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May - August 2004: 
Volume 17, Issue 2

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A study of paclitaxel in two dose combinations with carboplatin for the treatment of small cell lung cancer
Abstract
Taxanes are increasingly used in the management of small cell lung cancer (SCLC), but optimal dose and combination with other antineoplastic agents remains to be determined. We used two different dosage regimens of paclitaxel (P) in combination with carboplatin (C) in 148 chemotherapy-naive SCLC patients (age up to 75 years, WHO performance status 0-1) divided in two groups. All patients received C (AUC=6) with P at a dose of either 175 mg/m2 (Group A, 76 pts [68 men]) or 190 mg/m2 (Group B, 78 pts [73 men]), all given on day 1. The regimen was repeated every 28 days for up to 8 cycles. All responders received radiotherapy at the primary tumor site (48 Gy given over 4 weeks) between cycles 6 and 8. Complete responders were given additional prophylactic cranial irradiation. The overall response (OR) rate was 63.1% in Group A (LD: 81.1%, ED: 60%), and 66.6% in Group B (LD: 77.5%, ED: 58.3%) [not significant difference]. Median survival was 270 days in Group A (95% CI: 222-318) and 300 days in Group B (95% CI: 247-352) [p=0.05]. The median time to progression was 200 days in both groups. Toxicity: grade 3/4 neutropenia: 6.5% in Group A, 14.1% in Group B; grade 3/4 anaemia: 5.2% and 10.2%; grade 3 thrombocytopenia: 5.2% and 1.2%; and grade 1/2 neurotoxicity: 27% and 16.6%, respectively. Compared to conventional regimens in the management of SCLC, the combination of P with C is equally effective and well tolerated. There is no significant difference in response or survival rates with the higher dose of P, as indicated in the present study. Pneumon 2004, 17(2):186-194.
Full text

INTRODUCTION

Due to its early spread, small cell lung cancer (SCLC) is generally considered a systematic disease. In fact, two thirds of the patients have distant metastases at the time of diagnosis1. Chemotherapy is the established standard in the treatment of SCLC, especially in cases with extensive disease. Despite the documented sensitivity of the tumor in various chemotherapy regimens and the increased survival rates among patients who received combined chemotherapy, patients with extensive SCLC still have a poor prognosis (median survival 7-9 months), with the percentage of patients who live more than 2 years not exceeding 10%2-5.

To improve response rates, prolong periods of remission and, ultimately, increase survival of treated SCLC patients, new chemotherapy agents with significant efficacy against this malignancy need to be developed. Paclitaxel (P) was the first effective agent with a unique mechanism of cytotoxicity that appeared in the last years. In both in vitro and in vivo preclinical tumor models, P has shown significant anticancer activity6,7. In chemotherapy-naive patients with extensive SCLC, single-agent paclitaxel yielded response rates of 34% and 68% in trials by the Eastern Co-operative Oncology Group (ECOG) and the North Central Cancer Treatment Group, respectively8,9. Paclitaxel has also been shown to be effective in combination with carboplatin (C) in advanced non-small cell lung cancer (NSCLC), as well as in a three-drug regimen with C and etoposide in SCLC11.

Although chemotherapy in extensive-stage SCLC is a rather palliative than radical treatment, in the present phase II study we have attempted to offer a full chemotherapy regimen in selected SCLC patients (with good functional status) who agreed to receive such treatment. The objective of the study was to assess patient survival and toxicity with two chemotherapy regimens of paclitaxel and carboplatin, changing the dose of paclitaxel while the dose of carboplatin remains the same in both regimens.

 

PATIENT AND METHODS

Patients with histologically confirmed SCLC, aged up to 75 years, with good performance status (ECOG 0-1) and normal renal and liver function and without clinically significant heart failure were selected and included in the study. The characteristics of the patients and the clinical manifestations of the disease at the time of diagnosis are outlined in Tables 1 and 2, respectively. All patients gave written informed consent before entering the study.

 

Table 1. Patient characteristics

                                        Group A        Group B

Enrolled patients                   76                 78

Assessable patients              72                 76

Males:Females                    68:4              73:3

Limited disease              22 (30.5%)   40 (52.6%)

Extensive disease          50 (69.5%)   36 (47.4%)

Mean age (95% CI)

     Limited disease        70 (67-72,9) 66 (62.9-69)

     Extensive disease   62 (57.4-66.6) 61 (59.4-62.6)

Performance status (ECOG)

     Score 0                     57 (78.9%)   60 (78.9%)

     Score 1                     15 (20.8%)     16 (21%)

Weight loss

     0 kg                                 20                 25

     1-5 kg                              38                 44

     >5 kg                               10                 11

Weight gain                           4                   6

 

 

Table 2. Clinical manifestations of the disease at the time of diagnosis

                                                  No. of patients (%)

Assessable patients                        148

Cough                                              95   (64.1%)

Weight loss                                      69   (46.6%)

Pleuritic pain                                     40      (27%)

Hemoptysis                                      35   (23.6%)

Dyspnea                                           35   (23.6%)

Fever                                               31   (20.9%)

Weakness                                        31   (20.9%)

Hoarseness                                      31   (20.9%)

Bone pain                                         23   (15.5%)

Dizziness                                          14     (9.4%)

Hypertrophic pulmonary osteoarthropathy    7 (4.7%)

Superior vena caval obstruction         5     (3.4%)

Pleural effusion                                  1   (0.06%)

Dysphagia                                          1   (0.06%)

After selection, medical history data were obtained and all patients underwent physical examination; routine laboratory parameters (complete blood count and blood chemistry profile) were determined and electrocardiogram, chest radiographs, computed tomography of the chest and upper abdomen, computed tomography (and, in selected cases, magnetic resonance imaging) of the brain, bone scan and fiberoptic bronchoscopy were performed. Sites of distant metastases at the time of diagnosis appear in Table 3. None of the patients with liver metastases had abnormal liver enzyme activities at study entry.

 

 

Table 3. Sites of distant metastases in patients with extensive stage disease.

                                         Group A        Group B

No. of patients                      50                 36

Liver                                       7                   5

Brain                                       6                   5

Bones                                     9                 13

Pleural effusion                      1                   0

Pericardial effusion                 2                   2

Adrenal glands                        2                   3

Mediastinal lymph nodes      17                 16

Other lymph nodes               12                   9

 

The chemotherapy regimen included carboplatin (C) at an area under the curve (AUC) of 6 (calculated using the Calvert formula), administered over 30 minutes, in combination with paclitaxel (P) at a dose of either 175 mg/m2 (group A) or 190 mg/m2 (group B), administered over 3 hours. Both drugs were administered on day 1 of a 28-day cycle for up to 8 cycles. In order to prevent hypersensitivity reactions to paclitaxel, patients were pretreated with 32 mg of methylprednisolone orally, 3 hours before chemotherapy administration, and a solution containing hydrocortisone 250 mg, dexamethasone 16 mg and ondasetrone 32 mg infused intravenously over 1 hour; infusion was completed before the initiation of a chemotherapy course. For the assessment of response to treatment, toxicity and need for supportive treatment, a complete blood count was obtained on days 14 and 27 of every cycle; in addition, blood chemistry determinations as well as chest radiographs were performed on day 27. The decision to proceed to the next chemotherapy cycle was based on radiographic response, patient tolerance to chemotherapy and absence of serious toxicity.

Patients who completed six chemotherapy cycles underwent a staging procedure that included computed tomography (of the chest, upper abdomen and brain), bone scan and a new fiberoptic bronchoscopy examination (in patients with complete remission just for confirmation reasons). Patients that responded to chemothe­rapy also received radiation therapy, with the radiation field including the primary lesion and the mediastinum. The total radiation dose was 48 Gy and was administered over 3-4 weeks. Three weeks after the completion of radiation therapy, patients received two additional chemotherapy cycles. After the completion of 8 chemotherapy cycles, patients showing complete response (CR) underwent prophylactic cranial irradiation (PCI). Patients with early disease progression received the same dose of radiation therapy at an earlier stage. Additional investigations and/or palliative therapeutic interventions were applied as needed.

Patients with brain metastasis at the time of study entry received brain radiation therapy concurrently with the first cycle of chemotherapy (29 Gy over 3 weeks between day 7 and day 28 of the cycle).

Survival, time to disease progression and observed toxicity were assessed using the Kaplan-Meier method and comparisons between the two treatment groups (both for the total of the patients and separately for the patients with limited- or extensive-stage disease in each group) were made. A log-rank test was used for the statistical evaluation of the observed differences and the 95% confidence intervals (95% CI).

 

RESULTS

Response to chemotherapy

Between February 1995 and April 2000, 154 not pretreated patients with confirmed SCLC were enrolled in the study. Of them, 148 were assessable; these patients were almost equally distributed in groups A (72 patients, 4 females) and B (76 patients, 3 females). Four patients from group A and two from group B were excluded from the study due to violation of the protocol conditions. Although the distribution of the patients in the two treatment groups was not random, there were no significant differences in patient age, gender and initial performance status (PS). However, there was a difference in disease stage, with extensive disease (ED) dominating in group A and limited disease (LD) dominating in group B (Table 1).

Response to chemotherapy is shown in Table 4. Patients in group A received a total of 487 cycles of chemotherapy, with a median number of 7 cycles per patient (95% CI: 6.6-7.4). The overall response (OR) rate for all patients in group A was 66.6% (complete response [CR] rate 16.6%). The OR rate in patients with limited disease was 81.8% (CR rate 40.9%), whereas the respective rates in patients with extensive disease were 60% and 6%. Patients in group B received a total of 514 cycles of chemotherapy, with a median number of 8 cycles per patient (95% CI: 7.7-8). The OR rate for all patients in group B was 68.4% (CR rate 22.3%). The OR rate in patients with limited disease was 77.5% (CR rate 35%), whereas patients with extensive disease had an OR of 58.3% and a CR of 8.3%.

Overall median survival in group A was 270 days and in group B 300 days (Table 5). There was a borderline difference (p=0.05) in favor of group B, probably as a result of the higher percentage of patients with LD in this group. The overall median time to disease progression was 200 days in both groups. There was no significant difference in survival or time to disease progression between the two treatment groups when patients with the same disease stage (LD or ED) were separately compared.

 

Table 4. Response to chemotherapy.

                                                                     Group A                                  Group B

Chemotherapy cycles (median value)                 7                                             8

Response:

     Total of patients (%)                                    63.1                                        66.6

Limited disease: No. of patients                        22                                           40

     CR/PR (%)                                         9 (40.9)/9 (40.9)                     14 (35)/17 (42.5)

     SD/PD (%)                                          3 (13.6)/1 (4.5)                         8 (20)/1 (2.5)

Extensive disease: No. of patients                    50                                           36

     CR/PR (%)                                            3 (6)/27 (54)                         3 (8.3)/ 18 (50)

     SD/PD (%)                                           15 (30)/5 (10)                      10 (27.8)/ 5 (13.9)

CR = complete response, PR= partial response, SD= stable disease, PD= progressive disease

Table 5. Patient outcome

                                                                     Group A                                  Group B

Survival [median (95% CI)] (days)

     Total                                                    270 (222-318)                         300 (247-353)

     Limited disease                                   360 (261-459)                         335 (376-394)

     Extensive disease                               240 (197-283)                         240 (190-290)

Time to disease progression (days)

     Total                                                    200 (170-230)                         200 (180-220)

     Limited disease                                   240 (197-283)                         230 (167-293)

     Extensive disease                               180 (145-215)                         180 (151-209)

Toxicity

The main side effects of chemotherapy are listed in Table 6; they were generally mild and well tolerated. In group A, grade 3/4 neutropenia was observed in 5 (6.9%) patients, grade 3 anemia in 4 (5.5%) patients and grade 3 thrombocytopenia in 4 (5.5%) patients. In group B, there were 9 (11.8%) patients with grade 3/4 neutropenia, 7 (9.2%) patients with grade 3 anemia and 1 patient with grade 3 thrombocytopenia. Numbness in the fingers and tows was reported in 19 patients in group A and 13 patients in group B. Two patients developed more severe neurotoxicity and discontinued chemotherapy on cycle 6 and 7, respectively (these patients were included in the evaluation of the results). Systemic toxicity is shown in Table 7.

To avoid delays in the administration of a chemotherapy cycle, hematologic toxicity was appropriately treated with red blood cell transfusion and/or infusion of hemopoietic factors (erythropoietin, granulocyte-macrophage colony stimulating factor, GM-CSF).

 

 

Table 6. Chemotherapy side effects.

                                                     Group A                                Group B

                                    No. of Patients                                   No. of Cycles No. of Patients                  No. of Cycles

Anemia

     Grade 3                        4  (5.2%)               6                        7 (10.2%)             11

     Grade 4                        0                                                     1                            2

Neutropenia

     Grade 3                        5  (6.5%)               7                        9 (14.1%)             13

     Grade 4                        0                                                     2                            3

Thrombocytopenia

     Grade 3                        4  (5.2%)                                         1

Neurotoxicity

     Grade 1                      19   (25%)                                       13 (16.6%)

     Grade 3                        2                                                     0

 

 

Table 7. Chemotherapy systemic toxicity.

                                              Group A     Group B

                                             n=72 (%)    n=76 (%)

Alopecia                                 70 (97)       73 (96)

Appetite loss                         10 (13.8)    11 (14.5)

Fatigue                                  9 (12.5)     11 (14.5)

Diarrhea                                  6 (8.3)       9 (11.8)

Flushing (during infusion of P) 4 (5.5)      4 (5.2)

Allergic reaction                      4 (5.5)        4 (5.2)

(during infusion of P)

Severe bloating                      2 (2.7)        4 (5.2)

Mild fluid retention                  2 (2.7)        2 (2.6)

 

DISCUSSION

For many years treatment of SCLC remained practically unchanged, since progress in this field has been minimal. The development of new active chemotherapeutic agents such as the taxanes, has led to the implementation and assessment of new treatment strategies aiming to improve response and increase survival in patients with this deadly disease.

The present study begun in February 1995; at that time, knowledge on the effectiveness of taxanes in lung cancer and, in particular, in SCLC was still limited. Presently, paclitaxel, the first representative of this group of drugs, is one of the best studied drugs in the world, and many investigators include paclitaxel in first line regimens for SCLC. Research is continued in order to determine optimal dose and the most effective combination of paclitaxel with other antineoplastic drugs so as to optimize response of patients with SCLC.

The combination of paclitaxel (P) with carboplatin (C) has shown synergy and efficacy in SCLC11. Available data on the combination of P and C show that both agents can be safely administered in amazingly high doses. Langer et al have used P 135 mg/m2 given intravenously over 24 hours and C at an AUC of 7,5 with easily manageable myelosuppression10. Vafai et al reported that P 225 mg/m2 infused over 3 hours in combination with C at an AUC of 6 were well tolerated in patients with advanced NSCLC21. In both studies, the incidence of thrombocytopenia was lower than expected with single-agent carboplatin at comparable doses. This is probably due to some platelet protective effect, which has already been reported for the combination of P and C; a number of mechanisms have been proposed for the explanation of this effect25. Indeed, the incidence of grade 3 thrombocytopenia in our patients was only 3.3% (5/148 patients), which is comparable to that reported by Thomas et al (4%)15. Besides, only 11/148 patients developed grade 3 anemia in 17/1001 chemotherapy cycles (1.6%).

Neutropenia was the most common side effect in the study by Thomas et al (27%)15. In the present study, the overall incidence of neutropenia was only 6.5% in group A and 14.1% in group B, perhaps because chemotherapy courses were repeated every 4 instead of every 3 weeks. It should be noted, however, that the study by Thomas et al included only extensive disease patients.

In contrast with the low incidence of grade 3 alope cia (9%) reported by Thomas et al, almost all our patients (97%) developed alopecia. Another significant manifestation of toxicity in our study was peripheral neuropathy (overall incidence in group A 27.6%), which was severe in two patients (2.6%) who discontinued chemotherapy for this reason. Neurotoxicity in group A patients was treated with vitamin B6 250 mg three times daily on days 2-14 of each chemotherapy cycle; this treatment was initiated only after the onset of neurotoxicity symptoms. Patients in group B received vitamin B6 treatment (in the above described dosage regimen) from the first chemotherapy cycle. This probably explains the significantly lower incidence of neurotoxocity (17.1%) in group B despite the administration of higher paclitaxel doses in these patients. In view of this significant and clinically relevant difference, the recommendation of preventive treatment with vitamin B6 seems justified. Interestingly, 4 patients already receiving vitamin B6 developed herpes zoster with typical skin rash but without postherpetic neuralgia.

As regards response to treatment, there was no significant difference in overall response between group A (66.6%) and group B (68.4%), although the percentage of extensive disease (ED) patients in group A was unusually high (Table 4). These response rates are lower than those reported by Reck et al12 who studied 89 patients with SCLC (32 with ED among them): the use of a three drug regimen with P, C and etoposide led to an overall response rate of 82% and a median survival of 585 days compared to a 270-300 day survival in our study. However, the incidence of neutropenia with the three drug regimen was 45% (greater than three times the incidence of neutropenia in our study), although it did not cause significant problems in patient management.

In our study, ED patients showed an overall response rate of 60% in group A and 58.3% in group B. Complete response rates were 6% and 8.3% in groups A and B, respectively. These results are similar to those reported by Thomas et al15 and Deppermann et al17 (overall response 61-67%; complete response 7-10%). Furthermore, they are not different from the results of the SWOG 9705 study which included 89 SCLC patients with extensive disease who received P in combination with cisplatin and etoposide18. The median survival in this study was 11 months (3 months longer than median survival in our patients), but was accompanied by a grade 4 neutropenia incidence of 31% (twice the incidence in our study). Of 87 patients, 5 died from toxicity effects (4 from neutropenic sepsis) despite concurrent treatment with G-SCF. On the other hand, Hainsworth et al19 used the triple combination of paclitaxel, carboplatin and etoposide in SCLC patients with ED and reported particularly high overall response rates (84%).

Median survival of ED patients in our study was 8 months in both treatment groups. This survival is similar to that reported by the CALGB 9430 study (7.6 months), in which a combination of paclitaxel and cisplatin was administered every 3 weeks.

Overall response rates in LD patients were 81.8% in group A and 77.5% in group B (not significant difference). However, Hainsworth et al19, who added etoposide to the P-C combination, reported higher vales, with overall response rates in LD patients reaching 98%. Furthermore, there is a significant difference in median survival of LD patients between the two studies (12 months in our study versus 20 months in the study by Hainsworth et al). Nevertheless, the arresting results of Hainsworth et al have not been confirmed by any research group.

In our study, the use of high doses of paclitaxel in combination with carboplatin did not seem to significantly affect response and survival of patients with SCLC. The two drug combination of carboplatin and paclitaxel in ED patients yielded results similar to those obtained with previously used regimens, such as CAV (cyclophosphamide, doxorubicin, vincristine), VIP (vincristine, iphosphamide, cisplatin) and PE (a platin analog and etoposide)21-27. There is evidence in the literature that the addition of a third agent, such a etoposide, to a combination of paclitaxel/platin improves both response rates and survival of patients with SCLC, particularly those with LD. This, however, leads to a respective increase in toxicity, which appears to be manageable though19,23. Research on taxanes in various two- or three-drug combinations with standard and newer agents (e.g. camptothecines or gemcitabine) in phase II and III studies has a lot to offer and should be encouraged.

Needless to say that maybe not all specialists agree with the management of advanced SCLC using chemotherapy and radiation therapy. Our treatment choice was guided by the good performance status of the majority of our patients. Based on our experience, as well as the experience of other investigators, we believe that, in the absence of other contraindications, advanced SCLC itself should not dissuade oncologists from providing appropriate treatment. The determination of the optimum dosage regimen in such cases, with the best efficacy-toxicity profile remains an object of intensive research activity worldwide.

 

 

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