Clinical Trial Of Gamma Knife Combined With Temozolomide For Non-small Cell Lung Cancer Patient With Brain Metastasis

BackgroundA brain metastasis (intracranial metastasis), as the most common intracranial tumor in adults, refers to a cancer that has metastasized (spread) to the brain from another location in the body, whose incidence is10times greater than that of intracranial primary brain tumor. A great statistical result shows that brain metastases occur in8.5-9.6%of patients with colorectal cancer, lung cancer, breast cancer, kidney cancer and melanoma. For a specific disease, lung cancer metastatic to the brain has the highest incidence,16.3-19.9%; for the average time from diagnosis of primary lesions to discovery of brain metastases, the lung cancer is the shortest,6to9months. Brain metastasis, the stage IV lung cancer, is treated by palliative therapy which is mainly to prolong the survival period and improve the survival treatment. Therefore, it is imperative to develop research methods with definite therapeutic effect and with improvement of patient’s quality of life.Small cell lung cancer has found to be sensitive to the radiotherapy, but non-small cell lung cancer-related brain metastases are difficult to be treated. The treatments of it are complex.There are anatomy and physiological factors.(1) Anatomy factor:the way of lung cancer occurring brain metastasis is that tumor cells invade the cerebral craniumvia the blood stream and lymphatic system, which the position is related to the hemodynamics of the lesion and the tissue size. The lesions are divided into nodular and diffuse types. Therefore, it is of high risk and more complications in craniotomy, which is only to remove and minimize the tumor to relieve the increased intracranial pressure.(2) Physiological factor:the metastatic tumor is not the single primary diseases but the complications of the stage IV lung cancer, whose treatment has to consult patient’s treatment conditions of the primary lesion of the lung (operation of primary tumor, postoperative local radiotherapy and systemic chemotherapy) and general conditions (KPS scores and haematological indices) to obtain a comprehensive therapeutic schedule. To prolong patient’s survival period and improve the survival treatment, clinically, comprehensive therapeutic schedules are made by patient’s lesion site, gross tumor volume and general conditions. The common treatment is the whole brain radiotherapy (WBRT) after resection of the lesion or concurrent radiochemotherapy with temozolomide (TMZ).In recent years, evidence-based medicine has proved that stereotactic radiosurgery (SRS) plays a definite role in the treatment of non-small cell lung cancer-related brain metastases. In January,2010, American Association of Neurological Surgeons (AANS) issued Guidelines for SRT on Brain Metastases and made normative recommendations on different therapies of brain metastases. SRS, as a surgical technique, is a surgery treating intracranial diseases with large doses of a single precise ray. Radiosurgery, which treated brain metastases as a single treatment or pre/post-WBRT adjuvant therapy, has been widely used in clinic.For traditional fractional radiotherapy of sensitive tissues, the SBRT could control tumors by acting on vascular endothelial cells (VECs)(radiosensitive tissues) and block the blood supply of the tumor. The concomitant SRS with WBRT, in contrast to single SRS, shows significantly higher one-year tumor control probability (TCP)(69%and28%, respectively) but no significant differences in overall survival (OS).In theory, chemotherapies of brain tumors should be very attractive because they can also treat multiple brain metastases while treating primary tumors. However, the blood brain barrier (BBB) is still the biggest restriction on the application of chemotherapeutic drugs. If the primary lesion is the non-small cell lung cancer (NSCLC), the chemotherapeutic efficacy is poor; but the TMZ is the first orally-available antitumor imidazotetrazinones. Its cytotoxicity mainly depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7or O-6positions of guanine residues where it can result in tumor cell cycle arrest in G2-M phase and apoptosis by forming the nicks (which hinder the startup of the replication finally and will accumulate gradually with cell division) of the DNA substrand during DNA replication, playing a role in protecting systemic and central nervous system against malignant tumors. The oral bioavailability of TMZ is ranging from98%to100%, but the food may reduce9%of the absorption; TMZ is of moderate molecular weight, liposoluble and able to be apt to pass through the BBB and the brain tumor tissue; the CSF drug level is30%-40%of plasma drug level; it reaches effective therapeutic concentration range in the central nervous system; it is so far mainly used to treat gliomas and malignant melanomas in adults but it is of broad-spectrum antitumor effect.The treatment of metastases with TMZ combined with radiotherapy is synergistic and well-tolerated. Adjuant chemoradiotherapy can use not only the cytotoxicity of metabolites of TMZ and the cell-killing activity of the radiotherapy itself, but also the sensibilization of the radiotherapy of TMZ. Therefore, combination may lead to a synergistic effect. This article affirms the SRS for lung cancer-related brain metastases combined with chemotherapy of TMZ at the early stage, and demonstrates clinical effects of the treatment of non-small cell lung cancer-related brain metastases with gamma knife plus TMZ.ObjectiveBased on preliminary studies, eligible patients with non-small cell lung cancer-related brain metastases (see methods) are planned to be treated with gamma knife surgery (SRS) plus TMZ; contrastive analyses are made on efficacities between adjuvant chemoradiotherapy and traditional therapies (SRS and SRS with WBRT).1. To preliminarily discuss the therapeutic effect of SRS plus TMZ on lung cancer-related brain metastases, observe toxic and side effects of the combination therapy and provide a new concept for chemotherapy of non-small cell lung cancer-related brain metastases.2. According to preliminary experimental results, observe subsequent therapeutic responses on treating lung cancer-related brain metastases with SRS plus TMZ (corresponding emerging and concurrent diseases).MethodsLung cancer-related brain metastasis is the late manifestation of lung cancer. Its therapies are palliative, which should take all these factors into consideration, including age, systemic conditions, state of neurological function, conditions of primary tumors, pathology, extracranial metastases, numbers and sites of brain metastases, etc.1. General Data of Patients:This group of patients included48patients with brain metastases admitted to our hospital from January2010to June2012. Definite pathological diagnoses made in their lungs before operation were NSCLCs,29cases with squamous carcinoma and19cases with adenocarcinoma;31males and17females; ages ranged from46to70, with an average age of59.4. All the three groups of patients showed no significant difference (P>0.05) in general data (gender, age and severity of illness).2. Inclusion Criteria:All eligible patients satisfied all of the following requirements:a) there were measurable lesions on images; b) the maximum diameter of single tumor is less than4cm; c) definite pathology of NSCLC was seen; d) KPS scores were equal or greater than70points, numbers of metastases were equal or less than5, expected survival time was equal or greater than3months; e) blood routine, hepatorenal function and electrocardiogram were normal. Forty-eight patients were randomly divided into three groups (Group A, B and C) in hospitalization order,16patients per group. All the three groups of patients showed no significant differences (P>0.05) in general data (gender, age and severity of illness).3. Groups Group A.the SRS-TMZ treatment group, Patients were treated with SRS at12-25Gy peripheral dose while being given TMZ. Specific dosage:150mg/m2/d, dl-5, Q28d x6Cycles.Group B:the single SRS treatment group, Patients were treated with SRS at12-25Gy peripheral dose.Group C:the SRS-WBRT treatment group, Patients followed by WBRT at30Gy (2Gy x5d/w,3weeks) were treated with SRS at12-25Gy peripheral dose.4. TreatmentA. Perioperative treatment:Patients in all the three groups were routinely given intravenous drip of125ml mannitol plus oral dexamethasone to prevent encephaledemas in perioperative period; if Grade III or above toxic and side effects occur, symptomatic treatments (dehydration and increasing erythrocyte and granulocytes) should be given.B. Patients were followed up by form, re-hospitalization, telephone and Internet; the frequency of follow-up was once a month.C. Examinations:enhanced cerebral MRI plus Flair was to observe conditions of lesions and edemas; blood RT, hepatic and renal function evaluated toxic and side effects of radiotherapy and chemotherapy drugs.5. Response Evaluation CriteriaWho’s Response Evaluation Criteria In Solid Tumors (RECIST) is recently used to evaluate clinical effects, taking CT and MRI as evaluation criteria (the sum of changes of maximum diameters of measurable lesions). CR:the lesions observed completely disappear for over a month; PR:the tumor diminishes over50%; for multiple lesions, the sum of products of two maximum vertical diameters diminishes over50%; SD:the tumor diminishes less than50%or does not enlarge over25%; PD: single or multiple lesions enlarge over25%or new lesions emerge. The effective rate=(CR+PR)/total cases x100%. The locoregional rate=(CR+PR+SD)/total cases x100%.Survival time is defined as the date from acceptance of WBRT and oral administration of TMZ to death or the latest follow-up. All patients were followed up regularly after treatment. 6. Toxic and Side EffectsVarious adverse events were evaluated by the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), while toxic and side effects were evaluated by NCI-CTC3.0grading standard.7. Statistical AnalysisStatistical analyses were made by SPSS13.0; clinical effects of the three groups of patients were compared by x2test; the survival rate was calculated by Kaplan—Meier estimator and the survival curve was plotted; the significance test of the survival rate is performed by Log-rank test. If P<0.05, it might be statistically significant.Results1. Clinical effects of the three groups were as follows:Group A:the effective rate (ER) was81.3%and the tumor locoregional rate was93.7%; Group B:the ER was43.8%and the TCP was62.5%; Group C:the ER was81.3%and the locoregional rate was93.7%; there was significant difference in ER and (χ2=6.98, P=0.031) in TCP (χ2=7.50, P=0.023); and the difference was statistical significance (P<0.05).2. All the three groups of patients completed the treatment successfully without serious toxic and side effects but with alopecia (χ2=19.81, P<0.001), headache or dizziness (χ2=9.88, P=0.09), Grade Ⅲ or above nausea and vomiting (χ2=8.67, P=0.018), Grade Ⅲ or below granulocytopenia (χ2=8.14, P=0.018) and Grade Ⅲ or below thrombocytopenia (χ2-7.38, P=0.027). There was statistical significance among the three groups (P<0.05). All patients in Group C got alopecia and complained of obvious headache and dizziness after operation; patients in Group A showed majorly mild myelosuppression; all the three groups of patients were of no serious complications and symptoms were alleviated by symptomatic treatment.3. In treatment with SRS plus TMZ, as of the follow-up date, compared with the survival time and survival rate of the three groups of patients, there was no significant difference. Log-rank test showed that, χ2=2.29, P=0.318; the median survival time (MST) was10months,11months and10months, respectively. Due to the small case load and the intervention of clinical medication, long-term outcomes of the three therapies failed to be evaluated temporarily.Conclusions1. The treatment withSRS plus TMZ can control the tumor progression effectively.2. Toxic and adverse effects are majorly mild myelosuppression after treatment with SRS plus TMZ,and the symptoms like nausea, vomiting, headache and alopecia are alleviater than other groups.3. Postoperative follow-ups showed that there was no significant difference among the mediam survivals of patients in the three groups; but on the basis of survival curve, the2-years postoperative lifetime is prolongation in goup C, nevertheless, because of lacking cases, the lifetime of three groups are not significant, long-term outcome is unknown.