Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy

European Journal of Cancer (2013) 49, 1619– 1626

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Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy q Y. Jin a,c, X. Ye b,c, L. Shao a, B.C. Lin a, C.X. He a, B.B. Zhang a, Y.P. Zhang a,⇑ a b

Department of Medical Oncology, Zhejiang Cancer Hospital, China Department of Endocrinology, Zhejiang Provincial People’s Hospital, China

Available online 21 December 2012

KEYWORDS Metastatic nasopharyngeal carcinoma Palliative chemotherapy Serum lactic dehydrogenase

Abstract Background and objective: The survival outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ significantly between individuals. This study aimed to evaluate whether serum lactic dehydrogenase (S-LDH) level had a clinical value in predicting clinical response and survival outcome for patients with metastatic NPC. Methods: S-LDH level was measured at baseline and then before every cycle of treatment in 689 NPC patients with distant metastases. Correlations of pre-treatment and post-treatment S-LDH levels to response of treatment and survival were analysed retrospectively. Results: Patients with elevated values of pre-treatment S-LDH (>245 IU/L) had significantly worse survival than those with normal values of pre-treatment S-LDH (6245 IU/L) (P < 0.001). Patients with elevated values of post-treatment S-LDH had worse survival compared with those with normal values of post-treatment S-LDH (P < 0.001). Patients with normal values of pre-treatment and post-treatment S-LDH showed the highest response rate and the most favourable prognosis. Conclusion: S-LDH appears to be a significant independent prognostic index in patients with disseminated NPC that should be considered in the comparison of the results achieved with different therapies and in planning new randomised clinical therapeutic trials. Ó 2012 Elsevier Ltd. All rights reserved.

q Funding source: This work was supported by Zhejiang Provincial Health Bureau Foundation (Grant Nos. 2010KYA032, 2010KYA036) and Wu Jie Ping medical foundation (Grant Nos. 2011, 320.6750.11059 and 11091). ⇑ Corresponding author: Address: Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guang Ji Road, Hangzhou 310022, China. Tel./fax: +86 571 88122222. E-mail address: [email protected] (Y.P. Zhang). c These authors contributed equally to this work.

0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.11.032

1. Introduction Nasopharyngeal carcinoma (NPC) is a disease with a remarkable racial and geographical distribution. Although the incidence of NPC is very low (less than 1 per 100,000 person–years) in most parts of the world, it is a leading cancer in a few well-defined populations,

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including natives of southern China, southeast Asia, the Arctic, the Middle East and north Africa.1,2 Among head and neck cancers, NPC has the highest propensity to metastasise to distant sites. About 17–54% of patients with NPC had failed treatment due to distant metastases3,4 and systemic disease remains the major cause of death among patients with NPC.5–7 Once metastasis is diagnosed, the overall survival of the patients is never over 15 months under palliative chemotherapy.8,9 However, patients with metastatic NPC do not always behave uniformly. Several reports showed that for selected patients the overall survival had exceeded 10 years.10,11 With this discrepancy, it is desirable to identify patients with a more favourable prognosis. This knowledge may provide a more appropriate estimation of individual outcome as well as optimise patient stratification into clinical trials and therefore leads to improved assessment of such studies. Till now prognostic factors for metastatic NPC identified by several researches mainly included specific site of metastases and clinical performance status.12,13 Some laboratory parameters for survival outcome prediction in disseminated NPC, that have been reported, are haemoglobin12 and serum Epstein Barr-Virus level.14 The prognostic role of serum lactate dehydrogenase (S-LDH) has been explored in various kinds of malignancies. Elevated pretreatment S-LDH has been reported as a negative prognostic factor for survival in lymphoma,15,16 testicular cancer,17 lung cancer18 and so on. Liaw et al.19 also reported that in locoregional NPC high S-LDH level was correlated with poor survival. However, to our best knowledge, there has been limited or no research performed to explore the clinical application of S-LDH in patients with metastatic NPC in the literature currently. In this study, for the first time we investigated the prognostic value of S-LDH as a tumour marker in patients of NPC with distant metastases retrospectively. Pre-treatment and post-treatment S-LDH levels were measured in patients with disseminated NPC. Correlations of S-LDH levels to response of treatment and survival outcome were analysed.

complete follow-up data. Exclusion criteria were as follows: (i) patients with other types of malignancy; (ii) patients with brain metastases; (iii) patients with bonealone metastasis. Finally, we have been able to retrieve data for 689 patients. 2.2. Definition Metastasis at presentation was defined as patients who presented with distant metastasis while first diagnosed with NPC. It was analysed as a separate category from patients who presented with localised disease, but developed metastases at a later date. Progressionfree survival (PFS) was defined as the duration from the first diagnosis of metastasis to disease progression (newly occurring metastatic lesion, recurrence or expansion of the primary lesion). Overall survival (OS) was defined as the time from the first diagnosis of metastasis to the time of death. Patients whose deaths were not caused by cancer progression were excluded from the study. S-LDH was estimated employing the optimised standard method recommended by the German Society of Clinical Chemistry.20 S-LDH lower than 245 IU/L was considered normal, since this value corresponds to the extreme range that can be found in a normal population using the method described above. S-LDH > 245 IU/L was considered a sign of pathology. 2.3. Evaluation protocol Patients were evaluated for response every two treatment cycles during treatment and then every 3 months until death. The response evaluation of the tumour to therapy was based on computed tomography (CT) or magnetic resonance imaging (MRI) scan. The shortterm efficacy, based on Response Evaluation Criteria in Solid Tumors (RECIST), was assessed as Complete response (CR), Partial response (PR), Stable disease (SD) and Progressive disease (PD); CR and PR were regarded as treatment response. The long-term efficacy was evaluated according to the PFS and OS.

2. Patients and methods 2.4. Statistical analysis 2.1. Inclusion criteria and enrolment The charts of 1380 patients with metastatic NPC admitted to Zhejiang Cancer Hospital between January 2000 and December 2008 were reviewed. The inclusion criteria in this study consist of: (i) patients with histological confirmation of NPC; (ii) patients with radiological confirmation of distant metastatic lesion(s) and with at least one radiologically measurable lesion; (iii) patients with good performance status (Karnofsky Performance Scores P80); (iv) patients with normal renal, cardiac and liver function; (v) patients with complete baseline and post-treatment S-LDH record; (vi) patients with

Statistical analysis was performed using SPSS17.0 package. Survivals were analysed using the Kaplan– Meier method and were compared using the log-rank test. The relationship between short-term treatment efficacy and S-LDH was analysed using the Chi-Square test. Univariate and multivariable analyses were performed using the Cox proportion hazards model. P values for differences between proportions were calculated with Fisher’s exact test (two-tailed). Correlations between S-LDH level and different variables were assessed with the product moment correlation coefficient (r). Statistical significance was defined as P < 0.05.

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3. Results 3.1. Descriptive characteristics As shown in Table 1, all patients were of Chinese ethnicity with a male predominance (82.1%). The mean age of diagnosis of metastatic NPC was 45.6 years (ranging from 13 to 72 years). About one third of the patients had distant metastasis at presentation. Two hundred and eighty-six (41.5%) patients had more than one metastatic site with bone being the most common site (60.4%). The median PFS and OS were 7.9 (0.4  75.5) and 23.5 (2.0  108.0) months, respectively. The overall clinical response rate was 61.7% for all 689 patients (CR in 22 patients and PR in 403 patients). Three hundred and ten (45.0%) patients showed an increased pretreatment S-LDH. Sex and age, as well as metastases at presentation of patients, did not influence pretreatment S-LDH levels. The presence of an abnormal S-LDH level (>245 IU/L) was significantly correlated with more than one metastatic site involvement (P < 0.001, r = 0.150) and specific liver metastasis (P < 0.001, r = 0.133), as well as specific bone metastasis (P = 0.013, r = 0.094). Levels of S-LDH did not correlate with the presence of lung effusion. 3.2. Treatment An overwhelming majority (72.1%) of the patients were treated with cisplatinum-based doublets. The most frequently used regimens included cisplatin (25 mg/m2

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intravenously on days 1–3 every 21 days) plus 5-fluorouracil (600 mg/m2 intravenously on days 1–5 every 21 days) and paclitaxel (175 mg/m2 intravenously over 3 h on day 1 every 21 days) plus cisplatin (25 mg/m2 intravenously on days 1–3 every 21 cycles). One hundred and ninety-two (27.9%) patients received tri-drug combination of chemotherapy. The most frequently used regimen was paclitaxel (150 mg/m2 intravenously over 3 h on day 1 every 21 days) plus cisplatin (25 mg/m2 intravenously on days 1–3 every 21 cycles) plus 5-fluorouracil (500 mg/m2 intravenously on days 1–5 every 21 days). 3.3. Correlation between S-LDH and treatment response Mean pre-treatment S-LDH levels for all patients were 444.9 ± 25.8 IU/l (21  5295 IU/L). The response (CR and PR) rate was significantly higher in patients with a baseline S-LDH level equal to or below 245 IU/ l (CR = 19 and PR = 233) than those with a baseline S-LDH level above 245 IU/L (CR = 3 and PR = 170) (P = 0.004) (Fig. 1A). A drop of post-treatment S-LDH to a normal level at any time during treatment was noted in 483 (70.1%) patients. All 22 patients who achieved CR showed a normal post-treatment S-LDH. Seventy-three of PR and 32 of SD patients showed a drastic fall of S-LDH to normal level. The response rate was significantly higher in patients with normal post-treatment S-LDH level (CR = 22 and PR = 330) compared with those with sustained high level post-treatment S-LDH level (CR = 0 and PR = 73) (P < 0.001) (Fig. 1B).

Table 1 Increased serum lactic dehydrogenase (S-LDH) according to several variables in the 689 patients. No. of cases

Elevated S-LDH

%

r-Value

P-value

Sex Male Female

566 123

255 55

45.1 44.7

0.003

0.946

Age < 45 year P45 year

332 357

158 152

47.6 42.6

0.050

0.187

Metastasis at presentation Present Absent

227 462

100 210

44.1 45.5

0.013

0.729

Number of involved sites One Two or more

403 286

156 154

38.7 53.8

0.150

<0.001

Liver metastasis Present Absent

288 401

152 158

52.8 39.4

0.133

<0.001

Lung metastasis Present Absent

281 408

115 195

40.9 47.8

0.068

0.075

Bone metastasis Present Absent

416 273

203 107

48.8 39.2

0.094

0.013

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cific metastatic sites, metastasis at presentation, number of involved sites, pre-treatment and post-treatment SLDH level) and treatment factor (drug number of chemotherapy). In order to not miss potentially important prognostic factors, P 6 0.1 was used as the cut-off value of statistical significance for variable selection in the univariable modelling. The Cox multivariate analysis identified that only pre-treatment S-LDH level (HR = 1.595, P < 0.001) and post-treatment S-LDH level (HR = 2.935, P < 0.001) were independent prognostic factors for overall survival (Table 2).

3.6. Combination of the pre-treatment and post-treatment S-LDH status Patients were divided into four subgroups according to the pre-treatment S-LDH level and the post-treatment S-LDH level: (1) elevated pre-treatment S-LDH and elevated post-treatment S-LDH (307 patients); (2) elevated pre-treatment S-LDH and normal post-treatment S-LDH (72 patients); (3) normal pre-treatment SLDH and elevated post-treatment S-LDH (176 patients); (4) normal pre-treatment S-LDH and normal post-treatment S-LDH (134 patients). Median PFS for these four subgroups was 8.5, 4.1, 6.5 and 3.5 months, respectively (P < 0.001). Median OS was 26.5, 15.0, 21.0 and 8.5 months, respectively (P < 0.001) (Fig. 3).

4. Discussion Fig. 1. (A) Pre-treatment serum lactic dehydrogenase (S-LDH) level and tumor response to chemotherapy are shown (chi-square test, P = 0.004. (B) Post-treatment S-LDH level and tumor response to chemotherapy are shown (chi-square test, P < 0.001).

3.4. Correlation between S-LDH and survival outcome Till now, all of the 689 patients’ overall-survival data were obtained. The median PFS and OS in patients with a normal baseline S-LDH level were significantly longer than those with elevated S-LDH level (median PFS was 7.9 versus 5.5 months, P < 0.001; median OS was 22.5 versus 14.5 months, P0.001) (Fig. 2A and B). The same results were obtained in the relationship between post-treatment S-LDH and survival outcome. The median PFS and OS in patients with a normal post-treatment S-LDH level were significantly longer than those with elevated S-LDH level (median PFS was 7.5 versus 3.5 months, P < 0.001; median OS was 23.5 versus 12.0 months, P < 0.001) (Fig. 2C and D). 3.5. Prognostic factors for survival outcome Factors that were incorporated into analysis included patient factors (age group, gender), disease factors (spe-

Lactate dehydrogenase catalyses the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. It converts pyruvate, the final product of glycolysis, to lactate when oxygen is absent or in short supply and it performs the reverse reaction during the Cori cycle in the liver.21 Many different types of cells in the body contain this enzyme. Some of the organs relatively rich in LDH are the heart, kidney, liver and muscle. Although LDH is abundant in tissue cells, blood levels of the enzyme are normally low. However, when tissues are damaged by injury or disease, they release more LDH into the bloodstream. Conditions that can cause increased LDH in the serum include tissue injury as inflammatory conditions, degenerative processes, toxicity or malignancies.22–24 The increased activity of S-LDH in cancer patients is attributed to the release of enzymes from malignant cells.25 Elevation is most frequently encountered in patients with certain malignancies such as leukaemia, lymphoma and malignant germ-cell tumours.26,27 Till now, clinical application of the S-LDH in patients with NPC is rarely mentioned. This is the first time the prognostic role and the dynamic-changes’ significance of SLDH in patients with disseminated NPC have been

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Fig. 2. (A) Kaplan–Meier progression-free survival curves are shown according to the baseline serum lactic dehydrogenase (S-LDH) level. P < 0.001. (B) Kaplan–Meier overall survival curves are shown according to the baseline S-LDH level. P < 0.001. (C) Kaplan–Meier progressionfree survival curves are shown according to the post-treatment S-LDH level. P < 0.001. (D) Kaplan–Meier overall survival curves are shown according to the post-treatment S-LDH level. P < 0.001.

Table 2 Univariate and multivariate analyses for overall survival. Factors

Sex: male or female Age:<45 year or P45 year Metastasis at presentation: present or absent Lung metastasis: present or absent Pre-treatment S-LDH level: normal or elevated Post-treatment S-LDH level: normal or elevated Drug number of chemotherapy: two or three Number of involved sites: 1 or P1 Liver metastasis: present or absent Bone metastasis: present or absent

Univariate analysis

Multivariate analysis

P

HR (95% CI)

P

HR (95% CI)

0.893 0.330 0.091 0.988 <0.001 <0.001 0.782 0.670 0.941 0.949

0.980(0.803–1.195) 1.079(0.926–1.257) 1.154(0.977–1.362) 0.999(0.854–1.168) 1.591(1.357–1.866) 2.967(2.477–3.554) 0.976(0.825–1.156) 0.944(0.726–1.229) 0.991(0.788–1.248) 1.008(0.798–1.273)

<0.001 <0.001

1.595(1.362–1.867) 2.935(2.456–3.508)

S-LDH, serum lactic dehydrogenase; HR, hazard ratio; 95%CI, 95% confidence interval.

explored. A relatively large cohort of people was included in this study.

In our report, the presence of an elevated S-LDH level (>245 IU/L) was significantly correlated with spe-

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Fig. 3. (A) Kaplan–Meier progression-free survival curves are shown according to the combination of pre-treatment and post-treatment serum lactic dehydrogenase (S-LDH) level. (B) Kaplan–Meier overall survival curves are shown according to the combination of pre-treatment and posttreatment S-LDH level.

cific bone metastasis and specific liver metastasis, as well as more than one metastatic site involvement. Sagman et al. have reported that in patients with small-cell lung cancer, levels of S-LDH were positively correlated with both liver and bone metastasis.28 Several other researches have also demonstrated that elevated S-LDH levels are usually seen in metastatic liver tumour,25,29 although no clear reason has been established. In neoplasia, elevation of S-LDH may reflect

the release of the enzyme secondary to inflammation or tumour necrosis, higher levels correlating with not only tumour mass but also tumour aggressivity. In addition, our results showed that levels of S-LDH did not correlate with the presence of lung effusion. Further studies should be done to clarify the mechanism. Since NPC is a chemosensitive tumour, we found that S-LDH could serve as a marker to reflect the regression or progression during chemotherapy in patients with

Y. Jin et al. / European Journal of Cancer 49 (2013) 1619–1626

disseminated NPC. All 22 patients who achieved CR showed a normal post-treatment S-LDH. The response rate was significantly higher in patients with a drastic fall of S-LDH to normal level after chemotherapy compared with those with sustained high level post-treatment S-LDH level. Elevations of S-LDH levels have been found to reflect growth and regression of various malignant neoplasms. When tumour size was measured in 91 patients with various solid tumours, there was almost invariably a fall in the LDH level as tumour masses responded to therapy versus a rise in LDH as tumour growth resumed from relapse in therapy.30 Elevated serum levels of LDH have been associated with poor prognosis in several types of neoplasms.31,32 Turen et al.33 have also reported that high serum LDH level is an independent unfavourable risk factor for OS in patients with locoregionally advanced NPC. Our results were consistent with those reports. The median PFS and OS in patients with a normal pre-treatment S-LDH level were significantly longer than those with elevated pretreatment S-LDH level. The same results were observed in correlation between post-treatment S-LDH level and survival outcome. The Cox proportional hazard regression model revealed that only pre-treatment S-LDH level and post-treatment S-LDH level were independent prognostic factors for overall survival. Notably, when S-LDH was considered in analysis, liver and lung metastasis were no longer the independently negative factors as described by Ong et al.12 and Teo et al.13 As we reported previously,34 one reasonable explanation is that S-LDH can reflect tumour burden more sensitively and precisely than specific site of metastases. Even in the specific groups with liver metastasis or lung metastasis, there still exist patients with relatively good prognosis as Hui et al.11 reported. Additionally, the different sizes and quantity of the lesions may have different prognostic implications. Numerous, large lesions may represent a more extensive spread than fewer and smaller lesions. Therefore, we think it is rational that SLDH level but not liver or lung metastasis stood out to be independent prognostic factors for overall survival. After we determined the prognostic value of pretreatment and post-treatment S-LDH, we further separate the patients into four subgroups with different survival outcomes by analysing pre-treatment and posttreatment S-LDH in combination. Our result demonstrated that the combination of pre-treatment and post-treatment S-LDH was able to discriminate patients with good prognosis from those with poor prognosis in metastatic NPC. Generally speaking, S-LDH is a useful marker to predict survival and monitor response to chemotherapy for disseminated NPC. Of benefit is the fact that it is a simple inexpensive hospital test that is easily available with

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quick results. In addition, different from the prognostic value of Epstein–Barr virus which is majorly used for WHO II and III NPC, S-LDH is feasible not only for patients with NPC in endemic areas, but also for those in non-endemic areas. The role of the funding source Y.P. Zhang supported the fee of data acquisition and statistical analysis of this study. Conflict of interest statement None declared. Acknowledgements This work was supported by Zhejiang Provincial Health Bureau Foundation (Grant Nos. 2010KYA032, 2010KYA036) and Wu i.e. Ping medical foundation (Grant Nos. 2011, 320.6750.11059 and 11091). Reference 1. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15(10):1765–77. 2. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 2002;12(6):421–9. 3. Liu MT, Hsieh CY, Chang TH, et al. Prognostic factors affecting the outcome of nasopharyngeal carcinoma. Jpn J Clin Oncol 2003;33(10):501–8. 4. Chiesa F, De Paoli F. Distant metastases from nasopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec 2001;63(4):214–6. 5. Leung SF, Teo PM, Shiu WW, Tsao SY, Leung TW. Clinical features and management of distant metastases of nasopharyngeal carcinoma. J Otolaryngol 1991;20(1):27–9. 6. Tao Y, Bidault F, Bosq J, Bourhis J. Distant metastasis of undifferentiated carcinoma of nasopharyngeal type. Onkologie 2008;31(11):574–5. 7. Gunn GB, Villa RD, Sedler RR, Hardwicke F, Fornari GA, Mark RJ. Nasopharyngeal carcinoma metastasis to the pituitary gland: a case report and literature review. J Neurooncol 2004;68(1):87–90. 8. Razak AR, Siu LL, Liu FF, Ito E, O’Sullivan B, Chan K. Nasopharyngeal carcinoma: the next challenges. Eur J Cancer 2010;46(11):1967–78. 9. Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastatic nasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128(2):79–85. 10. Fandi A, Bachouchi M, Azli N, et al. Long-term disease-free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type. J Clin Oncol 2000;18(6):1324–30. 11. Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 2004;101(2):300–6. 12. Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic nasopharyngeal carcinoma. Eur J Cancer 2003 Jul;39(11):1535–41. 13. Teo PM, Kwan WH, Lee WY, Leung SF, Johnson PJ. Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 1996;77:2423–31.

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