Pitié Salpêtrière, Paris, France
³Clinique Hartmann, Neuilly sur Seine, France
⁴Aventis Pharma, Antony Cedex, France

The prognosis of patients with metastatic and advanced non-small cell lung cancer (NSCLC) is poor. The results of a recent randomized phase III study investigating newer cytotoxic agents including taxanes and gemcitabine, have demonstrated the limits of conventional chemotherapy with a median survival of 7.9 months [1].Among chemotherapeutic agents tested in NSCLC as monotherapy, several give an objective response rate of at least 15 %, including cisplatin, ifosfamide, mitomycin, vinblastine, vindesine, vinorelbine, gemcitabine, irinotecan, paclitaxel, and docetaxel [2]. Cisplatin is the backbone of chemotherapy combinations used for treating NSCLC. The dose of cisplatin used is important for achieving a response, and cisplatin-based regimens often use a dose of 75-100 mg/m². The response rates of regimens, which include a platinum salt, range from 10% (carboplatin–etoposide) to 60 % (mitomycin, vinblastine, or vindesine, and cisplatin) [2].When this study was designed in 1995, the synergistic combination of cisplatin and vindesine was considered one of the standard treatments for NSCLC. Two trials comparing cisplatin–vindesine with best supportive care (BSC) showed a significant improvement in survival for the chemotherapy-treated patients (27-32 weeks in the cisplatin-vindesine arm versus 10-17 weeks in the BSC arm) [3, 4]. A further study comparing vindesine (3 mg/m²) combined with either high- (120 mg/m²) or low- (60 mg/m²) dose cisplatin demonstrated that high-dose cisplatin provided both response and survival benefits [5]. Median duration of response (12 versus 5.5 months) and median survival (21.7 versus 10 months) were significantly higher in the high-dose arm compared with the low-dose arm. Complete and partial remission rates were similar in both arms.Docetaxel (Taxotere^®, Aventis Pharma, Antony, France), a semi-synthetic taxoid, has produced encouraging objective response rates of approximately 30 % when administered as a single agent (100 mg/m² every 3 weeks) in previously untreated patients with NSCLC [6]. The principal dose-limiting toxicity was neutropenia; other toxicities included fluid retention, asthenia, and neurotoxicity. The activity exhibited by single-agent docetaxel suggested that studies involving docetaxel combination chemotherapy regimens in first-line NSCLC were warranted.Norton and day hypothesized that the therapeutic effect of chemotherapy could be improved by administering two active drugs or regimens in a sequential schedule [7]. Sequential administration could also allow drug resistance to be circumvented at the molecular level. Such a schedule typically involves the administration of one specific treatment for a previously defined number of cycles, immediately followed by a second treatment for a specified number of cycles. Unlike the switch from first-line to second-line therapy after documented progression, the chemotherapy drugs are switched even if the response to the first regimen is positive with no signs of resistance.The choice of drug combination in a sequential chemotherapy regimen is critical, both to reduce the risk of cross-resistance and to maximize activity. In preclinical studies, Minotti et al. [8] found that cell lines resistant to taxanes were hypersensitive to vinca alkaloids and vice versa. This suggests a taxane–vinca alkaloid sequential regimen may be effective in the clinical setting.In order to test the efficacy of sequential docetaxel and cisplatin–vindesine, we conducted a pilot phase II study in chemotherapy-naïve patients with locally advanced or metastatic NSCLC. A docetaxel dose of 100 mg/m² was the recommended dose for phase II studies at the time of the study design [6]. The choice of this dose level for the study was based on administering the highest possible dose intensity with acceptable toxicity in a sequential setting. The primary aim was to evaluate the objective response rate, duration of response, and time to progression in these patients. Secondary objectives included tolerability and overall survival.

Materials and methods

Patients

Chemotherapy-naïve patients with histologically proven unresectable stage IIIB or stage IV progressive NSCLC were entered into this study. Patients were aged between 18 and 70 years, with a Karnofsky performance status ≥ 60 %, and adequate hematologic, renal, and hepatic function. The inclusion criteria required at least one bi-dimensionally measurable lesion. Patients were excluded if they were exposed to radiotherapy greater than 25 % of their bone marrow within 4weeks of entering the study. Other exclusion criteria included previous chemotherapy or immunotherapy; presence or history of central nervous system metastases; pre-existing motor or sensory neurotoxicity ≥ grade 1 by National Cancer Institute Common Toxicity criteria (NCI-CTC); other serious illness or medical conditions; concurrent treatment with bisphosphonates if initiated recently (< 3 months); and contraindications for the use of corticosteroids as premedication. All patients gave written informed consent before entering the study. Ethics Committee approval was obtained at all three centers.

Treatment

Treatment comprised three different chemotherapy regimens given in sequence as shown in ( figure 1 ). During sequence A, docetaxel 100 mg/m² IV was administered on day 1 every 3weeks. Patients received four cycles of docetaxel before proceeding to sequence B (cisplatin-vindesine). Patients with unacceptable toxicity who did not complete all four cycles of sequence A, and patients with disease progression proceeded directly to sequence B.

Sequence B was a 4-week cycle comprising cisplatin 120mg/m² (Cisplatyl^®, Rhône-Poulenc Rorer Ltd) as a1-hour infusion on day 1 and vindesine 3 mg/m² (Eldisine^®, Lilly, France) as a bolus injection on days 1, 8, 15 and 22. Patients received 4 cycles of the sequence except where disease progression or unacceptable toxicity occurred, in which case patients were withdrawn from the study. The doses of both cisplatin and vindesine were reduced in the case of unacceptable toxicity to 100 and 2 mg/m², respectively. Patients who responded to sequence A and who had a complete or partial response at the end of sequence B, had the option to receive an additional three cycles of 100 mg/m² docetaxel given every 3 weeks as consolidation treatment (sequence C).

Dosing of docetaxel or cisplatin-vindesine was delayed for up to two weeks in the event of neutrophil counts < 1.5 x 10⁹/L or platelet counts < 100 x 10⁹/L on day 21 (docetaxel) or day 29 (cisplatin) of a cycle or grade 3 nonhematologic toxicity, with the exception of alopecia. Patients were withdrawn if toxicities did not resolve within this period. Immediate discontinuation of treatment occurred in the event of grade 3 peripheral neuropathy or any grade 4 nonhematologic toxicity, with the exception of alopecia and cutaneous toxicity. Vindesine was withheld on days 8, 15, or 22 of a cycle in the event of neutrophils < 1.0 x 10⁹/L or platelets < 100 x 10⁹/L. Depending on the nature and grade of toxicity seen in a given cycle, the dose of docetaxel was reduced in subsequent cycles, initially to 75 mg/m² and then to 55 mg/m² if a further reduction was needed.

Assessments

Tumor response was assessed after cycles 2, 4, 6, 8, and 11 (and/or at the end of the study) and was classified according to World Health Organization criteria. An external panel reviewed tumor assessments. Safety was monitored by assessment of all adverse events and by regular measurements of hematologic and biochemical parameters. Clinical neurologic examinations were performed after cycles 4 and 8.

Statistical analysis

All patients who received at least one dose of chemotherapy were included in the safety analyses. Efficacy was assessed in those patients who received a minimum of 2 cycles of treatment (6 weeks on study) or less if a progression disease was noted and at least one follow-up assessment of tumor response. Duration of response, time to progression, and survival were calculated using the Kaplan–Meier method. Safety data were analyzed using descriptive statistics.

Results

Patients

A total of 32 patients from three French centers entered the trial over a period of 18 months (table 1( Table 1 )). One proved ineligible because of diagnosis of ovarian adenocarcinoma and lung metastases and thus was excluded from the study analysis. Thirty-one patients were included in the safety and survival analyses, while 30 patients were evaluable for response (1patient for whom no assessments were available after baseline). All the locally advanced patients were stage IIIB-N3 classified.

Treatment was discontinued because of disease progression in 14 patients.
Table 1 Baseline characteristics of patients and their disease

Characteristic	Number of patients (%)
Registered	32^a
Evaluable
- safety	31 (100)
- efficacy	30 (96.8)
Sex: male/female	24/7 (77.4/22.6)
Median age [range] in years	54.5 [40–70]
Performance status
- 0-1	25 (80.6)
- ≥2	6 (19.4)
Histology
- squamous cell carcinoma	13 (41.9)
- adenocarcinoma	11 (35.5)
- large cell carcinoma	7 (22.6)
Extent of disease
- locally advanced (IIIB)	12 (38.7)
- metastatic	19 (61.3)
Main organs involved
- lung	28 (90.3)
- lymph nodes	16 (51.6)
- bone	11 (35.5)
- pleura	6 (19.4)
- liver	3 (9.7)
- adrenal gland	3 (9.7)
Prior therapy
- no prior therapy	26 (83.8)
- radiotherapy only	2 (6.5)
- surgery only	1 (3.2)
- radiotherapy + surgery	2 (6.5)

^aOne patient excluded from the analysis (see text).

Efficacy

Among the 30 patients evaluable for response, four achieved a partial response, while one had a complete response, resulting in an overall response rate of 16.7 % (95 % confidence interval [CI], 11.6-47.8 %) (table 2( Table 2 )). Stable disease was observed in 17 patients (56.7 %), and progressive disease in the remaining 8 patients (26.7 %). Of the responders, one had large cell carcinoma, four had adenocarcinoma and one had squamous cell carcinoma. One patient had locally advanced disease (stage IIIB-N3) and four had metastatic involvement.

The median progression-free survival was 17.6 weeks (95%CI, 11.9-28.6 weeks) in 29 evaluable patients (no data was available for time to progression for two patients). Median overall survival was 11 months (95%CI = 8.0–15.4 months), with a 1-year survival rate of 47% calculated from the cohort of the 31 treated patients (( figure 2 )).
Table 2 Response data

n (%)	Sequence A		Sequence B		Sequence C
docetaxel		cisplatin–vindesine		docetaxel
(n = 30)		(n = 21)		(n = 5)
CR	PR	CR	PR	CR	PR
Best response over sequence A	0	3 (10.0 %)	–	–	–	–
Best response over sequence B	–	–	0	2 (9.5 %)	–	–
Best response over sequence C	–	–	–	–	1	1
Total (best response)	–	–	–	–	1/30 (3.3 %)	4/30 (13.3 %)

Safety

One hundred and eighty-eight cycles were administered to 31 patients evaluable for toxicity: 122 cycles of docetaxel (including 10 cycles administered during the consolidation phase) and 66 cycles of cisplatin-vindesine (table 3( Table 3 )). The median number of cycles given was 6 (range 1-11). Of the 188 cycles administered, 13 (6.9 %) were delayed for reasons of toxicity (hematologic: 3 cycles and non-hematologic: 10cycles). There were no delays during the docetaxel consolidation phase.

Forty-eight (25.5 %) of the 188 cycles were given at a modified dose in 22 patients, primarily for vindesine. All cycles but one had the dose modified during sequence B. Dose modification occurred as a result of hematologic toxicity in 16cycles, nonhematologic toxicity in an additional 15 cycles, and both hematologic and nonhematologic toxicities in 3cycles. Dose modification in the remaining 14 cycles was not drug-related.

Thirty-one, 21, and 5 patients were evaluated for toxicity after sequences A, B, and C, respectively; details are presented in table 4( Table 4 ). The most frequent hematologic toxicity was anemia, although the majority of cases were grade 1 or 2. Twenty-nine patients experienced at least 1 episode of leukopenia and neutropenia, with grade 3 and 4 neutropenia reported in 11and 15 patients, respectively. Five patients experiencedfebrile neutropenia. Thrombocytopenia was seen in only 3patients, with no cases of grade 3 or 4 toxicity.

The most common nonhematologic toxicities were alopecia, sensory neuropathy, nausea, and renal toxicity. Neuropathy was more common during the third phase of treatment, suggesting a cumulative toxicity. Two patients (6.5 %) experienced a hypersensitivity reaction to docetaxel, including one case of bronchospasm.

Of the six patients who discontinued treatment following adverse events, three were due to sensory neuropathy, one in combination with elevated creatinine levels; two additional cases were due to elevated creatinine levels, one of which required dialysis; and one case was due to liver toxicity. The dose intensity of each drug during cycle 1 and subsequent cycles for each sequence are shown in table 5( Table 5 ).
Table 3 Number of cycles by treatment phase

Treatment phase	Number of patients	Number of cycles
Total	Median (range)
1^st phase, sequence A:	31	112	4 (1–4)
docetaxel 100 mg/m²
2^nd phase, sequence B:	21	66	2 (1–4)
cisplatin/vindesin 120/12 mg/m²
3^rd phase, sequence C:	5	10	2 (1–3)
docetaxel 100 mg/m²
All	31	188	6 (1–11)

Table 4 Number of patients with hematologic and nonhematologic toxicities

No. of patients (%)	Sequence A docetaxel	Sequence B cisplatin/vindesine	Sequence C docetaxel
(n = 31)	(n = 21)	(n = 5)
Hematologic
Grade 4 neutropenia	7 (21.9)	15 (71.4)	1 (20.0)
Febrile neutropenia	2 (6.3)	3 (14.3)	0
Grade 4 thrombocytopenia	0	0	0

Nonhematologic
Grade 2 neuropathy	3 (9.7)	3 (14.3)	2 (40.0)
Grade 3 neuropathy	0	5 (23.8)	2 (40.0)
Grade 4 neuropathy	0	0	0
Grade 1 renal toxicity	0	3 (14.3)	0
Grade 2 renal toxicity	0	1 (4.8)	1 (20.0)
Grade 3 renal toxicity	0	0	0
Grade 4 renal toxicity	0	1 (4.8)	0

Table 5 Patients receiving at least 95% of startingdose

	Sequence A	Sequence B		Sequence C
Docetaxel	Cisplatin	Vindesine	Docetaxel
Cycle 1	31/31	–	–	–
Other cycles	24/31	–	–	–
Cycle 5	–	21/21	12/21	–
Other cycles	–	14/18	0/18	–
Cycle 9	–	–	–	5/5
Other cycles	–	–	–	1/5

Discussion

Despite recent advances in the treatment of NSCLC, phase III studies of platinum-based doublet regimens demonstrate a median survival of only 8-9 months [1, 9]. Although triplet combinations have shown promise in phase II studies [10], the use of these regimens remains controversial [11]. The reasons for this controversy include a potential increase in toxicity causing suboptimal dosing and undemonstrated survival benefits compared with doublet regimens to date. In an effort to improve tolerability, alternating and sequential administration of cytotoxics have been explored in several studies. A pilot phase II study with docetaxel alternating with cisplatin improved tolerability without compromising previously observed levels of response and survival for docetaxel-cisplatin combinations [12].

The response rate of 16.7 % seen in our pilot phase II study falls within the range observed for single-agent docetaxel [7] but is lower than that seen with docetaxel-cisplatin doublets (34-36 %) [13]. Almost 70 % of patients received sequence B as sequential treatment and 15% received sequence C. The median number of cycles given was six, while the usual median number of cycles received with a doublet combination is only four [1, 9]. While the median duration of response was not reached, the partial response ranged from 23 to 29weeks. This suggests patients were sensitive to cisplatin-vindesine after docetaxel treatment and supports the notion that sequential treatment reduces the risk of developing cross-resistance.

Although this sequential design succeeded in treating patients longer than in previous studies, there was no impact on the median time to progression (4 months). A median survival time of 11 months is promising when compared with the median of 8-9 months usually reported with platinum-based doublets. However, survival times may vary according to the patient population. In our study, only 31 patients were treated and 38.7 % had locally advanced disease. The population was relatively young, with a median age of 54.5 years. Although one-third of our patients had bone metastases, this population had a generally favorable prognosis that might have had a positive impact on the overall survival observed.

Patient tolerance of this sequential regimen was also of interest. No treatment-related deaths were reported and the grade of toxicities seen was generally low despite the median number of cycles received, excepted one severe renal toxicity directly related to cisplatin (dialysis required). Most of the common severe toxicities were observed during sequence B: neurosensory (23.8 % grade 3, no grade 4), and neutropenia (71.4 % grade 4). Febrile neutropenia occurred in 5 patients (2 during sequence A and 3 during sequence B), and no infections were documented. Mattson et al. [12] reported a similar trend in tolerance in the pilot study of docetaxel alternating with cisplatin. Additionally, the data reported in table 5 illustrates a favorable toxicity profile as the planned dose intensity was given in the majority of patients.

Sequential studies have been used in breast and ovarian cancer to facilitate giving full doses of chemotherapy, and higher doses have been given with support of hematologic growth factors in order to significantly prolong survival [14, 15]. However, the role of sequential chemotherapy in NSCLC remains to be defined. Our pilot phase II sequential study allowed full doses of docetaxel and cisplatin to be given and tolerated without the use of hematologic growth factors. The median length of treatment was also longer than commonly reported. For further studies, however, the use of cisplatin-vindesine should be reconsidered. This doublet is no longer considered optimal, since Le Chevalier et al. [16] demonstrated superior survival for cisplatin-vinorelbine compared with cisplatin-vindesine in a phase III setting [16]. To retain the potential advantage of combining taxanes with vinca alkaloids suggested by Minotti et al. [8], we recommend a new pilot study be performed of docetaxel followed in sequence by vinorelbine-based therapy. If this new sequential regimen proved feasible, it should be considered in a phase III setting vs. the vinorelbine doublet.

Acknowledgements

This study was supported by a grant from Aventis Pharma, 20 avenue Raymond Aron, 92165 Antony Cedex, France. The authors acknowledge J. Bloch, O. Ferment and R. Mouawad for their assistance with data management. This work was supported by the Fondation Betttencourt-Schueller and the Association pour la vie-Espoir contre le cancer (AVEC). The order of the first two authors is to be considered arbitrary.

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