- Email: [email protected]
Gemcitabine and Paclitaxel Combination as Second-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Phase II Study
Original Study
Gemcitabine and Paclitaxel Combination as Second-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Phase II Study Claudio Dazzi, Anna Cariello, Claudia Casanova, Alberto Verlicchi, Marco Montanari, Giorgio Papiani, Eva Freier, Valentina Mazza, Carlo Milandri, Alessandro Gamboni, Maximilian Papi, Maurizio Leoni, Giorgio Cruciani, Bernadette Vertogen Abstract We conducted a phase II study to evaluate the activity and toxicity of gemcitabine and paclitaxel as second-line chemotherapy in patients with refractory or relapsed small-cell lung cancer. Forty-one patients entered the study. The combination achieved a high disease control rate, but the schedule that we adopted appeared to be toxic. Background: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. Patients and Methods: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m2 days 1 and 8 immediately followed by gemcitabine at 1000 mg/m2 every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. Results: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response ⫹ stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The mostfrequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. Conclusions: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic. Clinical Lung Cancer, Vol. 14, No. 1, 28-33 © 2013 Elsevier Inc. All rights reserved. Keywords: Gemcitabine, Paclitaxel, Second-line chemotherapy, Small-cell lung cancer
Introduction The face of small-cell lung cancer (SCLC) has changed significantly over the past 3 decades. In an analysis of the SEER (Surveil-
IRST: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy Submitted: Jan 18, 2012; Revised: Mar 5, 2012; Accepted: Mar 5, 2012; Epub: Apr 25, 2012 Address for correspondence: Claudio Dazzi, MD, Dipartimento di Oncologia, Ospedale Santa Maria delle Croci, Viale Randi 5– 48121 Ravenna, Italy Tel: ⫹390544285245; fax: ⫹390544285217; e-mail contact: [email protected]
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lance, Epidemiology, and End Results) database, the proportion of SCLC among all lung cancers decreased, from 17.26% in 1986 to 12.96% in 2002.1 Treatments for SCLC are selected by stage and other features of disease extent. In patients with limited disease, the median overall survival (OS) is between 12 and 16 months, and only approximately 5% are cured. In patients with extensive disease, the median survival decreases to approximately 8 months, and only a few patients currently attain long-term survival.2 Between 60% and 70% of patients have extensive disease at diagnosis, with metastases that involve one or more sites, such as brain, liver, bone, or bone marrow.3 Untreated SCLC is lethal within 2 or 3 months from diagnosis
1525-7304/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. doi: 10.1016/j.cllc.2012.03.003
in most patients, and survival beyond 1 year is rare.4 Preferred regimens have evolved over time, and current guidelines recommend platinum-etoposide combinations.5 Although SCLC is a chemosensitive malignancy, with overall response rates of 80%-95% and 60%80% in patients with limited and extensive disease, respectively, most patients relapse within 1 year, and approximately 95% of them eventually die from disease progression. Results of second-line treatment for patients with relapsing or progressing disease are generally poor, with a median survival after relapse of 4-5 months. The degree of benefit of second-line treatment is related to the type of first-line chemotherapy used, the length of the treatment-free interval, the extent of disease at relapse, and the performance status.6 Patients who did not respond to first-line chemotherapy or who responded but progressed within 3 months from the end of induction treatment are considered “refractory” and might only respond to true non– cross-resistant combination chemotherapy. In contrast, patients who responded to first-line chemotherapy and who relapsed after a treatment-free interval ⱖ3 months are defined as “sensitive” and have a reasonable chance of responding to second-line chemotherapy or even to a first-line chemotherapy rechallenge.7 The disease control rate of second-line chemotherapy on disease progression is not clear. In an effort to improve survival rates in this disease, the newer agents that became available during the past 20 years, such as topotecan, docetaxel, paclitaxel, irinotecan, and gemcitabine, were introduced in first- and second-line treatment of SCLC. Among the active new agents in the second-line approach, taxanes and gemcitabine have emerged as promising agents. In a phase II study, paclitaxel demonstrated a 38% response rate in patients with sensitive disease and 29% in those with refractory disease.8 In 2 different series, gemcitabine produced a response rate of 27% in untreated patients9 and of 13% in pretreated refractory patients.10 Domine et al11 presented at the 2001 Annual Meeting of the American Society of Clinical Oncology (ASCO) the encouraging results of a small phase II study that tested the activity of a combination of gemcitabine and paclitaxel in second-line treatment. They treated 31 patients and obtained a 50% response rate and a 20% SD.11 Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP (gemcitabine triphosphate) accumulation, which might enhance the antitumor activity of gemcitabine.12 Furthermore, the lack of cross-resistance between gemcitabine and etoposide, and between paclitaxel and cisplatin has been demonstrated in human SCLC lines.13 The combination of gemcitabine and paclitaxel was already tested in phase I-II studies in patients affected by transitional cell cancer14 and non–small-cell lung cancer,15 which also demonstrates an activity in naive and pretreated patients. On these basis, we designed and conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy in patients with relapsed or refractory SCLC.
Patients and Methods To be eligible for the study, patients had to fulfill the following inclusion criteria: histologically or cytologically proven diagnosis of SCLC; refractory or relapsing disease after a first-line chemotherapy; age ⬎18 and ⬍75 years; the presence of at least 1 bidimensionally measurable tumor site outside of a previous radiotherapy field, unless there was definite evidence of disease progression at this site; ECOG
(Eastern Cooperative Oncology Group) performance status ⱕ2; adequate hematologic, hepatic, renal, and cardiac function. Exclusion criteria included the following: previous treatment with gemcitabine and/or paclitaxel; previous exposure to more than 1 chemotherapy line; the occurrence of central nervous system metastases as the only site of relapse; the presence of prior malignancies (except for basal cell carcinoma of the skin or carcinoma in situ of the cervix); a history of recent myocardial infarction, congestive heart failure, or arrhythmia that required medical treatment; an active infection; the absence of at least 1 bidimensionally tumor site. The trial was approved by our local ethical committee, and all patients gave written informed consent before enrollment.
Response and Toxicity Assessment Baseline evaluation included medical history, physical examination, thorax, and abdominal computed tomography. Computed tomography of the brain and radionuclide bone scanning were performed only in case of clinical suspect. Laboratory studies at presentation included a complete blood cell count, serum chemistries, and liver function tests. Blood count and platelets were repeated on day 8 and whenever clinically recommended. World Health Organization criteria have been used for response evaluation. A complete response was defined as the complete disappearance of all clinically detectable malignant lesions. A partial response (PR) required a 50% or greater reduction in the sum of the cross-sectional areas of all target lesions and no concomitant growth of new lesions. Stable disease (SD) was defined as a ⬍50% decrease or increase of ⬍25% in the product of the longest perpendicular diameters of target lesions. Progressive disease was defined as the appearance of new lesions or an increase of more than 25% in the sum of cross-sectional areas of all target lesions compared with the lowest value recorded. Restaging and tumor measurement were repeated every 3 courses of treatment. Response evaluation could be anticipated with respect to planned time points for clinically evident or suspected disease progression. Toxicity was evaluated according to National Cancer Institute–Common Toxicity Criteria version 2.0. Progression-free survival (PFS) was measured from the beginning of second-line chemotherapy until the date of progressive disease or death. OS was calculated from the first day of treatment to the date of death or was censored on the date of the last visit.
Treatment Plan The patients received paclitaxel at a dose of 135 mg/m2 via 3-hour intravenous infusion immediately followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes; both drugs were administered on days 1 and 8, every 3 weeks for up to 6 courses. Thirty minutes before paclitaxel infusion, the patients received 20 mg dexamethasone, 40 mg orphenadrine, and 50 mg ranitidine. The doses were modified as follows: on day 1 of each course, the drugs were administered at the full dose if the absolute neutrophil count (ANC) count was ⱖ1000/mm3 and platelets (PLTs) were ⱖ100,000/mm3; otherwise, the course was delayed until recovery for a maximum of 2 weeks. On day 8, administration of paclitaxel and gemcitabine was omitted if the ANC count was ⱕ1000/mm3 and the PLTs ⱕ100,000/mm3. Whenever febrile neutropenia, grade 4 neutropenia that lasted more than 5 days, or grade 4 thrombocytopenia occurred, doses of both drugs were reduced to 75% in the subsequent cycles. In case of grade 2 neurotoxicity, paclitaxel was administered at
Clinical Lung Cancer January 2013
29
Gemcitabine and Paclitaxel in Relapsed Small-Cell Lung Cancer 75% of the planned dose. If grade 3 neurotoxicity or worse occurred, then paclitaxel was withdrawn. In case of any other ⱖgrade 3 adverse event, except for an allergic reaction, we waited for complete resolution, and later both drugs were administered at 75% of the planned dose. Prophylactic use of granulocyte-colony stimulating factor to maintain dose intensity was not permitted.
Statistical Analysis Statistical analysis was carried out on the intention-to-treat principle. The primary study endpoint was the assessment of the response rate. The sample size was calculated by using the Simon 2-stage design with a 5% alpha error and 10% beta error.16 When assuming a poor ORR of 10% and an acceptable objective response rate of 30%, it was planned to recruit 18 patients. If the response number was ⬎3, then the combination would be considered active and at least other 18 patients would be enrolled. PFS and OS were assessed by using the Kaplan-Meier procedure.
Results Between January 2004 and December 2007, 41 patients were enrolled into the study (10 women, 31 men). The median age was 65 years (range, 36-75 years). ECOG performance status was ⱕ2 in 37(90%) of 41 patients and unknown in 4 (10%) patients. Patient characteristics are summarized in Table 1. Twenty-two (54%) of 41 patients who responded to first-line chemotherapy and relapsed after a treatment-free interval ⱖ3 months were defined as “sensitive,” whereas 19 (46%) of 41 patients who did not respond to first-line chemotherapy or who responded but progressed within 3 months from the end of induction treatment were considered “refractory.” Thirty five (85%) patients received first-line chemotherapy with cisplatin or with carboplatin and etoposide, whereas the other 7 (15%) patients were treated with cyclophosphamide, doxorubicin, and etoposide. Radiotherapy was administered for curative intent in 43% of patients with limited disease at diagnosis and for a palliative goal in 57% of patients with advanced disease. Only 1 patient underwent a surgical lobectomy as a first local approach. All the patients were considered evaluable for response. A total of 135 courses were administered (median, 3; range, 1-6). Nine patients (22%) achieved PR, and 10 (24%) had SD, with a disease control rate (PR ⫹ SD) of 46%. Disease control rate was achieved in 12 (55%) of 22 sensitive patients and in 7 (37%) of 19 patients who were refractory. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months (range, 1-74⫹ months). The results are summarized in Table 2. Median PFS was 2.7 months, and median OS was 5.5 months (range, 0.5-74⫹ months) (Figure 1). No differences were observed between patients who were sensitive and those refractory (Figure 2). Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The most frequent toxicities were hematologic. Grade 3-4 neutropenia occurred in 23 patients (56%), grade 3 thrombocytopenia in 3 (7%) and grade 3 anemia in 1 (2.5%). Two patients had grade 3 fever with infection, and 1 patient had grade 4 fever without infection. One toxic death occurred due to febrile neutropenia. Among nonhematologic toxicities, we observed a grade 3 neurologic toxicity in 5 (12%) patients, grade 3 asthenia 3 (7%), grade 3 liver toxicity in 2 (5%), grade 3-4 allergic reaction in 2 (5%) (Table 3).
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Clinical Lung Cancer January 2013
Table 1 Patient Characteristics Median Age (Range), Y
65 (36-75)
Sex, No. Patients (%) Women
10 (24)
Men
31 (76)
ECOG Performance Status, No. Patients (%) 0
11 (26)
1
20 (49)
2
6 (15)
Unknown
4 (10)
Disease at Diagnosis, No. Patients (%) Extensive
11 (26)
Limited
30 (74)
Sensitivity to First Line Chemotherapy, No. patients (%) Sensitive
22 (54)
Refractory
19 (46)
Median Number of Metastatic Sites (Range)
2 (1-6)
Metastatic Sites Involved at Study Enter, No. Patients (%) Lung
29 (71)
Distant lymph nodes
23 (56)
Liver
21 (51)
Adrenal
9 (22)
Pleura
9 (22)
CNS
5 (12)
Bone
3 (7)
Spleen
2 (5)
Peritoneum
1 (2.5)
Abbreviations: ECOG ⫽ Eastern Cooperative Oncology Group; CNS ⫽ central nervous system.
Table 2 Activity of P-Gem Schedule All Populations (n ⴝ 41), No. (%)
Sensitive (n ⴝ 22), No. (%)
Refractory (n ⴝ 19), No. (%)
PR
9 (22)
8 (37)
1 (5)
SD
10 (24)
4 (18)
6 (32)
Disease Control Rate (PR ⴙ SD)
19 (46)
12 (55)
7 (37)
PD
22 (54)
10 (45)
12 (63)
Abbreviations: P-Gem ⫽ paclitaxel 135 mg/m2 days 1 and 8 gemcitabine 1000 mg/m2 days 1 and 8; PR ⫽ partial response; PD ⫽ progressive disease; SD ⫽ stable disease.
Discussion A combination of cisplatin (or carboplatin) plus etoposide is currently the mainstay of the first-line approach to treating SCLC. Although initially highly sensitive to a wide variety of agents, SCLC tumors successively develop a chemoresistance to most available cytotoxic agents. In vitro data support the assumption of the existence
Claudio Dazzi et al Figure 1 Progression Free Survival and Overall Survival
100
100 Median 2.7 months (range 0.5-74) Percent Survival
Percent Survival
80 60 40 20
40
0 0
3 6 9 12 15 Progression Free Survival Months
18
Figure 2 Progression Free Survival: Sensitive Versus Refractory Patients
100 Percent Survival
60
20
0
Sensitive Refractory
80 60 40 20 0 0
Median 5.5 months (range 0.5-74)
80
3
6
9 Months
12
15
18
of chemotherapy-resistant clones at the beginning of treatment or the emergence of drug-resistant clones during treatment.17,18 New chemotherapy regimens with non– cross-resistant mechanism of action are needed. Second-line treatment could be considered in patients who are relapsing and with good performance status, and topotecan should be considered the referring treatment on the basis of the results of a phase III trial published several years ago.19 In a landmark phase 3 study, von Pawel et al [20] randomized 211 patients to receive either intravenous topotecan or a combination regimen that contained cyclophosphamide, Adriamycin, and vincristine (CAV). The response rate was observed in 26 (24.3%) of 107 patients treated with topotecan and 19 (18.3%) of 104 patients treated with CAV. The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for 4 of 8 symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P ⫽ .043). Grade 4 neutropenia occurred in 37.8% of topotecan courses vs. 51.4% of CAV courses (P ⬍ .001). In their conclusion, the researchers stated
0
3
6 9 12 Overall Survival Months
15
18
that topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms. However, the study enrolled only patients at more favorable prognosis, that is, with the date of progression being at least 60 days after completion of first-line chemotherapy and all were responsive to treatment.19 Our study reports on the activity of a combination of paclitaxel and gemcitabine. The response rate of 22% and the disease control rate of 46% suggest that the combination is active and, even if in an indirect way, compares well with the results of other published phase II studies and the above-mentioned phase III study. Our series included almost half of the patients with refractory disease and 15% with ECOG performance status of 2. When looking at the results of more recent second-line approaches in patients with SCLC, the activity of the proposed treatment varied from 0% to 68%, but, despite this great variability, probably due to the small sample size, the median survival is not very different among the different studies (Table 4). Because second-line chemotherapy in this particular setting has only a palliative role, we have to select a treatment with good compliance and few adverse effects. The toxicity of paclitaxel and gemcitabine with the schedule that we used in our study was conversely quite severe. In fact, 56% of patients experienced a grade 3-4 neutropenia and 12% a neurologic grade 3 toxicity. Our schedule was selected on the basis of the result of a phase I trial presented at 1999 ASCO annual meeting.14 Probably in the setting of patients with relapsed SCLC, a more careful approach in considering a weekly schedule of paclitaxel could be more appropriate. Dongiovanni et al20 treated 31 consecutive patients: 10 had refractory disease and 21 had sensitive disease. Treatment consisted of paclitaxel 80 mg/m2 on days 1, 8, and 15; and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks. Objective responses occurred in 8 (26%) patients, and 42% obtained a disease control rate (PR ⫹ SD). However, only one-third of patients had refractory disease. Noteworthy, the schedule was well tolerated, with grade 3-4 thrombocytopenia in 26% of the patients, grade 3 neutropenia in 26% and grade 3, and 1-2 sensory neuropathy in 0% and 32%,
Clinical Lung Cancer January 2013
31
Gemcitabine and Paclitaxel in Relapsed Small-Cell Lung Cancer Table 3 Severe Hematologic and Nonhematologic Toxicity 41 Patients Grade 3
Grade 4
Neutropenia
14
9
Thrombocytopenia
3
0
Anemia
1
Infections
2
Fever Without Infection Diarrhea
Total (%)
135 Courses
Total (%)
Grade 3
Grade 4
23 (56)
22
10
32 (24)
3 (7)
3
0
3 (2)
0
1 (2.5)
1
0
1 (0.7)
0
2 (5)
2
0
2 (1.5)
0
1
1 (2.5)
0
1
1 (0.7)
0
1
1 (2.5)
0
1
1 (0.7)
Mucositis
1
0
1 (2.5)
1
0
1 (0.7)
Neurologic
5
0
5 (12)
7
0
7 (5)
Liver
2
0
2 (5)
2
0
2 (1.5)
Asthenia
3
0
3 (7)
3
0
3 (2)
Allergic Reaction
1
1
2 (5)
2
1
3 (2)
Table 4 Results of Trial on Second-Line Treatments Published in the Past 10 Years Study
First-Line Chemotherapy
RR to First-Line chemotherapy, %
Refractory/ Sensitive
Second-Line Chemotherapy
RR, %
OS (Mo)
von Pawel et al,19 1999
CDDP(JM8)-VP16
100
0/107; 0/104
TPT vs. CAV
24 vs. 8
5.8 vs. 5.7
Sonpavde et al,22 2001
CDDP-VP16
85
14/32
ADM/PAC
41
5.8
Kosmas et al,
23
2003
Hainsworth et al,24 2003 Hirose et al,
25
JM8-VP16
76
20/13
CDDP/PAC/IFO
43
6.4
CDDP(JM8)-VP16
NR
17/12
VNR/gemcitabine
10
5
2004
CDDP(JM8)-VP16
88
9/15
JM8/CPT 11
68
6.4
Hoang et al,26 2003
CDDP(JM8)-VP16
NR
12/15
Gemcitabine
0
6.4
Joos et al,27 2003
JM8-VP16
NR
44/0
Paclitaxel
20
4
Dongiovanni et al,20 2006
CDDP(JM8)-VP16
81%
10/21
Paclitaxel/gemcitabine
26
7.4
O’Brien et al,28 2006
CDDP(JM8)-VP16
NR
35/35; 41/30
Topotecan os vs. BSC
7 vs. 0
6.5 vs. 3.5
Current Study
CDDP(JM8)-VP16 CDE
NR
19/22
Paclitaxel/gemcitabine
22
5.5
Abbreviations: ADM ⫽ doxorubicin; BSC ⫽ best supportive care; CAV⫽ cyclophosphamide, doxorubicin, vincristine; CDE ⫽ cyclophosphamide, doxorubicin, etoposide; CDDP ⫽ cisplatin; CPT11⫽ irinotecan; IFO ⫽ ifosfamide; JM8 ⫽ carboplatin; OS ⫽ overall survival; PAC ⫽ cisplatin, doxorubicin, cyclophosphamide; RR ⫽ relative risk; TPT⫽ topotecan; VNR ⫽ vinorelbine; VP16 ⫽ etoposide.
respectively. As has been stressed by the researchers, the acceptable tolerance may be at least partly attributed to the weekly administration scheme that permitted frequent dose adjustment and treatment delay or omission whenever necessary. But, as a result, the dose intensity of this regimen was relatively low, which may have influenced its overall activity.20 Because many of the newer agents have been tested in second-line chemotherapies for patients with SCLC and have demonstrated clinical activity, the question remains how to incorporate these in first-line therapies or to replace the so-called standard first-line treatments, eg, cyclophosphamide, doxorubicin and vincristine/etoposide (CAV/E), cyclophosphamyde, doxorubicin, etoposide or cisplatin, etoposide (PE). Some researchers have argued that investigational agents or new multidrug regimens should be tested upfront in patients with extensive SCLC disease, provided that an effective salvage regimen, eg, PE, is available. The advantage of such an approach would be that
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Clinical Lung Cancer January 2013
these agents or regimens can be tested at maximum dose intensity because patients do not experience toxicity of previous treatments. However, recently, a new step forward was made. Jotte et al21 reported at ASCO 2011 the results of a large randomized phase III trial, which compared amrubicin (a third-generation anthracycline and potent topoisomerase II inhibitor) vs. topotecan in second-line treatment. More than 600 patients have been enrolled into the study. Amrubicin significantly improved response rate compared with topotecan (31% vs. 17%). Survival trended in favor of amrubicin (hazard ratio [HR] 0.88), especially in the subgroup of patients with refractory disease.21 In conclusion, the combination of paclitaxel and gemcitabine investigated in our study achieved a relatively high disease control rate in patients with SCLC who were refractory to or relapsed after first-line treatment. The schedule we adopted seemed to be quite toxic, particularly regarding hematologic and neurologic toxicity, especially when tak-
Claudio Dazzi et al ing into account the goal of our treatment. It remains questionable whether the combination of gemcitabine and paclitaxel can improve the performance of each drug administered alone. The apparent non– crossresistance with the combination of platinum and etoposide, mostly used in the first-line setting, merits further investigation, possibly considering a weekly paclitaxel schedule or testing new drug formulation, more active and less toxic such as nab (albumin bound) paclitaxel.
Clinical Practice Points ●
● ● ● ● ●
Results of second-line treatment for patients with relapsing or progressing SCLC are generally poor, with a median survival from relapse of approximately 4 to 5 months. Topotecan should be considered the referring treatment. Our study reports on the activity of the combination of paclitaxel and gemcitabine. The response rate of 22% and disease control rate of 46% suggest that the combination is active. Conversely, the schedule we have used was severely toxic, particularly regarding hematologic and neurologic toxicity. The apparent non– cross-resistance with the combination of platinum and etoposide mostly used in the first-line setting probably merits further investigation, possibly when considering a weekly paclitaxel schedule or testing new drug formulation, more active and less toxic such as nab (albumin bound) paclitaxel.
Disclosure The authors have stated that they have no conflicts of interest.
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Gemcitabine and Paclitaxel Combination as Second-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Phase II Study Claudio Dazzi, Anna Cariello, Claudia Casanova, Alberto Verlicchi, Marco Montanari, Giorgio Papiani, Eva Freier, Valentina Mazza, Carlo Milandri, Alessandro Gamboni, Maximilian Papi, Maurizio Leoni, Giorgio Cruciani, Bernadette Vertogen Abstract We conducted a phase II study to evaluate the activity and toxicity of gemcitabine and paclitaxel as second-line chemotherapy in patients with refractory or relapsed small-cell lung cancer. Forty-one patients entered the study. The combination achieved a high disease control rate, but the schedule that we adopted appeared to be toxic. Background: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. Patients and Methods: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m2 days 1 and 8 immediately followed by gemcitabine at 1000 mg/m2 every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. Results: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response ⫹ stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The mostfrequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. Conclusions: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic. Clinical Lung Cancer, Vol. 14, No. 1, 28-33 © 2013 Elsevier Inc. All rights reserved. Keywords: Gemcitabine, Paclitaxel, Second-line chemotherapy, Small-cell lung cancer
Introduction The face of small-cell lung cancer (SCLC) has changed significantly over the past 3 decades. In an analysis of the SEER (Surveil-
IRST: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy Submitted: Jan 18, 2012; Revised: Mar 5, 2012; Accepted: Mar 5, 2012; Epub: Apr 25, 2012 Address for correspondence: Claudio Dazzi, MD, Dipartimento di Oncologia, Ospedale Santa Maria delle Croci, Viale Randi 5– 48121 Ravenna, Italy Tel: ⫹390544285245; fax: ⫹390544285217; e-mail contact: [email protected]
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lance, Epidemiology, and End Results) database, the proportion of SCLC among all lung cancers decreased, from 17.26% in 1986 to 12.96% in 2002.1 Treatments for SCLC are selected by stage and other features of disease extent. In patients with limited disease, the median overall survival (OS) is between 12 and 16 months, and only approximately 5% are cured. In patients with extensive disease, the median survival decreases to approximately 8 months, and only a few patients currently attain long-term survival.2 Between 60% and 70% of patients have extensive disease at diagnosis, with metastases that involve one or more sites, such as brain, liver, bone, or bone marrow.3 Untreated SCLC is lethal within 2 or 3 months from diagnosis
1525-7304/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. doi: 10.1016/j.cllc.2012.03.003
in most patients, and survival beyond 1 year is rare.4 Preferred regimens have evolved over time, and current guidelines recommend platinum-etoposide combinations.5 Although SCLC is a chemosensitive malignancy, with overall response rates of 80%-95% and 60%80% in patients with limited and extensive disease, respectively, most patients relapse within 1 year, and approximately 95% of them eventually die from disease progression. Results of second-line treatment for patients with relapsing or progressing disease are generally poor, with a median survival after relapse of 4-5 months. The degree of benefit of second-line treatment is related to the type of first-line chemotherapy used, the length of the treatment-free interval, the extent of disease at relapse, and the performance status.6 Patients who did not respond to first-line chemotherapy or who responded but progressed within 3 months from the end of induction treatment are considered “refractory” and might only respond to true non– cross-resistant combination chemotherapy. In contrast, patients who responded to first-line chemotherapy and who relapsed after a treatment-free interval ⱖ3 months are defined as “sensitive” and have a reasonable chance of responding to second-line chemotherapy or even to a first-line chemotherapy rechallenge.7 The disease control rate of second-line chemotherapy on disease progression is not clear. In an effort to improve survival rates in this disease, the newer agents that became available during the past 20 years, such as topotecan, docetaxel, paclitaxel, irinotecan, and gemcitabine, were introduced in first- and second-line treatment of SCLC. Among the active new agents in the second-line approach, taxanes and gemcitabine have emerged as promising agents. In a phase II study, paclitaxel demonstrated a 38% response rate in patients with sensitive disease and 29% in those with refractory disease.8 In 2 different series, gemcitabine produced a response rate of 27% in untreated patients9 and of 13% in pretreated refractory patients.10 Domine et al11 presented at the 2001 Annual Meeting of the American Society of Clinical Oncology (ASCO) the encouraging results of a small phase II study that tested the activity of a combination of gemcitabine and paclitaxel in second-line treatment. They treated 31 patients and obtained a 50% response rate and a 20% SD.11 Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP (gemcitabine triphosphate) accumulation, which might enhance the antitumor activity of gemcitabine.12 Furthermore, the lack of cross-resistance between gemcitabine and etoposide, and between paclitaxel and cisplatin has been demonstrated in human SCLC lines.13 The combination of gemcitabine and paclitaxel was already tested in phase I-II studies in patients affected by transitional cell cancer14 and non–small-cell lung cancer,15 which also demonstrates an activity in naive and pretreated patients. On these basis, we designed and conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy in patients with relapsed or refractory SCLC.
Patients and Methods To be eligible for the study, patients had to fulfill the following inclusion criteria: histologically or cytologically proven diagnosis of SCLC; refractory or relapsing disease after a first-line chemotherapy; age ⬎18 and ⬍75 years; the presence of at least 1 bidimensionally measurable tumor site outside of a previous radiotherapy field, unless there was definite evidence of disease progression at this site; ECOG
(Eastern Cooperative Oncology Group) performance status ⱕ2; adequate hematologic, hepatic, renal, and cardiac function. Exclusion criteria included the following: previous treatment with gemcitabine and/or paclitaxel; previous exposure to more than 1 chemotherapy line; the occurrence of central nervous system metastases as the only site of relapse; the presence of prior malignancies (except for basal cell carcinoma of the skin or carcinoma in situ of the cervix); a history of recent myocardial infarction, congestive heart failure, or arrhythmia that required medical treatment; an active infection; the absence of at least 1 bidimensionally tumor site. The trial was approved by our local ethical committee, and all patients gave written informed consent before enrollment.
Response and Toxicity Assessment Baseline evaluation included medical history, physical examination, thorax, and abdominal computed tomography. Computed tomography of the brain and radionuclide bone scanning were performed only in case of clinical suspect. Laboratory studies at presentation included a complete blood cell count, serum chemistries, and liver function tests. Blood count and platelets were repeated on day 8 and whenever clinically recommended. World Health Organization criteria have been used for response evaluation. A complete response was defined as the complete disappearance of all clinically detectable malignant lesions. A partial response (PR) required a 50% or greater reduction in the sum of the cross-sectional areas of all target lesions and no concomitant growth of new lesions. Stable disease (SD) was defined as a ⬍50% decrease or increase of ⬍25% in the product of the longest perpendicular diameters of target lesions. Progressive disease was defined as the appearance of new lesions or an increase of more than 25% in the sum of cross-sectional areas of all target lesions compared with the lowest value recorded. Restaging and tumor measurement were repeated every 3 courses of treatment. Response evaluation could be anticipated with respect to planned time points for clinically evident or suspected disease progression. Toxicity was evaluated according to National Cancer Institute–Common Toxicity Criteria version 2.0. Progression-free survival (PFS) was measured from the beginning of second-line chemotherapy until the date of progressive disease or death. OS was calculated from the first day of treatment to the date of death or was censored on the date of the last visit.
Treatment Plan The patients received paclitaxel at a dose of 135 mg/m2 via 3-hour intravenous infusion immediately followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes; both drugs were administered on days 1 and 8, every 3 weeks for up to 6 courses. Thirty minutes before paclitaxel infusion, the patients received 20 mg dexamethasone, 40 mg orphenadrine, and 50 mg ranitidine. The doses were modified as follows: on day 1 of each course, the drugs were administered at the full dose if the absolute neutrophil count (ANC) count was ⱖ1000/mm3 and platelets (PLTs) were ⱖ100,000/mm3; otherwise, the course was delayed until recovery for a maximum of 2 weeks. On day 8, administration of paclitaxel and gemcitabine was omitted if the ANC count was ⱕ1000/mm3 and the PLTs ⱕ100,000/mm3. Whenever febrile neutropenia, grade 4 neutropenia that lasted more than 5 days, or grade 4 thrombocytopenia occurred, doses of both drugs were reduced to 75% in the subsequent cycles. In case of grade 2 neurotoxicity, paclitaxel was administered at
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29
Gemcitabine and Paclitaxel in Relapsed Small-Cell Lung Cancer 75% of the planned dose. If grade 3 neurotoxicity or worse occurred, then paclitaxel was withdrawn. In case of any other ⱖgrade 3 adverse event, except for an allergic reaction, we waited for complete resolution, and later both drugs were administered at 75% of the planned dose. Prophylactic use of granulocyte-colony stimulating factor to maintain dose intensity was not permitted.
Statistical Analysis Statistical analysis was carried out on the intention-to-treat principle. The primary study endpoint was the assessment of the response rate. The sample size was calculated by using the Simon 2-stage design with a 5% alpha error and 10% beta error.16 When assuming a poor ORR of 10% and an acceptable objective response rate of 30%, it was planned to recruit 18 patients. If the response number was ⬎3, then the combination would be considered active and at least other 18 patients would be enrolled. PFS and OS were assessed by using the Kaplan-Meier procedure.
Results Between January 2004 and December 2007, 41 patients were enrolled into the study (10 women, 31 men). The median age was 65 years (range, 36-75 years). ECOG performance status was ⱕ2 in 37(90%) of 41 patients and unknown in 4 (10%) patients. Patient characteristics are summarized in Table 1. Twenty-two (54%) of 41 patients who responded to first-line chemotherapy and relapsed after a treatment-free interval ⱖ3 months were defined as “sensitive,” whereas 19 (46%) of 41 patients who did not respond to first-line chemotherapy or who responded but progressed within 3 months from the end of induction treatment were considered “refractory.” Thirty five (85%) patients received first-line chemotherapy with cisplatin or with carboplatin and etoposide, whereas the other 7 (15%) patients were treated with cyclophosphamide, doxorubicin, and etoposide. Radiotherapy was administered for curative intent in 43% of patients with limited disease at diagnosis and for a palliative goal in 57% of patients with advanced disease. Only 1 patient underwent a surgical lobectomy as a first local approach. All the patients were considered evaluable for response. A total of 135 courses were administered (median, 3; range, 1-6). Nine patients (22%) achieved PR, and 10 (24%) had SD, with a disease control rate (PR ⫹ SD) of 46%. Disease control rate was achieved in 12 (55%) of 22 sensitive patients and in 7 (37%) of 19 patients who were refractory. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months (range, 1-74⫹ months). The results are summarized in Table 2. Median PFS was 2.7 months, and median OS was 5.5 months (range, 0.5-74⫹ months) (Figure 1). No differences were observed between patients who were sensitive and those refractory (Figure 2). Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The most frequent toxicities were hematologic. Grade 3-4 neutropenia occurred in 23 patients (56%), grade 3 thrombocytopenia in 3 (7%) and grade 3 anemia in 1 (2.5%). Two patients had grade 3 fever with infection, and 1 patient had grade 4 fever without infection. One toxic death occurred due to febrile neutropenia. Among nonhematologic toxicities, we observed a grade 3 neurologic toxicity in 5 (12%) patients, grade 3 asthenia 3 (7%), grade 3 liver toxicity in 2 (5%), grade 3-4 allergic reaction in 2 (5%) (Table 3).
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Clinical Lung Cancer January 2013
Table 1 Patient Characteristics Median Age (Range), Y
65 (36-75)
Sex, No. Patients (%) Women
10 (24)
Men
31 (76)
ECOG Performance Status, No. Patients (%) 0
11 (26)
1
20 (49)
2
6 (15)
Unknown
4 (10)
Disease at Diagnosis, No. Patients (%) Extensive
11 (26)
Limited
30 (74)
Sensitivity to First Line Chemotherapy, No. patients (%) Sensitive
22 (54)
Refractory
19 (46)
Median Number of Metastatic Sites (Range)
2 (1-6)
Metastatic Sites Involved at Study Enter, No. Patients (%) Lung
29 (71)
Distant lymph nodes
23 (56)
Liver
21 (51)
Adrenal
9 (22)
Pleura
9 (22)
CNS
5 (12)
Bone
3 (7)
Spleen
2 (5)
Peritoneum
1 (2.5)
Abbreviations: ECOG ⫽ Eastern Cooperative Oncology Group; CNS ⫽ central nervous system.
Table 2 Activity of P-Gem Schedule All Populations (n ⴝ 41), No. (%)
Sensitive (n ⴝ 22), No. (%)
Refractory (n ⴝ 19), No. (%)
PR
9 (22)
8 (37)
1 (5)
SD
10 (24)
4 (18)
6 (32)
Disease Control Rate (PR ⴙ SD)
19 (46)
12 (55)
7 (37)
PD
22 (54)
10 (45)
12 (63)
Abbreviations: P-Gem ⫽ paclitaxel 135 mg/m2 days 1 and 8 gemcitabine 1000 mg/m2 days 1 and 8; PR ⫽ partial response; PD ⫽ progressive disease; SD ⫽ stable disease.
Discussion A combination of cisplatin (or carboplatin) plus etoposide is currently the mainstay of the first-line approach to treating SCLC. Although initially highly sensitive to a wide variety of agents, SCLC tumors successively develop a chemoresistance to most available cytotoxic agents. In vitro data support the assumption of the existence
Claudio Dazzi et al Figure 1 Progression Free Survival and Overall Survival
100
100 Median 2.7 months (range 0.5-74) Percent Survival
Percent Survival
80 60 40 20
40
0 0
3 6 9 12 15 Progression Free Survival Months
18
Figure 2 Progression Free Survival: Sensitive Versus Refractory Patients
100 Percent Survival
60
20
0
Sensitive Refractory
80 60 40 20 0 0
Median 5.5 months (range 0.5-74)
80
3
6
9 Months
12
15
18
of chemotherapy-resistant clones at the beginning of treatment or the emergence of drug-resistant clones during treatment.17,18 New chemotherapy regimens with non– cross-resistant mechanism of action are needed. Second-line treatment could be considered in patients who are relapsing and with good performance status, and topotecan should be considered the referring treatment on the basis of the results of a phase III trial published several years ago.19 In a landmark phase 3 study, von Pawel et al [20] randomized 211 patients to receive either intravenous topotecan or a combination regimen that contained cyclophosphamide, Adriamycin, and vincristine (CAV). The response rate was observed in 26 (24.3%) of 107 patients treated with topotecan and 19 (18.3%) of 104 patients treated with CAV. The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for 4 of 8 symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P ⫽ .043). Grade 4 neutropenia occurred in 37.8% of topotecan courses vs. 51.4% of CAV courses (P ⬍ .001). In their conclusion, the researchers stated
0
3
6 9 12 Overall Survival Months
15
18
that topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms. However, the study enrolled only patients at more favorable prognosis, that is, with the date of progression being at least 60 days after completion of first-line chemotherapy and all were responsive to treatment.19 Our study reports on the activity of a combination of paclitaxel and gemcitabine. The response rate of 22% and the disease control rate of 46% suggest that the combination is active and, even if in an indirect way, compares well with the results of other published phase II studies and the above-mentioned phase III study. Our series included almost half of the patients with refractory disease and 15% with ECOG performance status of 2. When looking at the results of more recent second-line approaches in patients with SCLC, the activity of the proposed treatment varied from 0% to 68%, but, despite this great variability, probably due to the small sample size, the median survival is not very different among the different studies (Table 4). Because second-line chemotherapy in this particular setting has only a palliative role, we have to select a treatment with good compliance and few adverse effects. The toxicity of paclitaxel and gemcitabine with the schedule that we used in our study was conversely quite severe. In fact, 56% of patients experienced a grade 3-4 neutropenia and 12% a neurologic grade 3 toxicity. Our schedule was selected on the basis of the result of a phase I trial presented at 1999 ASCO annual meeting.14 Probably in the setting of patients with relapsed SCLC, a more careful approach in considering a weekly schedule of paclitaxel could be more appropriate. Dongiovanni et al20 treated 31 consecutive patients: 10 had refractory disease and 21 had sensitive disease. Treatment consisted of paclitaxel 80 mg/m2 on days 1, 8, and 15; and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks. Objective responses occurred in 8 (26%) patients, and 42% obtained a disease control rate (PR ⫹ SD). However, only one-third of patients had refractory disease. Noteworthy, the schedule was well tolerated, with grade 3-4 thrombocytopenia in 26% of the patients, grade 3 neutropenia in 26% and grade 3, and 1-2 sensory neuropathy in 0% and 32%,
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31
Gemcitabine and Paclitaxel in Relapsed Small-Cell Lung Cancer Table 3 Severe Hematologic and Nonhematologic Toxicity 41 Patients Grade 3
Grade 4
Neutropenia
14
9
Thrombocytopenia
3
0
Anemia
1
Infections
2
Fever Without Infection Diarrhea
Total (%)
135 Courses
Total (%)
Grade 3
Grade 4
23 (56)
22
10
32 (24)
3 (7)
3
0
3 (2)
0
1 (2.5)
1
0
1 (0.7)
0
2 (5)
2
0
2 (1.5)
0
1
1 (2.5)
0
1
1 (0.7)
0
1
1 (2.5)
0
1
1 (0.7)
Mucositis
1
0
1 (2.5)
1
0
1 (0.7)
Neurologic
5
0
5 (12)
7
0
7 (5)
Liver
2
0
2 (5)
2
0
2 (1.5)
Asthenia
3
0
3 (7)
3
0
3 (2)
Allergic Reaction
1
1
2 (5)
2
1
3 (2)
Table 4 Results of Trial on Second-Line Treatments Published in the Past 10 Years Study
First-Line Chemotherapy
RR to First-Line chemotherapy, %
Refractory/ Sensitive
Second-Line Chemotherapy
RR, %
OS (Mo)
von Pawel et al,19 1999
CDDP(JM8)-VP16
100
0/107; 0/104
TPT vs. CAV
24 vs. 8
5.8 vs. 5.7
Sonpavde et al,22 2001
CDDP-VP16
85
14/32
ADM/PAC
41
5.8
Kosmas et al,
23
2003
Hainsworth et al,24 2003 Hirose et al,
25
JM8-VP16
76
20/13
CDDP/PAC/IFO
43
6.4
CDDP(JM8)-VP16
NR
17/12
VNR/gemcitabine
10
5
2004
CDDP(JM8)-VP16
88
9/15
JM8/CPT 11
68
6.4
Hoang et al,26 2003
CDDP(JM8)-VP16
NR
12/15
Gemcitabine
0
6.4
Joos et al,27 2003
JM8-VP16
NR
44/0
Paclitaxel
20
4
Dongiovanni et al,20 2006
CDDP(JM8)-VP16
81%
10/21
Paclitaxel/gemcitabine
26
7.4
O’Brien et al,28 2006
CDDP(JM8)-VP16
NR
35/35; 41/30
Topotecan os vs. BSC
7 vs. 0
6.5 vs. 3.5
Current Study
CDDP(JM8)-VP16 CDE
NR
19/22
Paclitaxel/gemcitabine
22
5.5
Abbreviations: ADM ⫽ doxorubicin; BSC ⫽ best supportive care; CAV⫽ cyclophosphamide, doxorubicin, vincristine; CDE ⫽ cyclophosphamide, doxorubicin, etoposide; CDDP ⫽ cisplatin; CPT11⫽ irinotecan; IFO ⫽ ifosfamide; JM8 ⫽ carboplatin; OS ⫽ overall survival; PAC ⫽ cisplatin, doxorubicin, cyclophosphamide; RR ⫽ relative risk; TPT⫽ topotecan; VNR ⫽ vinorelbine; VP16 ⫽ etoposide.
respectively. As has been stressed by the researchers, the acceptable tolerance may be at least partly attributed to the weekly administration scheme that permitted frequent dose adjustment and treatment delay or omission whenever necessary. But, as a result, the dose intensity of this regimen was relatively low, which may have influenced its overall activity.20 Because many of the newer agents have been tested in second-line chemotherapies for patients with SCLC and have demonstrated clinical activity, the question remains how to incorporate these in first-line therapies or to replace the so-called standard first-line treatments, eg, cyclophosphamide, doxorubicin and vincristine/etoposide (CAV/E), cyclophosphamyde, doxorubicin, etoposide or cisplatin, etoposide (PE). Some researchers have argued that investigational agents or new multidrug regimens should be tested upfront in patients with extensive SCLC disease, provided that an effective salvage regimen, eg, PE, is available. The advantage of such an approach would be that
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Clinical Lung Cancer January 2013
these agents or regimens can be tested at maximum dose intensity because patients do not experience toxicity of previous treatments. However, recently, a new step forward was made. Jotte et al21 reported at ASCO 2011 the results of a large randomized phase III trial, which compared amrubicin (a third-generation anthracycline and potent topoisomerase II inhibitor) vs. topotecan in second-line treatment. More than 600 patients have been enrolled into the study. Amrubicin significantly improved response rate compared with topotecan (31% vs. 17%). Survival trended in favor of amrubicin (hazard ratio [HR] 0.88), especially in the subgroup of patients with refractory disease.21 In conclusion, the combination of paclitaxel and gemcitabine investigated in our study achieved a relatively high disease control rate in patients with SCLC who were refractory to or relapsed after first-line treatment. The schedule we adopted seemed to be quite toxic, particularly regarding hematologic and neurologic toxicity, especially when tak-
Claudio Dazzi et al ing into account the goal of our treatment. It remains questionable whether the combination of gemcitabine and paclitaxel can improve the performance of each drug administered alone. The apparent non– crossresistance with the combination of platinum and etoposide, mostly used in the first-line setting, merits further investigation, possibly considering a weekly paclitaxel schedule or testing new drug formulation, more active and less toxic such as nab (albumin bound) paclitaxel.
Clinical Practice Points ●
● ● ● ● ●
Results of second-line treatment for patients with relapsing or progressing SCLC are generally poor, with a median survival from relapse of approximately 4 to 5 months. Topotecan should be considered the referring treatment. Our study reports on the activity of the combination of paclitaxel and gemcitabine. The response rate of 22% and disease control rate of 46% suggest that the combination is active. Conversely, the schedule we have used was severely toxic, particularly regarding hematologic and neurologic toxicity. The apparent non– cross-resistance with the combination of platinum and etoposide mostly used in the first-line setting probably merits further investigation, possibly when considering a weekly paclitaxel schedule or testing new drug formulation, more active and less toxic such as nab (albumin bound) paclitaxel.
Disclosure The authors have stated that they have no conflicts of interest.
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