局限期小细胞肺癌放射治疗研究进展

小细胞肺癌（small cell lung cancer,SCLC）是高度恶性肿瘤,生物学特点是倍增时间短、增殖指数高和侵袭能力强。尽管对化放疗高度敏感,但极易耐药和复发,预后很差。确诊时约1/3属于局限期（limited-stage,LS）。LS-SCLC具有潜在治愈的可能,采用以铂类为基础的化疗联合胸部放疗,长期生存率达20%～25%。初治达完全或部分缓解的LS-SCLC患者行预防性脑照射(prophylactic cranial irradiation,PCI)可降低脑转移发生率,改善生活质量。随着SCLC患者生存期延长,局部治疗变得非常重要,如何最大程度地降低局部复发的危险性一直是临床研究热点。本文中我们分析了LS-SCLC放射治疗的研究现状,探索最佳放射剂量、次数、靶区、时机及PCI。     

Prospective evaluation of the effect on initial brain metastases from small cell lung cancer of platinum-etoposide based induction chemotherapy followed by an alternating multidrug regimen

BACKGROUND:: During the 1980s reports describing the effect of systemic chemotherapyon brain metastases from chemosensitive tumours emerged, includinga few retrospective reports on small cell lung cancer (SCLC)patients. DESIGN:: Previously untreated SCLC patients with no other malignancy,but in some cases with mixed histological subtype, who had symptomaticbrain metastases verified by contrast enhanced CT-scan, weretreated with a multidrug combination chemotherapy regimen andno cranial irradiation. Radiotherapy was optional at cranialrelapse or progression at the discretion of the physician incharge. The intracranial effect was evaluated by 4-weekly CT-scanand neurological examination, according to a standardized scoringsystem. END POINTS:: Intracranial response, duration of response, neurological score,terminal CNS status, and survival. RESULTS:: 21 patients were included, corresponding to 8.6% of consecutiveSCLC patients at our institution. 8 patients died before follow-upleaving 13 evaluable for response. In the former group, allpatients had WHO performance status of 3–4 compared to6/13 in the latter group. Of the 13 evaluable patients, 1 hadearly progression in the CNS and 1 had no change. 11 had CT-scanverified response, with a median duration of 135 days. Mostpatients, including all complete responders, had improvementin their neurological score. 6 out of 11 responders died withoutactive CNS disease. The crude median survival was 111 days,whereas the median survival(early deaths excluded) was 197 days. CONCLUSION:: Systemic combination chemotherapy was effective for palliationof initial brain involvement in the majority of patients ina small consecutive series. The role of consolidating cranialirradiation in responders should be assessed by a randomizedtrial. small cell carcinoma, brain metastases, chemotherapy     

Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer

In order to evaluate the relationship between neurologic function and cranial irradiation, 20 patients treated on National Cancer Institute (NCI) small-cell lung cancer (SCLC) trials who were alive and free of cancer 2.4 to 10.6 years (median, 6.2) from the start of therapy were studied. All were tested with a neurologic history and examination, mental status examination, neuropsychologic testing, and review of serial computed cranial tomography (CCT) scans. Fifteen patients had been treated with prophylactic cranial irradiation (PCI), two patients with therapeutic cranial irradiation, and three received no cranial irradiation. All patients but one were ambulatory and none were institutionalized. Fifteen patients (75%) had neurologic complaints, 13 (65%) had abnormal neurologic examinations, 12 (60%) had abnormal mental status examinations, 13 (65%) had abnormal neuropsychologic testing, and 15 (75%) had abnormal CCT scans. Compared with those given low-dose maintenance chemotherapy during PCI using 200 to 300 rad per fraction, patients who were given high-dose induction chemotherapy during the time of cranial irradiation or large radiotherapy fractions (400 rad) were more likely to have abnormal mental status examinations (6/6 v 4/9) and abnormal neuropsychologic tests (6/6 v 4/9), but no major difference in CCT findings was present. CCT scans in the majority of cases (11/18) showed progressive ventricular dilatation or cerebral atrophy up to 8 years after stopping therapy. We conclude neurologic abnormalities are common in long-term survivors of SCLC, and may be more prominent in patients given high-dose chemotherapy during cranial irradiation or treated with large radiotherapy fractions. The CCT scan abnormalities are common and progressive years after prophylactic cranial irradiation and chemotherapy are stopped.     

Systemic chemotherapy of brain metastases from small-cell lung cancer: a review.

PURPOSE: For decades the treatment of choice in small-cell lung cancer (SCLC) with brain metastases has been corticosteroids and radiotherapy (RT) because of a presumed lack of penetrance of cytostatic agents into parenchymatous brain metastases. In recent years, several reports have appeared on radiologic and clinical responses to systemic chemotherapy without additional RT in patients with metastatic SCLC in the brain. We reviewed the literature and focused on the methodologic aspects in comparison with RT data. DESIGN: We reviewed 12 patient series that included 116 patients and were published between 1981 and 1990. RESULTS: The overall brain response to chemotherapy without irradiation in patients with intracranial metastases at diagnosis was 76%, whereas the response rate of brain relapses was 43%. CONCLUSIONS: We conclude that intracranial metastases from SCLC seem to respond to chemotherapy as readily as other metastatic locations of SCLC do. Thus first-line cranial irradiation probably should be applied routinely only in cases of delayed brain metastases. Whether consolidating cranial RT should be given after a few courses of initial chemotherapy in SCLC patients with brain metastases at diagnosis is unclear and warrants a randomized evaluation.     

Zerebrale Metastasierung: Prophylaxe und Behandlung

Small cell lung cancer (SCLC) is characterized by a high prevalence of brain metastases, which affect more than half of the patients during the course of the disease. Since the meta-analysis of the late 1990s prophylactic cranial irradiation is a key element in multimodal therapy of limited disease SCLC with complete remission after chemotherapy. Recently, moreover, a multicenter phase III study in patients with advanced disease demonstrated a survival advantage following prophylactic radiotherapy to the brain. In the palliation of cerebral metastases whole brain radiotherapy remains the standard of treatment. The poor survival rates, however, strongly support the need for effective prophylaxis.     

小细胞肺癌预防性脑照射的临床研究

目的 探讨性全脑照射（ＰＣＩ）对局限期小细胞肺癌（ＳＣＬＣ）脑转移率和生存率的影响。方法 １９９０年１月～１９９５年１２月间,５１例经化疗加放疗后完全缓解的局限期ＳＣＬＣ患者被承机分为脑照射组（２６例）和对照组（２５例）。脑照射组患者接受ＰＣＩ２５．２～３０．６Ｇｙ。结果 脑照射组患者的脑转移率为３．８％,明显你芋对照组的２８．０％（Ｐ〈０．０５）。脑照射组患者和,１,２,３年生存率分别为８４．６     

Prophylactic cranial irradiation in small-cell lung cancer

Prophylactic cranial irradiation is now known to improve survival to a significant degree in small-cell lung cancer (SCLC) patients; this is in addition to its established role in preventing the disabling symptoms of brain metastases. New information indicates that it confers a survival benefit for limited or extensive stage SCLC patients gaining a complete response in the chest. A review of causes of cerebral dysfunction as a complication indicates that such problems can be due to suboptimal radiation fractionation, chemotherapy, or an inappropriate combination of prophylactic brain irradiation with chemotherapy. Optimum treatment with prophylactic brain irradiation has been shown not to cause adverse effects with detailed psychometric testing. Several additional sources of information can be drawn together to suggest a dose-response pattern for prophylactic brain irradiation, leading to the recommendation that a dose of 25-36 Gy is optimal, delivered in 2-3 Gy daily fractions after the completion of chest irradiation and chemotherapy. This will be better defined in future clinical trials.     

Management of small cell lung cancer

Opinion statement Small cell lung cancer (SCLC) is an aggressive type of lung cancer characterized by rapid growth and early metastasis. It is chemosensitive and radiosensitive, yet decades of research investigating multimodality treatments have failed to control or cure this disease in most patients. First-line treatment of limited-stage disease consists of chemotherapy (often etoposide/cisplatin or etoposide/carboplatin) combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation to decrease brain metastases as a site of disease progression for those who experience complete remission or a very good partial response to multimodality treatment. In a Japanese trial, the combination of irinotecan and cisplatin had initially shown promise in treating patients with extensive-stage SCLC, but a confirmatory trial in the United States did not find a difference in overall survival with irinotecan/cisplatin versus etoposide/cisplatin. Adding a third drug to the etoposide/cisplatin combination, as well as other triplet therapies, has mostly been ineffective in improving outcomes. Variables in chemotherapy administration, including maintenance therapy, alternating non-cross-resistance regimens, and dose intensification, have not been shown to increase survival at large. In terms of radiation therapy, early administration of TRT concurrent with chemotherapy, and hyperfractionation, have been beneficial in treatment of limited-stage disease. In patients who relapse, second-line therapy options consist of reinduction of previous chemotherapy or administration of a single agent. Targeted biological therapies for SCLC are now being investigated, and although a great deal of research remains to be done, these agents and their derivatives may provide the most hope for future treatment of SCLC.     

小细胞肺癌的治疗进展与现状

肺癌为一种恶性程度较高的肿瘤性疾病,其病死率居各种恶性肿瘤之首,发病率逐年上升,近年随着禁烟教育力度的增强和普及,发病率已出现下降势头。小细胞肺癌(SCLC)是一种以生长迅速、早期转移、高度侵袭性为特点的肺癌类型。小细胞肺癌的肿瘤细胞对化疗和放疗都非常敏感,但几十年来多方案的临床试验并没能找到彻底治愈小细胞肺癌的有效方法,多数患者在一线治疗以后仍会复发或转移。局限期小细胞肺癌的一线治疗包括双药化疗(足量EP方案:依托泊甙 顺铂/卡铂)联合胸腔放射治疗(TRT)。当联合方案达完全缓解(CR)或疗效较好的部分缓解(PR)患者,应后续应用预防性脑照射(PCI),可明显降低未来复发性脑转移的风险。日本和德国的临床研究显示含有伊立替康的IP方案及IC方案(伊立替康 顺铂/卡铂)治疗广泛期小细胞肺癌效果可比标准EP方案。各种强化疗法并不能提高小细胞肺癌患者的生存率。胸腔放疗方案的研究显示局限期小细胞肺癌患者早期同步应用超分割放疗方案配合化疗可以改善预后,可能与放疗越早介入越能有效减少耐药克隆株的发生有关。对于小细胞肺癌复发患者,可依据是敏感复发或是难治复发相应选择再次应用首次化疗方案或用二线单药化疗方案。培美曲塞联合铂类方案已应用于SCLC的一线及二线治疗。PET-CT的应用对小细胞肺癌的精确分期非常重要。真正符合Ⅰ_A期及Ⅰ_B期(TNM分期)的小细胞肺癌患者可考虑手术治疗,术后应行正规化疗。生物靶向治疗小细胞肺癌的若干研究性试验正在进行之中,这些生物制剂及其衍生物有可能会为未来小细胞肺癌的治疗带来一线曙光。     

Chemotherapy for brain metastases in small-cell lung cancer

PURPOSE: Brain metastasis occurs commonly in patients with small-cell lung cancer (SCLC). Herein, we report the efficacy of irinotecan and carboplatin in the treatment of brain metastases from SCLC. In addition, we review the existing data on chemotherapy for brain metastases in SCLC. PATIENTS AND METHODS: Eighty patients with metastatic or relapsed SCLC were enrolled in a phase II trial of irinotecan and carboplatin. Patients naive to chemotherapy were treated with irinotecan 200 mg/m2 and carboplatin AUC of 5, and patients previously treated with chemotherapy received irinotecan 150 mg/m2 and carboplatin AUC of 5, every 21 days for 6 cycles. RESULTS: Among the 80 patients, 15 (19%) presented with brain metastases. An analysis of 14 assessable patients with brain metastases revealed an overall response rate of 65% after 2 cycles of chemotherapy and a median survival of 6 months (range, 1-24 months). Upon review of the literature, 8 studies were identified as having > 10 patients who received chemotherapy for brain metastases from SCLC. Based on these studies, the response rate of brain metastases from SCLC to a variety of chemotherapy and median survival of patients ranged from 22% to 85% and 3 months to 9 months, respectively. CONCLUSION: Chemotherapy, including the regimen of irinotecan and carboplatin, is an effective treatment for SCLC brain metastases.     

Combined modality therapy for limited-disease small cell lung cancer

Opinion statement Small Cell Lung Cancer (SCLC) is highly sensitive to chemotherapy and radiotherapy. However, despite initial responses, relapses are common and most patients eventually succumb to this disease. Patients with limited-disease SCLC represent approximately 30% of all patients with SCLC, and are potentially curable when treated with combined chemotherapy and thoracic radiotherapy (TRT). Chemotherapy consists of four cycles of the combination of cisplatin and etoposide (PE). Thoracic radiotherapy should be started with the first or second cycle of chemotherapy, and preferably administered twice daily for 3 weeks. Prophylactic cranial irradiation (PCI) is recommended for patients who achieve a complete response. Surgery is of limited value in SCLC, except in patients who present with a solitary pulmonary nodule. Approximately 20% to 25% of patients with limited disease (LD)-SCLC can be cured with this aggressive approach. Newer treatment modalities are currently under investigation.     

小细胞肺癌的治疗现状及进展

小细胞肺癌是一种恶性程度较高的肿瘤,具早期发生远处转移的倾向。因绝大多数患者于确诊时已伴有淋巴结或远处转移且无手术治疗的指征,小细胞肺癌的分期很少采用TNM分期法,而根据病灶范围简单地分为局限期与广泛期。不利的预后因素包括广泛期疾病、LDH值升高、不良的行为状态评分体重下降与男性性别。局限期小细胞肺癌的治疗应采用4—6个周期EP方案[（依托泊苷VP-16）＋顺铂（DDP）]化疗联合同期胸部放射的治疗方案。广泛期疾病以全身化疗为主,方案多采用VP-16联合顺铂或卡铂。即便对于老年或行为状态评分较差的患者,联合化疗仍值得推荐。治疗后肿瘤达完全缓解者应接受预防性全颅放疗,以降低颅脑转移率。     

Metastatic patterns in small-cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients

Postmortem material from 537 patients included in various protocols of intensive combination chemotherapy or chemoradiotherapy for the management of small-cell anaplastic carcinoma of the lung (SCLC) has been reviewed. Patterns of residual or recurrent disease were analyzed in relation to pretreatment clinical parameters. Residual primary tumor (P less than .05), regional lymph node involvement (P less than .01), hepatic (P less than .01), bone (P less than .05), and renal metastases (P less than .05) were all significantly less frequent among patients with initially limited-stage disease compared with extensively staged patients. The frequency of residual intrathoracic tumor and metastatic pattern did not significantly differ between partial responders (PRs) and nonresponders (NRs). Patients with limited disease achieving a complete remission had a lower frequency of intrathoracic tumor (P less than .001) at autopsy compared with limited-stage PRs. However, for extensive-stage patients the pattern of residual disease was essentially independent of tumor response. Prior surgery was associated with a reduced burden of metastases only in those who underwent a radical resection. The addition of radiotherapy to the primary tumor and mediastinum failed to modify the autopsy distribution of residual tumor compared with that in patients treated with chemotherapy alone. Metastatic patterns were similar with or without prophylactic abdominal radiotherapy, while prophylactic cranial irradiation (PCl) did not prevent the development of cerebral metastases in patients whose systemic response to treatment was either partial or nonexistent. However, a beneficial effect of PCl in compete responders (CRs) was not excluded.     

Is the Blood–Brain Barrier Relevant in Metastatic Germ Cell Tumor?

PURPOSE: Germ cell tumors are uniquely chemosensitive and curable, even with advanced metastatic disease. Central nervous system recurrence can terminate a complete remission in other chemosensitive tumors, such as small cell lung cancer, because of the blood-brain barrier (BBB). We propose to document that the BBB is also relevant in germ cell tumors despite their dramatic chemosensitivity. METHODS AND MATERIALS: We present five cases illustrating the concept of the BBB in patients with metastatic testicular cancer treated with chemotherapy. RESULTS: In our large series of patients with metastatic testicular cancer treated with chemotherapy, we identified 5 unique patients. These patients were rendered free of disease only to experience relapse in the brain alone. This included 1 patient who initially had good-risk metastatic disease by means of the International Germ Cell Collaborative Group staging system at the onset of chemotherapy. CONCLUSIONS: The BBB is relevant in patients with metastatic testicular cancer.     

Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.     

Limited small cell lung cancer of the lung treated with combination chemotherapy and radiotherapy: a retrospective analysis.

We assessed the outcome in 65 patients with limited small cell lung cancer (SCLC) treated from 1980 through 1989 with combination chemotherapy and chest and cranial irradiation. Of the 65 patients, 32.3% (21/65) achieved a complete remission (CR) prior to radiation therapy; six additional cases achieved a CR after radiotherapy with an improvement of 10% in the incidence of CR. In our group, 8 patients were alive and free of disease at 30 months (12.3%). We think that a combination of local thoracic irradiation in SCLC limited disease plus chemotherapy yields more CR and improves survival, especially in the group of patients who obtained the CR after initial induction chemotherapy.     

The role of topotecan in treating small cell lung cancer: second-line treatment

Small-cell lung cancer (SCLC) is highly chemosensitive but up to 70% of patients with limited disease and more than 90% of patients with extensive disease will relapse after first-line treatment. There are several standard chemotherapy regimens used for second-line treatment yet the prognosis for patients requiring this treatment remains poor. The topoisomerase-I inhibitor, topotecan, has achieved response rates of up to 22% in previously treated patients with SCLC and survival almost double that achieved with other single agents. Compared with cyclophosphamide/doxorubicin/vincristine (CAV), single-agent topotecan achieved a higher response rate, longer survival and statistically significant improvements in dyspnea, hoarseness, fatigue, anorexia and interference with daily activities. Brain metastases are common in SCLC. Topotecan crosses the blood-brain barrier and shows promise for the management of brain metastases.     

Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical setting

Background

Small cell lung cancer (SCLC) represents approximately 13 to 18% of all lung cancers. It is the most aggressive among lung cancers, mostly presented at an advanced stage, with median survival rates of 10 to12 months in patients treated with standard chemotherapy and radiotherapy. In approximately 15-20% of patients brain metastases are present already at the time of primary diagnosis; however, it is unclear how much it influences the outcome of disease according the other metastatic localisation. The objective of this analysis was to evaluate the median survival of SCLC patients treated by specific therapy (chemotherapy and/or radiotherapy) with regard to the presence or absence of brain metastases at the time of diagnosis.

Patients and methods

All SCLC patients have been treated in a routine clinical practice and followed up at the University Clinic Golnik in Slovenia. In the retrospective study the medical files from 2002 to 2007 were review. All patients with cytological or histological confirmed disease and eligible for specific oncological treatment were included in the study. They have been treated according to the guidelines valid at the time. Chemotherapy and regular followed-up were carried out at the University Clinic Golnik and radiotherapy at the Institute of Oncology Ljubljana.

Results

We found 251 patients eligible for the study. The median age of them was 65 years, majority were male (67%), smokers or ex-smokers (98%), with performance status 0 to 1 (83%). At the time of diagnosis no metastases were found in 64 patients (25.5%) and metastases outside the brain were presented in 153 (61.0%). Brain metastases, confirmed by a CT scan, were present in 34 patients (13.5%), most of them had also metastases at other localisations. All patients received chemotherapy and all patients with confirmed brain metastases received whole brain irradiation (WBRT). The radiotherapy with radical dose at primary tumour was delivered to 27 patients with limited disease and they got 4–6 cycles of chemotherapy. Median overall survival (OS) of 34 patients with brain metastases was 9 months (95% CI 6–12) while OS of 153 patients with metastases in other locations was 11 months (95% CI 10–12); the difference did not reach the level of significance (p = 0.62). As expected, the OS of patients without metastases at the time of primary diagnosis turned out to be significantly better compared to the survival of patients with either brain or other location metastases at the primary diagnosis (15 months vs 9 and 11 months, respectively, p < 0.001).

Conclusions

In our investigated population, the prognosis of patients with extensive SCLS with brain metastases at the primary diagnosis treated with chemotherapy and WBRT was not significantly worse compared to the prognosis of patients with extensive SCLC and metastases outside the brain. In extensive SCLC brain metastases were not a negative prognostic factor per se if the patients were able to be treated appropriately. However, the survival rates of extensive SCLC with or without brain metastases remained poor and novel treatment approaches are needed. The major strength of this study is that it has been done on a population of patients treated in a routine clinical setting.     

调强放疗联合化疗治疗局限期小细胞肺癌近期疗效分析

目的：分析化疗联合调强适形放疗治疗局限期小细胞肺癌（SCLC）的近期疗效和放射损伤情况。方法：42例局限期SCLC采用放化疗综合治疗,放疗常规分割,单次剂量2Gy,每周5次,中位总剂量58Gy。化疗采用卡铂或顺铂＋VP 16为主的方案,4-6个周期。中位随访32个月。结果：全组患者CR为35.7%（15/42）,PR为57.1%（24/42）,SD为7.1%（3/42）,有效率为92.8%。1年总生存率（OS）为75.8%,2年为37.5%,3年为21.5%,中位生存时间为23个月。2级急性放射性肺损伤为4.8%（2/42）,2级晚期放射性肺损伤为7.1%（3/42）,2级急性放射性食管损伤11.9%（5/42）,2级血液学毒性为11.9%（5/42）。结论：化疗联合IMRT用于局限期SCLC治疗,能获得较好的近期疗效和2年生存率,放射损伤在可接受范围,放疗剂量、照射范围值得进一步研究。     

Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review)

The brain requires a stable internal environment, which is established by the integrity of the blood-brain barrier (BBB). The efficacy of chemotherapeutics in the treatment of brain malignancies is often hampered by the presence of the BBB. BBB disruption can be performed either by osmotic disruption, bradykinin or irradiation. Radiotherapy with doses of 20 to 30 Gy with fraction size of 2 Gy may be used to increase the permeability of the BBB. These radiation doses by themselves will not give rise to serious side effects or long-term complications. Disruption of the BBB by radiotherapy might have implications in the treatment of primary brain tumors, cerebral metastases, and prophylactic cranial irradiation in small cell lung cancer since irradiation will cause cell kill and may enhance the effect of chemotherapy. We present a review on the effects of irradiation on the BBB and subsequently discuss the potential value for therapeutic applications.