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Epirubicin-docetaxel in advanced gastric cancer: two phase II studies as second and first line treatment

Bulletin du Cancer. Volume 93, Number 1, 10001-6, Janvier 2006, Electronic journal of oncology

Summary

Author(s) : Suzanne Nguyen, Christine Rebischung, Johan Van Ongeval, Michel Flesch, Mustapha Bennamoun, Thierry André, Marc Ychou, Erik Gamelin, Elisabeth Carola, Christophe Louvet , Service d’oncologie, Centre hospitalier, 40 avenue Léon-Blum, 60021 Beauvais Cedex, France, Service d’oncologie, CHU, Grenoble, France, Service d’oncologie, Hôpital Saint-Antoine, Paris, France, Clinique de Drevon, Dijon, France, Service d’oncologie, Hôpital de Montfermeil, France, Service d’oncologie, Hôpital Tenon, Paris, France, Centre de lutte contre le cancer Val d’Aurelle, Montpellier, France, Centre de lutte contre le cancer Paul Papin, Angers, France, Centre hospitalier, Senlis, France.

Summary : Methods: We evaluated the Epitax combination (epirubicin 60 mg/m ² and docetaxel 75 mg/m ², every 3 weeks) in advanced gastric cancer (AGC) as second-line treatment after fluorouracil and platinum in 50 patients, then as first-line treatment in 36 patients. We report here the results of these two phase II studies. Results: In the second-line treatment, the response rate (RR) was 15.5%. Grade 3-4 neutropenia was observed in 68% (febrile neutropenia in 40%, one treatment-related death). Median time to progression (TTP) and overall survival (OS) were 2.4 and 5.0 months, respectively. In the first-line treatment, the RR was 19.4%. With prophylactic granulocyte colony-stimulating factor, grade 3-4 neutropenia was reported in 38.9%. Then 22 patients received a second-line and 11 patients a third-line treatment. Median TTP and OS were 4.5 and 12 months, respectively. Conclusion: Epitax showed moderate activity in AGC. RR in both trials suggests a non-cross resistance with fluorouracil /platinum combination. The 12-month OS in the first-line treatment could be partly explained by early evaluation and active non-cross resistant second-line therapy.

Keywords : advanced gastric cancer, epirubicin, docetaxel, phase II, first-line, second-line

ARTICLE

Auteur(s) : Suzanne Nguyen¹, Christine Rebischung², Johan Van Ongeval³, Michel Flesch⁴, Mustapha Bennamoun⁵, Thierry André⁶, Marc Ychou⁷, Erik Gamelin⁸, Elisabeth Carola⁹, Christophe Louvet³

¹Service d’oncologie, Centre hospitalier, 40 avenue Léon-Blum, 60021 Beauvais Cedex, France
²Service d’oncologie, CHU, Grenoble, France
³Service d’oncologie, Hôpital Saint-Antoine, Paris, France
⁴Clinique de Drevon, Dijon, France
⁵Service d’oncologie, Hôpital de Montfermeil, France
⁶Service d’oncologie, Hôpital Tenon, Paris, France
⁷Centre de lutte contre le cancer Val d’Aurelle, Montpellier, France
⁸Centre de lutte contre le cancer Paul Papin, Angers, France
⁹Centre hospitalier, Senlis, France

The incidence of gastric cancer in France was estimated at 7,100 new cases per year in 2000; their annual cancer-related death was constantly decreased [1]. Treatment of gastric cancer remains a challenge, because two thirds of the patients are diagnosed with unresectable or metastatic tumors and the majority of patients with operable tumors develop metastases later during the course of the disease [2]. In advanced disease, two randomized trials demonstrated that chemotherapy was superior to best supportive care in terms of prolonging survival, increasing control of quality of life and cost-effectiveness [3, 4].Multiple drugs such as 5-fluorouracil (5FU), anthracyclines, mitomycin-C, etoposide and cisplatin have showed some activity in advanced gastric cancer (AGC) as single-agent chemotherapy, with a response rate ranging from 10 to 20% [5, 6].In order to improve the response rate and the outcome of patients with AGC, several combinations of these cytotoxic drugs were developed. Two EORTC (European Organization for Research and Treatment of Cancer) randomized phase III studies showed that the combination of FAM (5FU, doxorubicin, mitomycin-C) was less active than FAMTX (5FU, doxorubicin, high dose of methotrexate) [7], which had the same efficacy as 5FU-cisplatin (FUP) [8]. ECF combination (epirubicin, cisplatin, 5FU) gave a higher rate of response and improved the 2-year survival rate when compared to FAMTX in another randomized trial [9].Other combinations, such as EAP (etoposide, doxorubicin, and cisplatin), ELF (etoposide, leucovorin, and 5FU), or HLFP (hydroxyurea, leucovorin, 5FU, cisplatin) were also studied. These regimens demonstrated only moderate activity with a median survival rarely exceeding 9 months [10-12].New cytotoxic agents, such as irinotecan, taxanes, oxaliplatin displayed promising activity in combination with 5FU in gastrointestinal cancer [13-16]. The combination of oxaliplatin, 5FU and leucovorin (Folfox6) was found to give a response rate of 44.9% with hematologic toxicity being the main adverse event [17]. Irinotecan plus infusional 5FU and leucovorin (irinotecan + LV5FU2) induced a better response rate (40%) and median survival (11.3 months), when compared to LV5FU2 alone and LV5FU2 plus cisplatin in a randomized phase II study [18]. Paclitaxel combined with 5FU has been reported as active in second-line treatment after cisplatin, epirubicin and modulated 5FU (PEFL) regimen [19].In vitro, docetaxel is effective in human gastric cell lines, and is superior to paclitaxel [20]. Used as a single agent, docetaxel allowed a response rate of 23% in 59 Japanese patients with AGC resistant to a first-line treatment [21] and 24% in the EORTC study with 37 chemo naïve AGC patients [22]. The combination of docetaxel, cisplatin and 5FU (DCF) demonstrated a significantly higher response rate (38.6 versus 23%), time to progression (5.2 versus 3.7 months) and overall survival (10.2 versus 8.5 months) when compared to the 5FU and cisplatin regimen (CF) in a randomized phase III study [23]. It was demonstrated in metastatic breast cancer that the association of taxanes (docetaxel or paclitaxel) with epirubicin did not influence the pharmacokinetics of the compounds [25] and data from phase I study indicate that epirubicin at 60 mg/m² and docetaxel at 75 mg/m² were the maximum tolerated dose (MTD) recommended [26].The large amount of active drugs in AGC allows treatment strategies using several lines of chemotherapy, as it is now recognized to have an important impact on the overall survival in advanced colon cancer [24]. However, a rapid impairment of performance status is often observed in progressive AGC patients. This suggests the need for early assessment, in order to detect progression before the impact on general status, and to allow for a second-line therapy.With the objective of testing new regimens after failure of 5FU and platinum salts in AGC and because of the promising activity of docetaxel, we conducted a second-line epirubicin-docetaxel combination (Epitax) phase II trial. Based on the encouraging results of this study, we then investigated this combination as the front line phase II study.The results of these two consecutive trials are reported in this paper. Most of the methodology was similar in both studies; the differences will be emphasized.

Patients and methods

Eligibility

All eligible patients had histologically proven metastatic or locally inoperable gastric cancer, at least one measurable lesion ≥ 2 cm, age between 18 and 75 years old, World Health Organization (WHO) performance status (PS) ≤ 2, life expectancy ≥ 3 months, adequate hematologic (neutrophils ≥ 2,000/mm³, platelets ≥ 100,000/mm³), renal (creatinine < 140 μmol/l or creatinine clearance > 60 ml/min) and hepatic functions (bilirubin < 2 upper normal limit (UNL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 UNL, phosphatase alkaline ≤ 2.5 UNL). They all signed a written informed consent.

No prior chemotherapy was allowed in the first-line study. For the second-line study only, patients had to have an objective disease progression after 5FU and platinum-based regimens in order to be eligible.

Exclusion criteria were: non measurable disease (peritoneal carcinosis as unique site of metastasis was accepted in the second-line but not in the front line), any concurrent experimental treatment or participation in other clinical study for ≤ 21 days ; other medical diseases that could interfere with the evaluation of tolerance such as: congestive heart failure, angina pectoris even if medically controlled, myocardial infarction ≤ 12 months before entering the study; significant neurological or psychiatric disorders; severe uncontrolled infection; simultaneous elevation of hepatic enzymes; definite contraindications for the use of corticosteroids; potential childbearing women with no adequate contraceptive measures, pregnant or lactating patients; past history of neoplasm, except for excised in situ cervical cancer and curatively treated basal cell carcinoma of the skin; symptomatic or uncontrolled cerebral metastases; pre-existing neuropathy > grade 2 according to National Cancer Institute Common Toxicity Criteria (NCI-CTC); history of allergy to polysorbate 80; unique bone metastasis as measurable disease.

The protocols were reviewed and approved by the Ethics Review Committee of Paris, France. The studies were conformed to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.

Study design

Both studies were multicenter, prospective, open-label, phase II, non-randomized, with the response rate (RR) as primary endpoint. The secondary endpoints were toxicity, time to progression (TTP) and overall survival (OS).

Chemotherapy administration

Eligible patients received epirubicin 60 mg/m² intravenous (IV) over 30 minutes, followed one hour later by docetaxel 75 mg/m² over 1-hour IV infusion, day 1. Each cycle was repeated every 21 days.

Prophylactic medication with prednisolone 50 mg/day was given from the day before (day - 1) until the fourth day (day 4) of the cycle. Antiemetics (setrons, with or without corticosteroids) were strongly recommended. Due to the high rate of grade 3-4 neutropenia in the second-line study, granulocyte colony–stimulating factor (G-CSF) was systematically administered from day 3 to 9 of the first cycle onwards for the first line only.

In case of hypersensitivity reaction grade 2 or 3 to the use of docetaxel, in spite of preventive measures (corticosteroids and antihistamines), patients were strictly monitored for the first 2 cycles, especially for the first minutes of infusion.

Treatment was continued for at least 3 cycles before the first evaluation, or until objective disease progression, unacceptable toxicity (in spite of dose reductions or treatment delay), patient refusal or physician decision. Patients with complete response (CR), partial response (PR) or stable disease (SD) after the first evaluation received 6 cycles. Then, treatment could be continued at the discretion of the investigator, if there was some benefit for the patient.

In first-line treatment, in the case of disease progression, the combination of leucovorin, 5FU and platinum was recommended as second-line treatment.

Dose adjustments

All adverse events and toxicities were graded using the NCI-CTC score. In the event of toxicity, the following dose reductions and treatment delays were planned:

– In case of insufficient hematologic function (neutrophils < 1,500/mm³ and platelet count < 100,000/mm³) on day 22 of any cycle, treatment was delayed for up to 2 weeks, and if there was no recovery at day 35, treatment was discontinued.
– In case of febrile neutropenia, or neutropenia < 500/mm³ more than 7 days, or platelet count < 25,000/mm³, dose reduction was 60 mg/m² for docetaxel and 50 mg/m² for epirubicin. If grade 4 hematologic toxicity persisted, in spite of dose reduction, treatment was discontinued.
– For grade 3 non-hematologic toxicities, treatment was delayed for up to 2 weeks until resolution, then dose was reduced with docetaxel 60 mg/m² and epirubicin 50 mg/m².
– For grade 4 non-hematologic toxicities, treatment was discontinued.

Treatment assessment

- Baseline data. Prior to treatment, all patients had to have a detailed medical history, a complete physical examination with WHO performance status, weight, body surface, evaluation of symptoms and dose of analgesics. All clinical signs and precise tumor measurement were recorded. Biologic analyses included: blood cell count, serum creatinine, hepatic function (phosphatase alkaline, AST, ALT, bilirubin), serum CEA, CA19-9, CA125. Cardiologic function such as: ECG, left ventricular ejection fraction determined by echocardiography or radionuclide angiocardiography (MUGA scan) was performed at the investigator’s discretion, depending on the clinical sign. Appropriate measurement of the tumor size by CT scan or MRI was realized at least 21 days before registration, and was the same after.
- Before each cycle, toxicities occurring between the cycles were recorded and complete physical examination was conducted, including: WHO PS, weight, symptoms, dose of analgesics, complete blood count and creatinine.
- Every three cycles, response to treatment was evaluated, according to the same criteria (targets and methods) than for the baseline evaluation, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All responses were required to be confirmed 4 to 6 weeks later.

Patients receiving less than three cycles were considered as treatment failure. All patients receiving at least one cycle were eligible for the evaluation of tolerance.

Statistical methods

These studies were designed with an interim analysis after the evaluation of the first 14 patients: if no objective response was observed, then the study would be stopped. If there was one response, then 50 patients were included in the second line and 36 patients in the first line (according to Simon’s optimal two stage design).

Overall survival (OS) was defined as the time from study entry to death, and time to progression (TTP) was calculated as the time between the study entry and the time of progression of the disease. OS and TTP were generated by the Kaplan-Meier method. Response rate (RR) and all quantitative variables were described with the confidence interval (CI) of 95%. All tests were a two-sided formulation with α error of 5%.

Results

Patient population

Second-line study

Fifty eligible patients were enrolled into this study in 6 centres. The patients’ characteristics are listed in table 1( Table 1 ). All patients had histologically confirmed adenocarcinoma of the stomach: 34% had a signet-ring cell carcinoma. They all had metastatic disease. The median time during which they were treated in the first line was 5.5 months (range 1-13 months), with a control of disease in 33 patients (66%). Thirty nine patients (78%) were symptomatic at the time of inclusion. 85% of these patients were previously treated with 5FU, leucovorin, cisplatin +/- hydroxyurea and 15% with Folfox6 combination (Folfox6 = oxaliplatin, leucovorin, 5FU bolus and 46 h continuous infusion).
Table 1 Patient characteristics at baseline

	Second line	First line
Total number of patients	50	36
Age (years)
- Median	57	55
- Range	28-74	29-75
Sex (%)
- Male	70	81
- Female	30	19
WHO PS (%)
- 0	24	33
- 1	32	50
- 2	44	17
Stage of disease (%)
- Locally advanced	0	19
- Metastatic disease	100	81
Metastatic sites (%)^a	58	53
- Liver
- Lung	0	14
- Peritoneum	44	14
- Bone	0	8
- Distant lymph nodes	40	11
- Pleura	4	0

^aSome patients had more than one metastatic site.

First-line study

Thirty six patients were enrolled in this first line study at 12 centres. All patients were eligible. The patients’ characteristics are also summarized in table 1. The most frequent symptoms at baseline were: anorexia (39%), dysphagia (22%) and ascitis (11%).

Efficacy

Second-line study

Of the 50 patients enrolled, 5 were not evaluable for response. In one patient, toxic death occurred after the first cycle of chemotherapy and in the other four, there was no measurable disease (only peritoneal involvement). Response rate (RR) is described in table 2( Table 2 ). Control of disease [complete response (CR) + partial response (PR) + stable disease (SD)] was found in 21 of 45 patients (46.6%) [95% CI = 31.7 to 61.5]. Nineteen (48.7%) of the 39 patients who were symptomatic at inclusion had symptom relief after Epitax treatment. The median TTP was 2.4 months with 16% of the intention-to-treat population still without progression after 6 months. The median OS was 5.0 months with 42 and 22% of patients alive after 6 and 12 months, respectively.
Table 2 Response rate

	Second line		First line
	N	%	n	%
Total number of patients	50	100	36	100
Not assessable	5	10.0	0	0.0
Evaluable patients	45	90.0	36	100
Complete response (CR)	1	2.2	1	2.7
Partial response(PR)	6	13.3	6	16.7
Total objective response: (95% confidence interval)	7	15.5 (4.6-26.3)	7	19.4 (6.5-32.3)
Stable disease (SD)	14	31.1	10	27.8
Control of disease (CR+PR+SD)	21	46.6	NA	NA
Progression disease (PD)	24	53.3	19	52.8
Median overall survival	5.0 months		12 months
1-year survival	22%		50%
Median time to progression	2.4 months		4.5 months

First-line study

All 36 patients were evaluable for response. Response rate is also listed in table 2. Pain, anorexia and dysphagia were improved at the first evaluation in one-third of the patients. Three patients received less than three cycles of chemotherapy. All patients were evaluable for response. One patient (2.7%) had CR and 6 (16.7%) had a PR, resulting in an overall RR in 7 patients (19.4%) [95% CI = 6.5 to 32.3].

About two-third of the patients (22 patients, 61%) received a second-line treatment: 19 patients with 5FU and cisplatin combination, three with irinotecan. There was no complete response, 2 PR, 9 SD and 6 patients had progressive disease (PD) after the second-line treatment.

Then 11 patients received a third-line chemotherapy: four patients with irinotecan, two with oxaliplatin, two with 5FU and cisplatin combination, one with capecitabin, one with mitomycin C and one with cisplatin and VP16. The response rate of the third line was: 3 SD, 7 PD and one non evaluable.

Three patients had surgery after best response, all with palliative intent. With a median follow-up of 1 year, the median TTP was 4.5 months and the median OS was 12 months.

Tolerance

Second-line study

A total of 227 cycles were analyzed, with a median of 3 cycles per patient (range 1 to 11). Thirty six patients (72%) received at least 3 cycles of chemotherapy and seventeen patients (34%) received at least 6 cycles. One death was considered to be treatment-related.

Toxicities per patient experienced during the second-line treatment are listed in table 3( Table 3 ). The most common severe toxicity was hematologic with grade 3-4 neutropenia being reported in 68% and febrile neutropenia in 40% of patients. Neuropathy was only grade 3 in one patient (2%).

Twenty-two patients were hospitalized during treatment because of severe toxicity. Twenty- four of the 27 hospitalizations (10.5% of administered cycles) concerned febrile neutropenia. G-CSF was then given in 20.3% of cycles.
Table 3 Grade 3-4 toxicities per patient (NCI-CTC criteria)

	Second line	First line
Number of cycles (n)
- Total	227	174
- Median	3	5
- Range	1-11	1-9
Toxicities per patient (%)	Grade 3 -4	Grade 3 -4
Neutropenia	68.0	38.9
Febrile neutropenia	40.0	0.0
Thrombocytopenia	46.0	5.6
Anemia	N/a*	11.1
Nausea/vomiting	2.0	13.9
Stomatitis	8.0	0.0
Diarrhea	4.0	5.6
Neuropathy	2.0	0.0

First-line study

A total of 174 cycles of the combination were administered (median 5 cycles, range 1-9) Thirty-three patients (91.5%) received at least three cycles and 18 patients (50%) received 6 cycles.

Toxicities experienced during treatment are also summarized in table 3. As expected, the most common toxicity was hematological, with grade 3 and 4 neutropenia and anemia per patient in 38.9 and 11.1% respectively. No patient experienced febrile neutropenia. Only one patient was hospitalized for neutropenia grade 4 without fever, this event was considered as treatment related. No toxic death was observed.

No other severe toxicities (grade 3 or 4) as hypersensitivity reaction, skin or cardiac toxicity were found in both studies.

Discussion

In our second-line study with epirubicin-docetaxel combination (Epitax), the objective response rate (CR and PR) was 15.5%. About the same response rate was obtained in the first-line study with the same regimen (19.4%), which was quite low and disappointing.

What have we learned from these studies? First, Epitax certainly shows some activity in the second-line treatment. However, this activity is moderate in the first line.

Our overall response rate is inferior to those reported with the combination of 5FU and cisplatin regimens [8, 23]. New regimens with irinotecan combinations achieved a higher range of response rate [13, 14]. Moreover, the overall response rate of our study is much closer to the 17 to 23% reported with docetaxel-based chemotherapy given in single-agent or in second-line treatment [28, 29].

The hematotoxicity of the combination docetaxel-epirubicin was predictable and manageable. Neutropenia represents the major hematological toxicity in most trials with docetaxel-based chemotherapy [23, 29, 30]. Murad et al. [31] in their phase II first-line study combining docetaxel, 5FU and epirubicin found a high percentage of febrile neutropenia and 6% toxic deaths in 34 patients. In our trial, with the prophylactic use of G-CSF in the first-line, grade 3-4 neutropenia was less than in the second-line treatment (38.9 instead of 68%) and no febrile neutropenia was recorded (40% in second-line). Non-hematological toxicities were mild and acceptable. Grade 3-4 neuropathy in the second line was probably due to the platinum-based (oxaliplatin, cisplatin) regimens in the first line but it was uncommon (2%).

Finally, although we obtained a moderate response rate, the median overall survival in the first-line study was quite long (12 months) with a TTP of 4.5 months. The long interval between TTP and OS may be related to the efficacy of the second or third-line treatment. The ECF regimen, with a very high response rate never obtained in this indication, demonstrated an overall survival of 8.7 months in a phase III randomized trial in chemonaïve patients [9]. Newer combinations, such as DCF, Folfiri, or Folfox showed an overall survival of no more than 12 months [13, 14, 17, 18, 23].

Our population in these phase II trials was indeed selected: all patients of the second line and 80% of the first line had metastatic disease but most of them had a good performance status (56 and 81% had WHO PS 0 or 1, respectively). Survival benefits observed in these two studies may certainly be due to the good performance status of these patients, who were eligible to receive a second and even third-line treatment. Additional non-cross resistant chemotherapy could thus participate in prolonging survival.

Some authors have also studied second-line chemotherapy with the docetaxel or irinotecan-based combinations, with promising activity [14, 15, 27-29]. Roth [32] recently stated that metastatic disease can now be treated with a large choice of regimens: front line with aggressive combinations in patients with good performance status followed by other less toxic options for second-line management.

With the result of these two studies, we suggest that treatment of advanced gastric cancer should be managed by active agents in well tolerated first-line combination of chemotherapy with a strategy of early radiological assessment every 2 months to detect progressive disease. Therapy should then promptly be switched to second-line treatment with an active non-cross resistant regimen, in order to improve outcome and prolong survival of these patients.

Acknowledgements

These studies were partially supported by a grant from Aventis France.

Conflict of interest statement. The authors indicated no potential conflicts of interest.

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