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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 5  |  Page : 22-25
 

Clinical interrogation and application of super-selective intracranial artery infusion chemotherapy for lung cancer patients with brain metastases


Department of Intervention, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin 300060, China

Date of Web Publication3-Nov-2015

Correspondence Address:
J Rong
Department of Intervention, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin 300060
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.168951

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 » Abstract 

Objective: The purpose of this study was to evaluate the clinical efficacy of super-selective intracranial artery infusion chemotherapy and to determine correlated prognostic parameters for advanced lung cancer patients with brain metastases. Patients and Methods: Fifty-four lung cancer patients with brain metastasis who had no previous treatment were enrolled for the study. These patients received super-selective intracranial artery infusion chemotherapy, as well as arterial infusion chemotherapy for primary and metastatic lesions. The procedure was performed once every 4 weeks. Patients were monitored to evaluate short-term clinical outcomes 4 weeks after the first 2 treatments, and follow-up visits performed every 4 weeks after the first 4 treatments until the appearance of disease progression or intolerable toxicity. Results: All 54 cases were treated at least 4 times. The overall response rate was 55.56% (30/54), and the disease control rate was 85.19% (46/54). The median overall survival was 7 months, with a 95% confidence interval (CI) of 5.87–8.13 months, and the median progression-free survival was 4 months, with a 95% CI of 3.20–4.80 months. The 6-month survival rate and 1-year survival rate were 81.48% (44/54) and 18.52% (10/54), respectively. Conclusion: Super-selective intracranial artery infusion chemotherapy provides a clinically efficacious avenue of treatment for lung cancer patients with brain metastases. Pathological classification, Karnofsky performance status, and extracranial metastases may serve as reliable prognostic parameters in determining the clinical outcomes for lung cancer patients with brain metastases.


Keywords: Artery infusion, brain metastases, chemotherapy, lung cancer, prognostic factors


How to cite this article:
Rong J, Chunhua M, Yuan L, Ning M, Jinduo L, Bin W, Liwei S. Clinical interrogation and application of super-selective intracranial artery infusion chemotherapy for lung cancer patients with brain metastases. Indian J Cancer 2015;52, Suppl S1:22-5

How to cite this URL:
Rong J, Chunhua M, Yuan L, Ning M, Jinduo L, Bin W, Liwei S. Clinical interrogation and application of super-selective intracranial artery infusion chemotherapy for lung cancer patients with brain metastases. Indian J Cancer [serial online] 2015 [cited 2021 Jul 31];52, Suppl S1:22-5. Available from: https://www.indianjcancer.com/text.asp?2015/52/5/22/168951

FNx01Jiang Rong and MA Chunhua contribute equally to this work



 » Introduction Top


Lung cancer represents one of the most common and notorious malignancies that afflict a large population in China and the world alike. Despite increased morbidity and mortality over the past few years, the clinical efficacy after treatment with radiotherapy and chemotherapy for advanced stage lung cancers remains merely 20–40% with a 5-year survival rate just between 8% and 12%.[1],[2],[3] The poor prognosis for lung cancer patients primarily results from local recurrence or distant metastasis; particularly, brain metastasis occurs in 25% of the patients with often extremely poor prognosis and median survival of 1–2 months.[4],[5] Currently available avenues of clinical interventions comprise surgery, whole brain radiation, stereotactic radiosurgery, and chemotherapy; however, their clinical efficacy and benefits remain to be fully satisfactory, especially as palliative treatment for advanced cancer patients.[6] In this study, the super-selective intracranial artery infusion chemotherapy was administered to lung cancer patients with brain metastasis. Our experimental and clinical results demonstrated superior efficacy using this approach in alleviating symptoms, improving life quality, and prolonging patient survival. As described below, we carried out a retrospective analysis on the clinical efficacy of this clinical intervention and determined its relevant prognostic factors through treating 54 advanced lung cancer patients with brain metastasis from September 2007 to August 2011.


 » Patients and Methods Top


Patients

Selection criteria

(1) Histology- or cytology-verified diagnosis with lung cancer; (2) intracranial metastasis detected by enhanced cranial magnetic resonance imaging (MRI), with at least one measurable lesion; (3) no previous anti-tumor treatment and no intention to receive surgery, radiotherapy, and intravenous chemotherapy; (4) Karnofsky performance status (KPS) scores >50; (5) expected survival of more than 12 weeks; (6) no severe organ dysfunction; (7) signed informed consent agreement.

Patient information

A total of 54 patients (30 males and 24 females, ranging from 32 to 79 years old with a median age of 59 years old) with no treatment history were enrolled for the study. They received intracranial arterial infusion chemotherapy from September 2007 to August 2011 in our hospital. All patients were confirmed to harbor brain metastasis by computed tomography or MRI after admission, including 20 cases with no more than 3 intracranial metastasis and 34 with more than 3 intracranial metastases. Fourteen cases were diagnosed with extracranial metastasis, commonly in lymph node, bone, lung, and liver. The KPS scores were between 40 and 80 for the group, with 30 cases >60. Histological classification identified squamous cancer (14 cases), adenocarcinoma (30 cases), and small cell carcinoma (10 cases).

Therapeutic approach and outcome assessment

Therapeutic approach

Patients were treated with combination therapies using teniposide (VM-26), nimustine (ACNU), and carboplatin (CBP). With the Seldinger technique through femoral artery puncture, we performed radiography imaging of carotid and vertebral artery using a single bend Cordis 5F catheter that selectively migrated into intracranial artery through aortic arch to confirm the presence of tumor-supporting artery. We then successively infused 20 ml of 20% mannitol, 50 mg VM-26, 25 mg ACNU and 100 mg CBP diluted in 20 ml of 0.9% saline or 5% glucose at 3 ml/min to perform targeted artery infusion-based chemotherapeutic treatment for the primary lung tumor and extracranial metastases. The infusion therapy was carried out once every 4 weeks until disease progression or intolerable toxicity. Eight weeks later after the first 2 treatments, intensified cranial MRI scanning was performed for clinical outcome evaluation, and 4 weeks after the first 4 treatments, follow-up visits were conducted. For patients experiencing postoperative intracranial hypertension, intravenous infusion of 250 ml 20% mannitol was administered with specific procedures being adjusted according to the degree of cerebral edema and overall clinical symptoms.

Outcome assessment

(1) Evaluation of short-term outcomes: Based on Response Evaluation Criteria in Solid Tumors that measures the sum of the longest diameter of targets lesions, responses can be classified as complete response (CR), namely, disappearance of all lesions for over 4 weeks; partial response (PR), at least 30% shrinkage of lesions for over 4 weeks; stable disease (SD), a condition between PR, and progression disease (PD); PD, at least a 20% increase in diameter of a single lesion or multiple lesions or appearance of new lesions. Objective response rate (ORR) is defined as CR and PR, whereas disease control rate (DCR) is defined as CR, PR, and SD.

Survival

Progression-free survival (PFS) is the time interval starting from a patient's first treatment to the appearance of PD. The date of the last tumor evaluation was used for those who did not show disease progression or die before the last follow-up visit (April 30, 2015) and for those who were not available for follow-up visits. The overall survival (OS) is the time interval starting from a patient's first treatment to the date of his/her death by any reason. The date of the last following-up visit was used for those who did not die before the last follow-up visit (April 30, 2015) and for those who were not available for follow-up visits. All the 54 patients in the group completed treatment for 4 times, and, 4 weeks later, were subject to intensified intracranial MRI scanning and follow-up visits.

Adverse drug reactions assessment

Based on the grading criteria provided by the National Cancer Institute-Common Toxicity Criteria (version 3.0), all patients were assessed with possible adverse drug reactions that may occur during treatment or following-up visits.

Statistical analysis

The results were computed and analyzed via SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). Chi-square test was used to determine the differential role of distinct variables in influencing overall response rate (ORR) and DCR. Survival analysis was performed with the Kaplan–Meier method, and log-rank test utilized to evaluate differential survival distributions. P ≤ 0.05 was considered as statistically significant.


 » Results Top


Short-term clinical outcomes

All 54 patients received the treatment for at least 2 times with the median being 4. No case of death occurred to any patient during the period of treatment. Short-term outcome evaluation revealed 0 CR case, 30 PR cases (55.56%), 16 SD cases (29.63%), and 8 PD cases (14.81%). The ORR for patients with intracranial lesions was 55.56% (30/54), and the DCR was 85.19% (46/54).

Survival analysis

Until the last follow-up visit on April 30, 2015, all patients had experienced disease progression or died. Our results showed that patients had a median PFS of 4 months (95% confidence interval [CI]: 3.20–4.80 months) and median OS of 7 months (95% CI: 5.87–8.13 months). In addition, the 6-month survival rate was 81.48% (44/54), and 1-year survival rate 18.52% (10/54). Subgroup analysis of the clinical baseline characteristics for all 54 patients demonstrated that, patients with nonsmall cell lung cancer (NSCLC)-derived brain metastases, KPS scores >60 and few than 3 intracranial metastases had considerably better median survival than those with small cell lung cancer-derived brain metastases, KPS scores <60 and >3 intracranial metastases (P < 0.05), respectively. Patients' gender, age, or development of extracranial metastases did not significantly affect their median progress-free survival or median survival [P > 0.05, [Table 1].
Table 1: Correlation of various clinical baseline characteristics with prognosis for 54 cases

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Adverse drug reactions and complications

All enrolled 54 patients received femoral artery puncture with a success rate of 100% without any local complications, such as subcutaneous hematoma, pseudoaneurysm, blood leaking, and leg vein/arterial thrombosis. Only one case with anterior cerebral arterial spasm occurred, who was immediately treated with catheter-mediated artery infusion of 60 mg papaverine diluted in 20 ml 0.9% saline to successfully alleviate the symptoms and the patient ultimately completed the therapy. Adverse reactions relating to chemotherapeutic drugs were mild, which were mostly I or II grade gastrointestinal reactions in 37.0% (20/54) patients and blood toxicity in 44.0% (24/54). No adverse reactions above the III grade were found in this group.


 » Discussion Top


Lung cancer poses a formidable health challenge as one of the most common malignant tumors that adversely influences human welfare across the globe. About 80% patients have already progressed into the mid-late stage when initially diagnosed with lung cancer. This results in an OS of only 10%,[1] and currently no efficacious avenues of clinical intervention are available. It has long been established that low OS of these lung cancer patients principally results from the metastatic brain tumor, in the form of either single or multiple metastases, which unfavorably allows for survival of merely 1–2 months without timely and targeted treatment. Approximately, 80% of the metastatic brain tumors were identified in cerebral hemispheres, in contrast to 15% in the cerebellum. Previous postmortem studies have shown that over 60% of the patients with metastatic brain tumors had multiple brain metastasis.[5],[6],[7],[8],[9] The tumors may cause cerebral edema and hydrocephalus due to their infiltrating development and the mechanical compression on normal brain tissues; notably, clinical symptoms indicative of impaired nervous system or even cerebral hernia also often develop in parallel as a result of increased intracranial pressure.

Super-selective intracranial arterial infusion chemotherapy is an established clinical strategy intended to overcome the many clinical caveats of intravenous medication. Instead of becoming highly diluted via systemic and pulmonary circulations, this clinical approach induces direct drug transportation via tumor-supporting vessels by catheter-mediated drug introduction, and thus creates a high intravascular drug concentration that significantly enhances tumoricidal capacity. This enables full utilization and incorporation of the strengths of local chemotherapy. Furthermore, local drug administration only requires one-third of the drug dosage used in systemic chemotherapy. More importantly, lower dosage can favorably alleviate possible drug-induced systemic complications and thus enhance the chemotherapy resistance in patients. This is primarily because of the unique pharmacodynamics the approach entails, where drugs first circulate back to the venous system from vessels of the targeted region and then enter the systemic circulation. Recent investigations have reported that the blood-brain barrier becomes structurally and functionally compromised during the process of brain metastasis, and dehydration-causing drugs, such as mannitol, may temporarily disrupt the barrier, thus making it accessible to chemotherapeutics that can migrate to the central nervous system to exert its tumor-killing abilities.[10] The intracranial arterial infusion chemotherapy regimen can then be patient-specific tailored to incorporate the use of nimustine (ACNU), teniposide (VM-26), carboplatin (CBP), and combined with catheter-introduced mannitol that impairs the integrity of the blood-brain barrier. In the current clinical investigation, intensified MRI scanning on 54 patients 4 weeks after repeated treatments for revealed the ORR of 55.56% (30/54) and the DCR of 85.19% (46/54). In addition, the median PFS was 4 months and median OS was 7 months. Currently, whole brain radiation therapy represents a major strategy of clinical intervention for brain metastasis that, as recently reported, has a median survival of 3–6 months.[11],[12],[13],[14] We argue that super-selective intracranial artery infusion chemotherapy can promptly alleviate neurological complications resulting from brain metastases and constrain local metastatic progression. Moreover, the therapy can be accomplished with simple and straightforward procedures that cause little trauma and complications with high regional drug concentration that enhance tumor cell killing. Furthermore, our results suggested that pathological classification, KPS scores, and intracranial metastases are relevant prognostic indicators for lung cancer patients. In contrast, our analysis showed that gender, age, and extracranial metastases did not significantly influence the clinical outcomes of patients. However, given the complex pathological conditions for lung cancer patients with particularly extracranial metastases, studies with a larger sample size are necessary to corroborate our findings and conclusions.

In this study, all 54 patients received femoral artery puncture with a success rate of 100%. No treatment-related complications, including subcutaneous hematoma, pseudoaneurysm, blood leaking, and leg vein/arterial thrombosis, was detected. Only 1 case of anterior cerebral arterial spasm occurred during surgery, which might result from local irritation of the use of catheter and microcatheter; the complications were greatly ameliorated through slow transcatheter arterial infusion of papaverine, and the patient successfully completed the treatment regimen with no postoperative cerebrovascular complications. The drug doses in intracranial artery infusion chemotherapy require only one-third of that in systemic administration, thus entailing mild drug-related adverse reactions (mostly the I or II grade gastrointestinal reactions and blood toxicity). Indeed, no adverse reactions above the III grade were found in our patient group.

In summary, compared with surgery, whole brain radiation, stereotactic radiosurgery and chemotherapy,[13],[14] arterial infusion chemotherapy can be specifically formulated and tailored, depending upon KPS scores, neurological function assessment and parameters of primary and metastatic tumors (e.g., tumor size, number, location and histology). This enables significant improvements in patients' life quality and their tolerance to palliative treatment. Notably, favorable prognostic parameters, such as NSCLC as the pathological type, KPS scores >60, and fewer than 3 intracranial metastases may be indicative of beneficial clinical outcomes for lung cancer patients with brain metastases.

 
 » References Top

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Guessous I, Cornuz J, Paccaud F. Lung cancer screening: Current situation and perspective. Swiss Med Wkly 2007;137:304-11.  Back to cited text no. 1
    
2.
Zheng R, Zeng H, Zhang S, Fan Y, Qiao Y, Zhou Q, et al. Lung cancer incidence and mortality in China, 2010. Thorac Cancer 2014;5:330-6.  Back to cited text no. 2
    
3.
Chen W, Zheng R, Zhang S, Zou X, Zhao P, He J. Lung cancer incidence and mortality in China, 2009. Thorac Cancer 2013;4:102-8.  Back to cited text no. 3
    
4.
Gaspar LE, Chansky K, Albain KS, Vallieres E, Rusch V, Crowley JJ, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: A retrospective review by the Southwest Oncology Group. J Clin Oncol 2005;23:2955-61.  Back to cited text no. 4
    
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Sajama C, Lorenzoni J, Tagle P. Diagnosis and treatment of brain metastasis. Rev Med Chil 2008;136:1321-6.  Back to cited text no. 5
    
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Schuette W. Treatment of brain metastases from lung cancer: Chemotherapy. Lung Cancer 2004;45 Suppl 2:S253-7.  Back to cited text no. 6
    
7.
Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 2009;27:5255-61.  Back to cited text no. 7
    
8.
Potter CS, Wang Z, Silva KA, Kennedy VE, Stearns TM, Burzenski L, et al. Chronic proliferative dermatitis in Sharpin null mice: Development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. PLoS One 2014;9:e85666.  Back to cited text no. 8
    
9.
Gril B, Evans L, Palmieri D, Steeg PS. Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies. Eur J Cancer 2010;46:1204-10.  Back to cited text no. 9
    
10.
Peacock KH, Lesser GJ. Current therapeutic approaches in patients with brain metastases. Curr Treat Options Oncol 2006;7:479-89.  Back to cited text no. 10
    
11.
Khan AJ, Dicker AP. On the merits and limitations of whole-brain radiation therapy. J Clin Oncol 2013;31:11-3.  Back to cited text no. 11
    
12.
Zhang C, Zeng X, Li Z, Wang Z, Li S. Immunoglobulin a nephropathy: Current progress and future directions. Transl Res 2015;166:134-44.  Back to cited text no. 12
    
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Mahmood U, Kwok Y, Regine WF, Patchell RA. Whole-brain irradiation for patients with brain metastases: Still the standard of care. Lancet Oncol 2010;11:221-2.  Back to cited text no. 13
    
14.
Patil CG, Pricola K, Garg SK, Bryant A, Black KL. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 2010;16:CD006121.  Back to cited text no. 14
    



 
 
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