|Year : 2017 | Volume
| Issue : 6 | Page : 930-935
Quantitative determination of tumor platinum concentration of patients with advanced Breast, lung, prostate, or colorectal cancers undergone platinum-based chemotherapy
Hesameddin Mostaghimi1, Ali Reza Mehdizadeh1, Mohammad Jahanbakhsh2, Amir Reza Dehghanian3, Ramin Askari4
1 Department of Biomedical Physics and Engineering, School of Medicine, Shiraz University of Medical Sciences, Shiraz; Advanced Health Technologies Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Biomedical Physics and Engineering, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
3 Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
4 Chemistry Department, Islamic Azad University of Firouzabad, Firouzabad, Iran
|Date of Web Publication||13-Dec-2017|
Dr. Ali Reza Mehdizadeh
Department of Biomedical Physics and Engineering, School of Medicine, Shiraz University of Medical Sciences, Shiraz; Advanced Health Technologies Research Center, Shiraz University of Medical Sciences, Shiraz
Source of Support: None, Conflict of Interest: None
Context: Previous studies have reported direct relationship between tumor reduction and its platinum concentration following platinum-based (Pt-based) chemotherapy. However, quantitative data of tumor platinum concentration have not yet been reported for the most common cancers.
Aims: Determination of tumor platinum concentration of breast, lung, prostate, and colorectal cancers after Pt-based chemotherapy; and evaluation of the influence of chemo drug type, chemotherapy regimen, and time lapse from last chemotherapy on tumor platinum concentration.
Materials and Methods: Tumor samples of patients with advanced breast, lung, prostate, and colorectal cancers undergone Pt-based chemotherapy were collected from pathology collection of various hospitals. The platinum concentration of each sample was measured by inductively coupled plasma optical emission spectrometry. The data were categorized by drug type, time lapse from last chemotherapy, and regimen type to evaluate their effects on platinum concentration.
Statistical Analysis: ANOVA, Mann–Whitney U and Kruskal–Wallis tests were used.
Results: Tumor platinum concentrations of breast, lung, prostate, and colorectal cancers were all obtained in the range of 1–10 μg/g tumor tissue. Large values of P (>0.05) indicate no significant differences between various chemo drug, regimen, and time groups.
Conclusions: In general, the platinum concentration was higher in prostate and lower in lung tumors. The type of Pt-based chemo drug, time lapse from the last chemotherapy, and concurrency of other antineoplastic agents administered with Pt-based chemo drugs had no significant effect on tumor platinum concentration.
Keywords: Breast cancer, colorectal cancer, lung cancer, platinum concentration, prostate cancer
|How to cite this article:|
Mostaghimi H, Mehdizadeh AR, Jahanbakhsh M, Dehghanian AR, Askari R. Quantitative determination of tumor platinum concentration of patients with advanced Breast, lung, prostate, or colorectal cancers undergone platinum-based chemotherapy. J Can Res Ther 2017;13:930-5
|How to cite this URL:|
Mostaghimi H, Mehdizadeh AR, Jahanbakhsh M, Dehghanian AR, Askari R. Quantitative determination of tumor platinum concentration of patients with advanced Breast, lung, prostate, or colorectal cancers undergone platinum-based chemotherapy. J Can Res Ther [serial online] 2017 [cited 2019 Nov 14];13:930-5. Available from: http://www.cancerjournal.net/text.asp?2017/13/6/930/208748
| > Introduction|| |
According to the World Health Organization, malignant neoplasms are one of the leading causes of death around the world., Since the occurrence of cancers increases by population aging, it is predicted that 70% of malignancies occur among people older than 65 years until 2030. The most common and lethal malignancies are lung, colorectal, prostate, and breast cancers. Prostate and breast cancers are the most common and lethal malignancies among men and women, respectively; while colorectal cancer is the second deadliest after lung cancer in both groups.,, Platinum-based (Pt-based) chemo drugs such as cisplatin, carboplatin, and oxaliplatin are generally the most important candidates for chemotherapy. Cisplatin is used in the treatment of almost 85% of different cancers. Pt-based chemo drugs are also beneficial to enhance the effect of radiotherapy., Nowadays, concurrent chemo-radiotherapy has become a common treatment modality superior and more efficient than sequential therapies., Due to platinum properties and its definite effects on DNA damage and apoptosis, concurrent chemo-radiotherapy is performed using mentioned Pt-based chemo drugs. Some studies have reported the affiliation of antineoplastic effects and tumor platinum accumulation so that more platinum concentration would increase tumor reduction., Although multiple statistical studies concerning concurrent chemo-radiotherapy with Pt-based chemo drugs have reported positive effects in tumor response and survival rate,,,,,,,,,,, quantitative analysis of platinum effects on dose enhancement is not practically possible due to lack of clinical data of platinum concentration;, while the application of novel methods and drugs (selective local therapy, cisplatin nanocarriers NC6004, multinuclear triplatin BBR3464, and bisplatinum),, increases the platinum concentration and the importance of its effect on dose change. Therefore, according to the prevalence of mentioned cancers and chemo drugs, it is essential to determine tumor platinum concentration of patients with advanced breast, lung, prostate, or colorectal cancers undergone Pt-based chemotherapy.
| > Materials and Methods|| |
A total of 0.5 g samples of malignant tumors of patients with breast, lung, or colorectal cancers undergone neoadjuvant Pt-based chemotherapy with carboplatin, cisplatin, or oxaliplatin in combination with other antineoplastic agents (through trastuzumab, carboplatin (TCH), EP, or m-FOLFOX regimens) were gathered from pathology collection of various hospitals of Shiraz University of Medical Sciences (SUMS). Compliance with ethical principles related to patient's rights and privacy, each sample is stored in pathology collection with complete patient records. Prostate tumor samples were collected from patients with metastatic castration-resistant prostate cancer participated in a pilot study with administration of carboplatin plus docetaxel who had undergone palliative surgery through a transurethral resection of the prostate (TURP). Due to relatively large size of advanced tumors which leads to improbable central blood supply and central necrosis, all samples were resected from tumors external surfaces. Samples were transfered to laboratory of analysis and identification of chemical elements of Shiraz University, and platinum concentrations were measured by standard method of measuring heavy metals in living organs.,,
Breast cancer samples were related to some selected patients with locally advanced malignancies who had become operable following neoadjuvant carboplatin-based chemotherapy. Among 16 samples, 10, 5, and 1 samples were related to patients of Stages IIIA (T3N1M0), IIIB, and inflammatory, respectively. All patients were human epidermal growth factor receptor 2-positive (HER2- positive) who had undergone mastectomy and specific chemotherapy regimen of TCH plus pertuzumab. Among patients, one case had undergone surgery <2 weeks, nine cases between 2 and 3 weeks, four cases between 3 and 4 weeks, and two cases more than 4 weeks after last chemotherapy. Carboplatin dosage was calculated by AUC 6 IV. Patients' status is completely mentioned in [Table 1].
|Table 1: Patients' specifications by cancer type, stages, regimen type, and time lapse from last chemotherapy|
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Lung tumor samples were related to the patients undergone neoadjuvant cisplatin-based chemotherapy. Among 11 samples, 8, 2, and 1 samples were related to the patients with advanced non-small-cell lung cancer (NSCLC) stages IIIA-N2(T1–T3), IIIB (T4, N0, 1), and limited-Stage IB (N0) small-cell lung cancer (SCLC), respectively. Among 8 samples of Stage IIIA-N2 NSCLC, two cases had tumor cell <1.5 cm with acceptable performance status and six cases with tumor size between 1.5 and 3 cm with acceptable/borderline performance status. The multimodal therapies used for most patients were neoadjuvant cisplatin-based chemotherapy plus 45 Gy radiotherapy followed by surgical resection. The cisplatin-based chemotherapy had been given by four cycles of 50 mg/m 2 or two cycles of 100 mg/m 2 cisplatin. Other chemo drugs administered with cisplatin were etoposide or vinblastine. The only case of SCLC had tumor size between 3 and 5 cm and treated by four cycles EP regimen plus radiotherapy. Among all patients, one case had undergone surgical resection <4 weeks, five cases between 4 and 5 weeks, four cases between 5 and 6 weeks, and one case >6 weeks after last chemotherapy. Patients' status is completely mentioned in [Table 1].
Five tumor samples of patients with advanced metastatic castration-resistant prostate cancer who had undergone TURP through a palliative surgery were gathered from pathology collection center. A Pt-based chemotherapy with carboplatin plus docetaxel had been given to the patients 3–9 months before surgical resection in an ongoing pilot study. The carboplatin dosage was calculated by AUC 4 IV method. Among five patients, two and three cases had undergone surgery in a time lapse between 3–6 and 6–9 months after last chemotherapy, respectively. Patients' status is completely mentioned in [Table 1].
Colorectal tumor samples were related to the patients with advanced resectable metastatic cancer undergone neoadjuvant oxaliplatin-based chemotherapy. Among 9 samples, 5 and 4 samples were related to patients with Stage IIIB (T3, 4a, N1, 2a) and IIIC (T4a, b, N1, 2), respectively. The standard regimens of m-FOLFOX, m-FOLFOX plus Bevacizumab, or m-FOLFOX plus cetuximab were used, all with 85 mg/m 2 oxaliplatin in particular cycles. Among all patients, one case had undergone surgery <6 weeks, three cases between 6 and 8 weeks, and five cases >8 weeks after last chemotherapy. Patients' status is completely mentioned in [Table 1].
All samples used in this study were collected from pathology collection of various hospitals of SUMS. Ethical principles related to patients' rights and privacy are fully respected by authors in accordance with SUMS Ethics Committee Protocol with Ethics Committee number ir.sums.rec. 1395.S.632. The clinical trial number is related to MSc. thesis no. 95-11304.
Preparation for spectrometry
Using 4 ml HNO3 plus 1 ml H2O2, each tumor sample was digested in a Teflon vessel while adding acids. After initial reaction at room temperature, a 5 step microwave digestion was carried out. The solution was evaporated on a hot plate at 120°C to a residue of about 500 μl HNO3. 0.1 ml hydrofluoric acid and 2 ml HCl were added to the solution and another digestion procedure was done. The solutions were evaporated gently to 200 μl, and 2 ml aqua regia was added. The solution was again evaporated to 200 μl. Mentioned procedure was repeated with 1 ml HCl. The whole process has been described completely by Rudolph et al.
Using ultrapure subboiled water, the solutions were diluted to a final mass of 5 g and stored at 4°c until measurment. Platinum concentration was measured with inductively coupled plasma optical emission spectrometry (ICP-OES) by Vista-PRO system manufactured by Varian Inc., Palo Alto, California, USA, which is used in laboratory of analysis and identification of chemical elements at Shiraz University, Shiraz, Iran.
Using IBM SPSS statistics 18, (released by IBM corporation, New York, USA), different analyses were done to obtain the results. To analyze the mean differences between groups with various Pt-based chemo drugs (cisplatin vs. carboplatin vs. oxaliplatin), the ANOVA test was done. The nonparametric Mann–Whitney U and Kruskal–Wallis tests were done to analyze the mean difference between time and regimen groups, respectively.
| > Results|| |
[Figure 1] indicates tumor platinum concentrations of breast, lung, prostate, and colorectal cancers which were obtained in the range of (1.87–6.91 μg/g), (0.17–7.23 μg/g), (1.92–6.38 μg/g), and (0.83–7.01 μg/g) with the average of 3.81, 3.12, 4.05, and 3.85 μg/g, respectively. These data are also presented by type of cancers (treated with different types of chemo drugs), different chemotherapy regimens, and time lapse from last chemotherapy in [Table 2]. Statistical analyses were done by ANOVA, Mann–Whitney U and Kruskal–Walis tests between different chemo drugs type, time, and regimen groups. P value between different chemo drug types was 0.619. P values between time groups were obtained 0.175, 0.584, 1.000, and 0.806 for data of breast, lung, prostate, and colorectal cancers, respectively; and P values between regimen groups were 0.584 and 0.561 for data of lung and colorectal cancers, respectively. All statistical data and P values are presented completely in [Table 2]. [Figure 2] indicates tumor platinum concentration of lung and colorectal cancers categorized into two and three regimen groups, respectively.
|Figure 1: Tumor platinum concentration of breast, lung, prostate, and colorectal cancers|
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|Table 2: Statistical data and P values between different groups (drug type, time lapse, and regimen type)|
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|Figure 2: Tumor platinum concentration of lung and colorectal cancer patients categorized into 2 and 3 regimen groups|
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| > Discussion|| |
Following the spectrometry, the platinum concentration of each sample was measured and reported by type of cancer, time, and regimen groups in [Table 2]. All samples were related to the patients' undergone chemotherapy with the same regimen or same dosage of Pt-based chemo drug in a specific regimen. The TCH plus pertuzumab regimen was used for all patients with breast cancer by specific dosage of carboplatin calculated by AUC 6 IV. Lung cancer patients had undergone neoadjuvant cisplatin-based chemotherapy by cisplatin-etoposide (four cycles of 50 mg/m 2 cisplatin) or cisplatin-vinblastine (two cycles of 100 mg/m 2 cisplatin). The total dosage of cisplatin was same in both regimens. All samples of prostate cancer were related to the patients suffered from advanced metastatic castration-resistant cancer who had participated in a pilot study with chemotherapy regimen included carboplatin (calculated by AUC 4 IV) plus docetaxel. Patients with advanced resectable colorectal cancer were divided into three regimen groups of m-FOLFOX, m-FOLFOX plus bevacizumab, or m-FOLFOX plus cetuximab; all with same dosage of oxaliplatin (85 mg/m 2). In general, all patients of each group were treated with a specific dosage of Pt-based chemo drug. Patients of breast and prostate cancers were all female and male, respectively. Seven men and 4 women were among lung cancer patients and 5 men and 4 women among colorectal cancer patients. According to the results, tumor platinum concentrations of breast, lung, prostate, and colorectal cancers were generally obtained in the range of 1–10 μg/g tumor tissue. P value between cancer groups (each one treated with a specific type of Pt-based chemo drug) was 0.619 which indicates no significant difference caused by different drugs (carboplatin vs. cisplatin vs. oxaliplatin). In addition to platinum concentration, the effect of other variables on platinum concentration was also evaluated. Breast cancer patients were categorized into two time groups less and more than 3 weeks after last chemotherapy (10 patients <3 weeks vs. 6 patients >3 weeks). Lung cancer patients were categorized into two time groups less and more than 5 weeks after last chemotherapy (6 patients <5 weeks vs. 5 patients >5 weeks). Prostate cancer patients were categorized into two time groups 3–6 and 6–9 months after last chemotherapy (2 patients 3–6 months vs. 3 patients 6–9 months). Colorectal cancer patients were categorized into two time groups less and more than 8 weeks after last chemotherapy (4 patients <8 weeks vs. 5 patients >8 weeks). Statistical analyses were done by Mann–Whitney U test, and P values between different time groups were obtained 0.175, 0.584, 0.999, and 0.806 for data of breast, lung, prostate, and colorectal cancers, respectively. According to mentioned P values, the time lapse from last Pt-based chemotherapy had no significant effect on tumor platinum concentration. Patients of lung and colorectal cancers were treated with 2 (R1 = cisplatin + etoposide vs. R2 = cisplatin + vinblastine) and 3 (R1 = m-FOLFOX vs. R2 = m-FOLFOX + bevacizumab vs. R3 = m-FOLFOX + cetuximab) regimens, respectively. The influence of other antineoplastic agents used concurrently with cisplatin or oxaliplatin was also evaluated. Statistical analyses were done by Mann–Whitney U and Kruskal–Wallis tests for two and three regimens. P values between different regimens were obtained 0.584 and 0.561 for lung and colorectal cancers, respectively. These results indicate that concurrency of other anticancer drugs had no significant effect on tumor platinum concentration in lung and colorectal cancers. In a study conducted by Stewart et al., the platinum concentration of different human tissues after cisplatin chemotherapy have been measured. Authors have reported higher concentrations in liver, prostate, and kidneys and lower concentrations in heart, lung, adrenal, and cerebrum. It is also mentioned that tumor concentrations were even lower than tissues'. Although tumor platinum concentration obtained in this study is a bit higher in prostate (ave = 4.05 μg/g) and lower in lung (ave = 3.12 μg/g) as well, the data are relatively a little higher than Stewart's report. Hence, it is important to point out that all samples were related to advanced sizeable tumors (of Stages IIIA, IIIB, or IIIC) and resected from tumors external surfaces due to central necrosis. Accordingly and based on tumor inhomogeneity and higher blood supply at tumor external surfaces, it was expected to observe higher platinum concentration compared to Stewart's study. Another study conducted by Kim et al. has reported lung tissue platinum concentration after Pt-based chemotherapy in the range of 0–0.008 absorbed unit per milligram (equal to 0–8 × 10−6 per gram). In this study, lung tumor platinum concentrations were obtained in the range of 0.17–7.23 μg/g (ave = 3.12 μg/g) which indicate close quantity between lung tissue and its tumor external surfaces in comparison with Kim's report. It is also recognized that platinum can significantly remain up to 20 years after completion of chemotherapy. In this study, comparable amount of platinum was found up to 9 months after last chemotherapy in prostate samples. In the end, it is important to point out that data reported in this study are reliable for future evaluation of dose enhancement in concurrent chemo-radiotherapy with Pt-based chemo drugs because drug delivery to tumor center is improbable due to central necrosis.
| > Conclusions|| |
In this study, tumor platinum concentration of patients with advanced breast, lung, prostate, or colorectal cancers who had received Pt-based chemotherapy before surgical resection was measured by ICP spectrometry. The type of chemotherapy regimen used for a particular cancer or total dosage of Pt-based chemo drug administered in different regimens was the same. In general, platinum concentration was obtained in the range of 1–10 μg/g tumor tissue and a little higher in prostate and lower in lung tumor samples. The influence of chemo drug type, time lapse from last chemotherapy, and concurrency of other antineoplastic agents on platinum concentration were evaluated, and no significant differences were observed out of results. According to multiple statistical studies reported survival increase in concurrent chemo-radiotherapy with Pt-based chemo drugs, quantitative data reported in this study can be considered in the future studies related to concurrent chemo-radiotherapy or simulation studies aimed to evaluate the dose enhancement.
Authors would like to thank vice-chancellery for research and technology affairs of SUMS for supporting this research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]