Medical Oncology

, Volume 28, Supplement 1, pp 570–576

Short-term outcomes of cetuximab combined with standard chemotherapy as first line setting for Chinese patients with non-small cell lung cancer: a report of 12 cases

Authors

  • Liang-Ping Xia
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Hui-Juan Qiu
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Xu-Xian Chen
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Pi-Li Hu
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Gui-Fang Guo
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Fang Wang
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Fei-Fei Zhou
    • Tumor Center, The Foshan First People’s Hospital
  • Wen-Zhuo He
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
  • Bei Zhang
    • State Key Laboratory of Oncology in South China
    • VIP Region, Sun Yat-sen University Cancer Center
    • State Key Laboratory of Oncology in South China
    • Department of Medical OncologySun Yat-sen University Cancer Center
Original Paper

DOI: 10.1007/s12032-010-9709-7

Cite this article as:
Xia, L., Qiu, H., Chen, X. et al. Med Oncol (2011) 28: 570. doi:10.1007/s12032-010-9709-7
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Abstract

Cetuximab combined with chemotherapy has been used to treat Non-small cell lung cancer (NSCLC) in recent years, however, the data from China was rare. This study was to summarize our experiences in treating NSCLC patients with cetuximab in the first line setting. From October 1st 2006 to Jun 30th 2010, twelve NSCLC patients were treated with cetuximab combined standard chemotherapy as first line setting in Sun Yat-sen University Cancer Center entered the study and the short-term efficacy and safety were analyzed. A total of 132 cycles of cetuximab treatment, with a median of nine cycles in the whole group were administered. The ORR was 41.7% (5/12), DCR was 83.3% (10/12), median TTP was 5.5 months (2–23), and median OS was 9 months (2–48) in the whole group. There were 75% (9/12) patients occurred acne-like rash within first 3 weeks, their ORR was 55.6% (5/9), DCR was 100% (9/9), however, ORR and DCR in patients who didn’t occurred acne-like rash within first 3 weeks were 0 and 33.3% (1/3), the difference ORR between two group was insignificant (P = 0.091), however, DCR was significant different (P = 0.007). There no treatment-associated death and no cetuximab-associated discontinuation. The incidence of acne-like rash was 83.3% (10/12) and 75% (9/12) occurred within first 3 weeks, there were eight patients suffered side effects associated with chemotherapy. So we can draw a conclusion that the short-term outcome of cetuximab application in first line setting for patients with NSCLC were promising since the higher ORR and DCR, especially those occurred acne-like rash within the first 3 weeks, and the addition of cetuximab in this population was safe.

Keywords

CetuximabNon-small cell lung cancerEfficacySafetyFirst lineChemotherapy

Abbreviations

NSCLC

Non-small cell lung cancer

CR

Complete response

PR

Partial response

SD

Stable disease

PD

Progression disease

ORR

Overall response rate

DCR

Disease control rate

TTP

Time to progression

OS

Overall survival

EGFR

Epidermal growth factor receptor

TKIs

Tyrosine kinase inhibitors

FLEX

First-line treatment for patients with EGFR-EXpressing advanced NSCLC

ASCO

American Society of Clinical Oncology

NCCN

National Comprehensive Cancer Network

WCLC

World Conference on Lung Cancer

Introduction

It is consensus that both erlotinib and gefitinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, are promising therapeutic targets in first line setting if EGFR mutation [13], second line setting regardless the EGFR status [4, 5], and even improve survival as maintenance therapy immediately after chemotherapy with platinum-based doublets in non-small-cell lung cancer (NSCLC) [6, 7]. Cetuximab, an anti-EGFR immunoglobulin G1 monoclonal antibody which works on the EGFR pathway too, has shown activity in clinical trails which given in combination with the standard platinum-based doublets regimens for patients with NSCLC in the first line setting [816]. Furthermore, both of the two meta-analysis studies [17, 18] and one summary [19], based on some important clinical trails, demonstrated again the benefit after the addition of cetuximab. However, the application of cetuximab in patients with NSCLC having faced challenge since FLEX trail revealed its result in ASCO 2008 [20], and the indication of recommendations of cetuximab by NCCN guideline changed from 2009 as “if met criteria” to 2010 as “2B” which means the category of evidence decreased even after the report of meta-analysis in WCLC 2009 [17]. Maybe, those are claiming for more data of cetuximab in NSCLC. Furthermore, the efficacy of TKIs were different between West NSCLC patients and East NSCLC patients that only Asian patients can get OS benefit [4, 5]. Does cetuximab, the monocolonal antibody of EGFR, face the same question as TKIs between West NSCLC patients and East NSCLC patients? However, the study of cetuximab on Chinese patients with NSCLC was rare [21, 22]. So, it is urgent to summarize the data of cetuximab used in Chinese patients with NSCLC. Thereafter, we collected 12 patients with NSCLC treated with cetuximab combined with standard chemotherapy as first line setting in Sun Yat-sen University Cancer Center in the purpose to analyze short-term efficacy and safety.

Materials and methods

Eligibility of patients

The criteria of eligibility: (1) All patients had pathological diagnosis of NSCLC; (2) Only the patients treated from Oct. 1st 2006, the marketing time of this medicine, to Jun 30th 2010 in Cancer Center of Sun Yat-sen University were screened; (3) The patients were treated by combination of cetuximab and standard first line cytotoxic regimens for NSCLC; (4) With complete clinical and pathological data. Total of 18 cases were found in the database, and 6 patients were excluded from analysis since one patient lost follow-up after accepting one cycle cetuximab, one patient accepted radiotherapy before cetuixmab treatment and also received heavy iron radiation after cetuximab treatment though with stable disease for 3 months after two cycles of cetuximab, and other 4 patients are ongoing treatment.

Evaluation of efficacy and safety

The short-term effect were evaluated by the independent group based-on criterion of RESIST: complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD). In principle, all the patients test by CT which covered all lesions every two cycles. And the adverse events, divided into cytotoxic agent-related side effects and cetuximab-related side effects, were evaluated according to the standards of NCI-CTC with category of 0 to IV.

Clinical data

The characteristics of all the 12 patients with NSCLC were listed in Table 1. There were 2 patients with squamous cell carcinoma and 10 patients with adenocarcinoma. The regimens included Gemcitabine + Cisplatin/Carboplatin for 2 patients, Norvelbine + Cisplatin for 1 patients, Pemetrexed + Cisplatin/Carboplatin for 7 patients, and Taxol + Carboplatin for 1 patient. There was one patients treated with single cetuximab also entered this study since the original plan was designed as pemetrexed + carboplatin + cetuximab, however, only cetuximab was administered since pneumonia.
Table 1

The basic characteristics of the 16 patients

Patients’ number

Gender

Age (years)

Initial stage

Pathological type

Line setting

Regimens

Cycles of chemotherapy

Cycles of cetuximab

Efficacy

TTP (months)

Status

Acne-like rash (time λ)

OS¥ (months)

1**

Male

71

T1N2M0§

Adeno-*

1

Cetuximab

0

3

SD

2

Died

Yes/<3

5/48

2

Male

61

T1N1M1

Adeno-

1

GC

4

12

SD

6

Died

Yes/<3

9/12

3

Male

54

T2N3M1

SCC

1

GP

7

21

Good PR

23

Alive

Yes/<3

23/24

4

Male

67

T3N2M1

SCC

1

NP

6

26¢

Good PR

5@

Died

Yes/<3

7/8

5

Male

48

T4N3M0

Adeno-

1

Peme + Carbo

3

9

CR

14

Alive

Yes/<3

14/14

6

Male

75

T4N3M0

Adeno-

1

Peme + Carbo

4

PR

2

Died

Yes/<3

4/4

7

Male

43

T4N2M1

Adeno-

1

Peme + DDP

6

SD

12

Alive

Yes/<3

12/12

8

Male

63

T3N2M1

Adeno-

1

Peme + DDP

2

6

PD

Died

No

3/3

9

Male

58

T2N2M1

Adeno-

1

Peme + DDP

4

12

SD

10

Alive

No

10/10

10

Male

52

T4N1M0

Adeno-

1

Peme + DDP

3

9

SD

2

Alive

Yes/<3

5/6

11

Male

50

T1N2M1

Adeno-

1

Peme + DDP

6

18

PR

5

Alive

Yes/<3

5/5

12

Male

71

T × N×M1

Adeno-

1

TC

2

6

PD

Died

Yes/=4

2/2

Adeno-: Adenocarcinoma; SCC: squamous cell carcinoma; Adeno-squamous-: Adeno-squamous-carcinoma; ** Pemetrexed + Carboplatin regimen was recommended to patient No. 1, single cetuximab was given since the pneumonia which prevent chemotherapy; §: The patient with invasion of sternal bone and extensive pleural metastasis when recurrence; £: Cetuximab was administrated every 3 week; ¢: Cetuximab was used as maintenance therapy weekly after the end of chemotherapy; ¥: from cetuximab given /from diagnosis; GC: Gemcitabine + Carboplatin; GP: Gemcitabine + Cisplatin; TC: Taxol + Carboplatin; NP: Norvilbine + Cisplatine; λ: time of occurring acne-like rash(weeks); @ Progression in brain, however, primary tumor controlled well, and patient died of pneumonia

The administration of cetuximab

Cetuximab was intravenously infused at a starting dose of 400 mg/m2 over 2 h on day 1, and from day 8 onwards at a dose of 250 mg/m2 over 1 h per week. Premedication with an antihistamine drug (diphenhydramine) and Cimetidine were mandatory before the first infusion and was recommended for all further infusions. Cetuximab was infused before chemotherapy on days when both treatments were given [8, 23]. All patients accepted cetuximab weekly except two patients whose cetuximab was administered every 3 week accompanied with chemotherapy since refusing from patients. And the standard chemotherapy regimens were administered on standard schedule.

Statistics

The Chi-square test was used to calculate the ORR and DCR between the patients weather or not occurred acne-like rash within the first 3 weeks after giving cetuximab. And Pearson Chi-Square test was adopted due to the small sample size.

Follow-up

All the 12 patients followed up closely, and the last follow-up time was Jun 30th 2010. No patient lost follow-up. There were 6 patients had died and another 6 patients are still alive.

Results

A total of 132 cycles of cetuximab with a median cycle of 9 were administered, the range from 3 to 26 cycles. And the efficacy and side effects were listed in Tables 1 and 2. There no treatment related death, only two kinds of adverse evince were studied which include the cetuximab related acne-like rash, hypomagnesemia, and the cytotoxic agents related hematology and function of liver and kidney.
Table 2

The side effects of cetuximab-contained regimens

Patients’ number

Cytotoxic agents related side effects

Cetuximab related side effects (Acne/allergic reactions/Hypomagnesemia/nail change)

1

No

Degree 2 rash within 3 weeks

2

Neutropenia, degree 3; thrombopenia, degree 4; Liver function damage, degree 1

Degree 1 rash within 3 weeks

3

Neutropenia, degree 3

Degree 2 rash within 3 weeks

4

Neutropenia, degree 1; Liver function damage, degree 1

Degree 1 rash within 3 weeks

5

Neutropenia, degree 1

Degree 3 rash within 3 weeks

6

No

Degree 1 rash within 3 weeks

7

Stomatitis degree 3

Degree 2 rash within 3 weeks

8

No

No

9

No

No

10

Liver function damage, degree 1

Degree 4 rash within 3 weeks

11

Fatigue degree 3; Liver function damage, degree 1

Degree 3 rash within 3 weeks, degree 1 hypomagnesemia and severe parionychia of the toes occurred

12

Thrombopenia, degree 2

Degree 2 rash at the fourth week

The efficacy

There were 1, 4, 5, and 2 patients got CR, PR, SD, and PD, respectively. ORR was 41.7% (5/12), and DCR was 83.3% (10/12). The median TTP was 5.5 months (ranged from 2 to 23 months), the median OS was 9 months (ranged from 2 to 48 months).

Relationship between efficacy and acne-like rash

There were 9 (75%) patients occurred acne-like rash within first 3 weeks, among them there were 1, 4, and 4 patient(s) got CR, PR, and SD, respectively. And the ORR was 55.6% (5/9) and DCR was 100% (9/9) in this population; There were 3 patients didn’t occurred acne-like rash within first 3 weeks, only SD (n = 1) and PD (n = 2) were observed and the ORR, DCR were 0 and 33.3% (1/3) among this population. DCR between patients whether or not occurred acne-like rash within first 3 weeks were significant different (P = 0.007), however, the difference of ORR was insignificant (P = 0.091). And median TTP and median OS were 5 months (2–23 months) and 12 months (4–48 months) in patients occurred acne-like rash within first 3 weeks, median OS was 3 months (2–10 months) in patients didn’t occurred acne-like rash within first 3 weeks.

Adverse events

Total of 132 cycles of cetuximab and 77 cycles cytotoxic chemotherapy were administered, there were 10(83.3%) patients occurred acne-like rash, and 9(75%) patients occurred within the first 3 weeks among them. There were 3, 4, 2, and 1 patient(s) suffered rash with degree 1, 2, 3, and 4, respectively, and among them, 1 patient with degree 2 rash occurred after first 3 weeks. There was 1 patients suffered hypomagnesemia and who without symptoms and untreated. The side effects related to cytotoxic agents included 8 patients and most of them were tolerable.

Classical case

The No. 11th patient with left NSCLC (adenocarcinoma, T2N2M1) with extensive metastasis to the mediastinal lymph nodes, right pulmonary hilar lymph nodes, brain, liver, right adrenal gland, nodule subcutaneous in the left thigh, extensive bones (Fig. 1). The pathological examination shown that the tumor featured as more than 90% cells with two copy of EGFR, the EGFR mutation was unavailable due to insufficiency of tissue. The nodule subcutaneous of the left thigh shrunk in 3 days after administration of the combined regimen, both the primary tumor in the lung and metastastic lesion in brain reached good PR, tumor markers included of CA125, CA199, and CA153 decreased too (Fig. 2), however, the hypomagnesemia occurred too during the treatment (Fig. 3), the side effect included the grade 3 acne-like rash which occurred at the 5th day after addition of cetuximab and severe parionychia of the toes occurred.
https://static-content.springer.com/image/art%3A10.1007%2Fs12032-010-9709-7/MediaObjects/12032_2010_9709_Fig1_HTML.jpg
Fig. 1

All lesions changed before and after cetuximab-contained chemotherapy in the classical patient. The symbol of alphabet and number of A1-3 ~ I1-3 means that alphabet stand for the site of lesion, and number means the timing of images taken that 1, 2, and 3 stand for the timing of before chemotherapy, after two cycles of chemotherapy, and after six cycles of chemotherapy. The primary cancer in the right lung (A1), metastatic lesions in left adrenal gland (B1), right thighbone (C1), level IV lymph node in the right neck (D1), No. 8 thoracic vertebra (E), mediastinal lymph nodes (F1), nodule subcutaneous in the left thigh (G), liver (H1), and brain (I1); Except the lesions in the bones, all the lesions shown by PET-CT or MRI reached PR/good PR

https://static-content.springer.com/image/art%3A10.1007%2Fs12032-010-9709-7/MediaObjects/12032_2010_9709_Fig2_HTML.gif
Fig. 2

The changes of tumor markers of the classic patients during treatment period. The tumor markers, included CA125, CA153, and CA199, showed a trend of decreasing with the administration of cetuximab-contained regimen. Especially, the CA125, which was 2398 U/ml before treatment, decreased to the normal level 1 month after end of chemotherapy

https://static-content.springer.com/image/art%3A10.1007%2Fs12032-010-9709-7/MediaObjects/12032_2010_9709_Fig3_HTML.gif
Fig. 3

The changes of blood concentration of magnesemia of the classic patients during treatment period. Hypomagnesemia was the unique side effect of cetuximab, and also a symbol of effectiveness of cetuximab. The concentration of magnesemia, at normal level before treatment, decreased step by step and increased nearly to the normal level again 1 month after discontinuation of cetuximab

Discussion

Though small molecule compounds TKIs (Tyrosine kinase inhibitors) can produce OS up to 20–30.5 months if tumor bearing EGFR mutation [13], however, only about 17.1% patients can benefit from this treatments since the lower incidence of EGFR mutation (60% in Asian patients and 10% in West patients) and low proportion of patients provided sufficient sample for EGFR mutation test [2], also, the high price of the drug limited the use in clinic too, all of those encourage scientists to attempt new regimens. Though the activity of cetuximab when given in combination with chemotherapy in preclinical studies [24, 25], clinical trails [816], pooled summary [19], and meta-analysis [17, 18] were fully demonstrated in West population, and though the cetuximab were successfully applied in Chinese patients with colorectal cancer [26] and head and neck squamous cell carcinoma(HNSCC) [23], however, the challenges faced by cetuximab [20], experiences lacked in Chinese patients with NSCLC [21, 22], and the different effective of TKIs between West NSCLC patients and East NSCLC patients required urgently more data collection, especially the data of cetuximab used in Chinese patients with NSCLC.

The attempt of cetuximab in colorectal cancer was started from the irinotecan refractory patients [27], however, the attempt of cetuximab in NSCLC was begun from the first-line setting. The poor prognosis of NSCLC may require new drug attempt urgently may explain the reason why attempt was different between colorectal carcinoma and NSCLC though the real reason was unknown. The efficacy and safety had been demonstrated completely in four randomized clinical trails [8, 12, 13, 16] and two meta-analysis [17, 18], especially the meta-analysis presented in WCLC 2009 which based on the individual patient dada that all of ORR, PFS, and OS were improved after the addition of cetuximab to the standard first line regimens [17]. In our study, the ORR, DCR, median TTP, and median OS were 41.7%, and 83.3%, 5.5, and 9 months, respectively, which was similar as the west studies. And the promising results without more side effects as demonstrated in meta-analysis conducted by Liu et al. [18] that only the cetuximab related side effects appeared, however, without the addition of hematological side effects.

The challenges of cetuximab use in Chinese patients should not be ignored. First of all, how to predict the efficacy of cetuximab in NSCLC patients was the key problem facing by doctors and patients worldwide. The EGFR FISH(fluorescent in situ hybridization) had throw some light on this issue, that patients with high EGFR FISH will have longer PFS [28], however, the EGFR protein test by IHC(immunohistochemistry), EGFR mutation, EGFR FISH and Kras gene mutation all haven’t the ability to predict the ceutixmab efficacy based on data from BMS 099 trail [29]. However, the acne-like rash whether or not appeared within first 3 weeks shown potential power to predict the usefulness of cetuximab in NSCLC patients that patients appeared rash within first 3 weeks will have a higher ORR and DCR just accordance with the data from FELX trail [30]. However, the predictive role of rash severity were controversial in studies, as for local advanced HNSCC who were treated with combination of cetuximab and radiotherapy, overall survival was significantly improved in those who experienced an acne-form rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34–0.72; P = 0.002) [31], however, the situation may different from colorectal cancer where, though, more man than women and more younger than older patients developed severe rash, the rash failed to predict the efficacy of cetuximab [32]. Second, should cetuximab be used as maintenance therapy after the end of cytotoxic chemotherapy? This was difficult to conduct in Chinese patients with NSCLC since the expensive drug which was not covered by medical insurance, and administration of cetuximab weekly may cause inconvenience for most of patients who come from countryside. In our study, only 2 in 12 patients accepted maintenance therapy of cetuximab, in other word, 10 in 12 patients only accepted cetuximab during the period of cytotoxic agent giving. The efficacy may demonstrate that the usage of cetuximab during period of chemotherapy also useful though the survival curves in FELX divided during the period of maintenance therapy [8]. Of course, the efficacy of cetuximab given just in period of chemotherapy should be demonstrated in randomized clinical trails with large patient population. Finally, which regimen was the optimal regimen can combine with cetuximab in first line setting for patients with NSCLC. There no head-to-head comparison focused on this issue available now, however, all the standard cytotoxic regimens in first line setting of NSCLC was attempted in clinical trails and all of them shown benefit in some degree. As used in this study, cetuximab combined pemetrexed plus cisplatin/carboplatin accounted for 63.6% (7/11) since the pemetrexed-based regimen shown priority in adenocarcinoma [33].

Conclusions

All the 12 Chinese patients with NSCLC in this study were advance stage or recurrent cancer, however, the ORR, DCR, median TTP, and median OS were 41.7%, and 83.3%, 5.5, and 9 months, repectively, after addition of cetuximab during period of chemotherapy, almost without cetuximab maintenance therapy. The side effects were tolerable and without excess incidence expect for the cetuximab-related acne-like rash.

Acknowledgments

All the doctors who conducted the cetuximab-contained regimen treatment and all patients received this kind treatment in this paper were appreciated. This work was supported by Grants: Major Science and Technology Project of “national significant new drug creation” (2008ZX09312 - 002) and National Nature Science Fund (81071872).

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