Multicenter phase II study of chemo-immunotherapy in the treatment of metastatic renal cell carcinoma

The purpose of this study was to evaluate the potential efficacy of a chemo-immunotherapy regimen for the treatment of metastatic renal cell carcinoma (MRCC). Forty-one patients with progressing MRCC and with a median age of 63 years were recruited. Planned treatment consisted of 6 courses of capecitabine 1000 mg/m twice daily on days 1 to 14 every 4 weeks, pegylated alpha-interferon 2b 50 microg every week, interleukin-2 1.8 M IU subcutaneously, and oral 13-cis-retinoic acid 0.5 mg/kg, all given 5 days/wk, 3 weeks of each month. After 6 courses of concomitant biochemotherapy, biotherapy was continued in patients who had a clinical benefit. The primary end point was response; secondary end points were the evaluation of the immunologic parameters, toxicity, progression-free, and overall survival. The treatment was well-tolerated. Grade 3 and 4 neutropenia and thrombocytopenia occurred in 5% and 7% of patients, respectively. The overall response rate in the 41 evaluable patients was 53.6% (95% confidence interval 37%-69%). Median progression-free and overall survivals were 14.7 and 27.8 months, respectively. A sustained improvement in all evaluated immunologic parameters was observed in the 36 patients treated with maintenance biotherapy. Six cycles of biochemotherapy, being followed by maintenance immunotherapy is well-tolerated and shows significant activity in patients with MRCC.     

多西他赛每周方案联合顺铂二线治疗治疗非小细胞肺癌

目的 研究多西他赛每周方案联合顺铂二线治疗非小细胞肺癌(NSCLC)的疗效和毒性反应.方法 48例晚期非小细胞肺癌患者,既往曾接受1个含铂方案治疗,采用多西他赛30 mg/m2,静脉滴注60 min,第1、8、15 d给药,顺铂40 mg静脉滴注60 min,第1～3 d,每28 d为1周期.患者的行为状态评分(PS)均为ECOG≤2.结果 48例患者均可评价,总共化疗周期数为189周期.1例完全缓解(CR)占2.1%,14例部分缓解(PR)占29.2%,有效率(ORR)为31.3%,中位生存时间为37周,1年生存率为33%,粒细胞减少与乏力为主要的毒性反应,其他的毒性反应为脱发和体液潴留.结论 多西他赛30 mg/m2每周给药联合顺铂二线治疗NSCLC有确切的疗效且耐受性好.     

周剂量多西紫杉醇联合顺铂二线治疗进展期胃癌的临床研究

目的 研究多西紫杉醇(TXT)联合顺铂(DDP)方案二线治疗进展期胃癌的疗效和毒副作用.方法 既往应用FOLFOX4或XELOX方案化疗进展的晚期胃癌患者36例,采用多西紫杉醇(艾素)35 mg/m2,第1、8天,静滴;顺铂20 mg/m2,第1～5天,静滴,21 d为1个周期.结果 36例患者中,CR 0例,PR 10例,SD 12例,PD 14例,客观有效率(CR+PR)27.8%,中位生存期6.5个月,中位肿瘤进展时间4.4个月.毒副作用主要为中性粒细胞减少.结论 多西紫杉醇联合顺铂方案二线治疗进展期胃癌有效率较高,有生存优势,毒副作用可耐受.     

周剂量多西紫杉醇联合顺铂二线治疗进展期胃癌的临床研究

目的研究多西紫杉醇（TXT）联合顺铂（DDP）方案二线治疗进展期胃癌的疗效和毒副作用。方法既往应用FOLFOX4或XELOX方案化疗进展的晚期胃癌患者36例,采用多西紫杉醇（艾素）35mg／m2,第1、8天,静滴;顺铂20mg／m2,第1～5天,静滴,21d为1个周期。结果36例患者中,CR0例,PR10例,SD12例,PD14例,客观有效率（CR＋PR）27．8％,中位生存期6．5个月,中位肿瘤进展时间4．4个月。毒副作用主要为中性粒细胞减少。结论多西紫杉醇联合顺铂方案二线治疗进展期胃癌有效率较高,有生存优势,毒副作用可耐受。     

Multicenter phase 2 study of interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced non-small-cell lung cancer

High serum levels of vascular endothelial growth factor (VEGF) are a poor prognostic factor for patients with advanced non-small-cell lung cancer (NSCLC). We have previously shown that low-dose interleukin (IL)-2 and 13-cis retinoic acid (RA) decreased VEGF and improved the immune function of patients with advanced tumors treated with chemotherapy. The primary end point of this study was to verify whether IL-2 and RA decreased serum VEGF in NSCLC patients showing a clinical benefit from chemotherapy. The secondary end point was the evaluation of clinical outcome. We treated 38 patients with advanced NSCLC who had a complete or partial response or disease stability to chemotherapy and had a median serum VEGF level of 508 ng/mL; as maintenance therapy, they received subcutaneous IL-2 (1.8 x 10(6) IU) and oral RA. Matched controls (n = 87) were selected from a large cohort of patients with a similar disease status, including clinical benefit from chemotherapy. The most common adverse events were mild cutaneous skin rash and fever. Serum VEGF decreased to a mean level of 152 ng/mL (P = 0.0002). A statistically significant improvement in immune function was observed (lymphocyte and natural killer cell numbers and CD4+/CD8+ ratio) with respect to baseline values and controls. An improvement in the clinical outcome was also observed compared with controls. These data show that the administration of low-dose subcutaneous IL-2 and oral RA to patients with advanced NSCLC showing a clinical benefit from chemotherapy is feasible with a low-toxicity profile, decreases VEGF, and seems to improve progression-free and overall survival.     

泰索帝联合顺铂治疗26例蒽环类耐药性晚期乳腺癌临床观察

目的:观察泰索帝联合顺铂方案治疗蒽环类耐药性晚期乳腺癌的疗效与副反应。方法:运用泰索帝联合顺铂方案治疗蒽环类耐药性晚期乳腺癌26例,观察其疗效与副反应。结果:本文运用泰索帝联合顺铂化疗方案治疗26例蒽环类耐药的晚期乳腺癌患者,完全缓解(CR)7.7%,部分缓解(PR)42.3%,疾病稳定(SD)30.8%,疾病进展(PD)19.2%,RR50.0%,CBR80.8%,中位肿瘤进展时间(TTP)5.6个月(2～24个月),1年生存率为61.5%。主要副反应为胃肠道反应和骨髓抑制,胃肠道反应以恶心、呕吐常见,3级副反应发生率分别为3.8%、3.8%,无4/5级副反应发生,骨髓抑制以粒细胞减少最为常见,其中3/4级发生率分别为34.6%,无5级副反应,仅出现1/2级厌食、腹胀、乏力、外周神经炎、心电图异常、肝、肾功能异常等副反应,均能较好地耐受。结论:泰索帝联合顺铂方案治疗蒽环类耐药性晚期乳腺癌疗效较好,副反应较小,是治疗蒽环类耐药性晚期乳腺癌的有效化疗方案。     

调强放疗联合多西他赛和顺铂化疗并卡培他滨维持治疗中晚期食管癌的临床观察

目的 评价调强放疗联合多西他赛和顺铂同期化疗并卡培他滨维持治疗中晚期食管癌的临床疗效和安全性.方法 46例Ⅲ/Ⅳ期的中晚期食管癌患者根据入选标准随机分成调强放疗联合多西他赛和顺铂化疗并卡培他滨维持治疗（治疗组）和调强放疗联合多西他赛和顺铂化疗（对照组）,每组23例,治疗组在放疗第1天同时给予多西他赛75 mg/m2,第1天静脉滴注,顺铂25 mg/m2,第1～3天静脉滴注,21 d为1个周期,直至放疗结束后行卡培他滨维持治疗;对照组在放疗的同时联合多西他赛和顺铂化疗.两组放疗方法相同,采用X线和CT检查比较两组疗效,并且比较两组间毒副反应的差别.结果 治疗组与对照组完全缓解率（CR）分别为56.5％和47.8％,有效率（CR＋ PR）分别为91.30％和82.61％,差异无统计学意义.中位生存时间（OS）分别为22.9个月和18.2个月,中位无进展生存期（PFS）分别为11.7个月和9.5个月,两组有统计学差异（P≤0.001）.治疗组1、2、3年生存率分别为82.6％、47.8％和21.7％,对照组1、2、3年生存率分别为60.9％、30.4％和13.0％,两组有统计学差异（P≤0.001）.毒性反应方面,对照组Ⅱ～Ⅲ度的放射性食管炎、胃肠道反应较治疗组严重（P＜0.05）.结论 调强放疗联合多西他赛和顺铂同期化疗并卡培他滨维持治疗较单纯调强放疗联合多西他赛和顺铂化疗疗效好,可提高中晚期食管癌的有效率、局部控制率,延长生存期,提高生活质量,且毒副反应患者均能耐受.     

An immunotherapy schedule in endocrine-dependent metastatic breast cancer: correlation between clinical course and immunologic parameters

The authors reported important benefits and survival with an immunotherapy schedule in patients with endocrine-dependent breast cancer with distant metastases. Here they update clinical outcome and correlate it with immunologic data. Twenty-nine consecutive patients with metastatic disease stable or responsive to first-line antiestrogens were recruited and treated with cyclic administration of beta-interferon and interleukin-2 combined with continuous conventional anti-estrogen therapy. Eosinophils and the total number of lymphocytes and CD4+, CD8+, and CD16+56+ cells were determined in the peripheral blood during first-line hormone immunotherapy before and 24 to 72 hours after the administration of interleukin-2. At the last observation (June 30, 2004), 10 patients had died. After a mean follow-up of 59 +/- 37 months (range 9-163), definite median time had not yet been reached either for clinical benefit or for overall survivals; estimated values were 38, 103, and 106 months for clinical benefit and overall survival from first-line anti-estrogen treatment and from diagnosis of distant metastases, respectively. Two patients maintained complete remission 108 and 163 months after the beginning of first-line anti-estrogen therapy. In patients with clinical benefit, eosinophils, total lymphocytes, and CD4+, CD8+, and CD16+56+ cells significantly increased after interleukin-2 administration (from P < 0.012 to P < 0.000). In the patients with progressive disease, only a slight increase in eosinophils occurred (P = 0.038). No further adverse events other than the minimal ones described occurred. The estimated median benefit and survivals are more than three times longer than previously shown in similar populations. The differing response to interleukin-2 can be explained by the hypothesis that resting cancer cells during clinical benefit do not inhibit the immune system, while at the onset of resistance they recover the constitutive ability to inhibit it.     

多西紫杉醇联合顺铂治疗晚期非小细胞肺癌

目的：探讨多西紫杉醇联合顺铂治疗晚期非小细胞肺癌（Non-Small Cell Lung Cancer,NSCLC）的临床疗效和不良反应。方法：42例晚期NSCLC患者,采用多西紫杉醇75 mg/m^2加入5%葡萄糖注射液500 mL中静脉滴注1 h,第1天;顺铂25 mg/m^2加入0.9%氯化钠注射液500 mL中静脉滴注,第1-3天。21 d为一个周期,至少二个周期评价疗效。结果：42例患者中,完全缓解（CR）2例,部分缓解（PR）19例,无变化（NC）13例,进展（PD）8例;初治组有效率为54.5%,复治组有效率为45.0%,两组比较,差异无统计学意义（P〉0.05）。中位生存期为10.9个月,中位疾病进展时间为4.8个月,1年生存率为40.5%。Ⅲ-Ⅳ度不良反应：白细胞减少为33.3%,脱发为19.0%,口腔黏膜炎为11.9%。结论：多西紫杉醇联合顺铂治疗晚期非小细胞肺癌有较好的疗效,不良反应轻,耐受性好,值得进一步研究。     

周剂量多西他赛联合顺铂治疗老年非小细胞肺癌的临床研究

目的观察周剂量多西他赛联合顺铂治疗老年晚期非小细胞肺癌的近期疗效和毒副反应。方法86例经病理证实的晚期非小细胞肺癌患者,多西他赛35mg/m^2。第1、8天给药,联合顺铂25mg／m^2,第1～4天给药,21d为1个周期。结果86例患者完成2个周期化疗后评价近期疗效,完全缓解3例,部分缓解38例,稳定40例,进展5例,总有效率47．67％。主要毒副反应为骨髓抑制、脱发、消化道反应,但均较轻微。结论周剂量多西他赛联合顺铂方案治疗老年非小细胞肺癌疗效明显,毒副反应轻．耐受性好。     

紫杉醇联合顺铂治疗晚期乳腺癌32例分析

目的分析紫杉醇联合顺铂治疗晚期乳腺癌的疗效、毒性。方法32例晚期乳腺癌患者,应用紫杉醇联合顺铂治疗,化疗周期为21~30 d,中位治疗周期数为4(2~7)。紫杉醇中位剂量为162.5mg/m2(132.2~200.0 mg/m2);联合顺铂中位剂量74.5 mg/m2(67.5~85 mg/m2)。结果(1)全组患者有效率为40.6%,其中CR 1例,PR 12例,SD 15例,PD 4例(2)既往曾用过蒽环类药物患者有效率为45.8%;KPS评分70~80的有效率为33.3%,KPS评分90~100的有效率为45.0%。(3)肺转移患者的有效率为60.0%,肝转移患者的有效率为50.0%,软组织转移患者有效率为66.7%,而骨转移未见有效病例。(4)主要毒性反应为恶心呕吐和骨髓抑制。Ⅲ度和Ⅳ度恶心、呕吐发生率为5%。Ⅲ度和Ⅳ度白细胞减低发生率为75%,Ⅲ度和Ⅳ度血红蛋白减低发生率为25%;Ⅲ度和Ⅳ度血小板减低发生率为15%。结论紫杉醇联合顺铂治疗晚期乳腺癌疗效较好,毒性反应可以耐受。     

A phase II study of docetaxel and infusional cisplatin in advanced non-small-cell lung cancer

BACKGROUND: To evaluate the efficacy and safety of combination chemotherapy of cisplatin (5-day continuous infusion) and docetaxel for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients had an ECOG performance status of 0-2 with measurable NSCLC. Patients received continuous infusion cisplatin 20 mg/m2/day on 5 days and bolus docetaxel 60 mg/m2/day (day 1; PiD therapy) at a 4-week interval. RESULTS: Forty-three patients were enrolled. The mean number of cycles administered per patient was 2, and ranged from 1 to 4. The response rate was 49% (95% confidence interval, 33.9-63.8%). The median survival time was 47 weeks and the 1-year survival rate was 47%. The major toxic effects were grade 3 or 4, neutropenia (88%), leukopenia (81%), thrombocytopenia (14%) and anemia (42%). There were no treatment-related deaths. CONCLUSION: PiD therapy was a well-tolerated and active regimen for patients with advanced NSCLC. The major toxicity was neutropenia.     

多西他赛联合奈达铂方案治疗晚期食管癌的临床观察

目的观察多西他赛联合奈达铂方案治疗晚期食管癌的近期疗效和毒副反应。方法 69例晚期食管鳞状细胞癌患者随机分为2组:观察组35例,多西他赛75 mg/m2静脉滴注,第1天,奈达铂100 mg/m2静脉滴注,第1天;对照组34例,多西他赛75 mg/m2静脉滴注,第1天,顺铂75 mg/m2静脉滴注,第1天;每3周1个周期,至少完成2个周期。结果 2组的总有效率相比,差异不具有统计学意义。治疗组Ⅲ~Ⅳ度毒性反应主要是白细胞及血小板减少,对照组Ⅲ~Ⅳ度毒性反应主要是恶心呕吐、食欲不振。结论在晚期食管癌中,多西他赛联合奈达铂方案与多西他赛联合顺铂方案疗效相近,但在毒副反应方面,多西他赛联合奈达铂方案耐受性良好,更具有优势。     

DG及DP方案治疗晚期非小细胞肺癌的临床研究

目的 探讨多西紫杉醇＋吉西他滨（DG方案）和多西紫杉醇＋顺铂(DP方案)治疗晚期非小细胞肺癌的临床疗效和毒性反应。方法 经病理学或细胞学确诊不可手术的Ⅲb／Ⅳ期NSCLC患者125例,DG组65例,DP组60例。DG组：多西紫杉醇100㎎/㎡,d1;吉西他滨1 100㎎/㎡,d1、8。DP组:多西紫杉醇100㎎/㎡,d1; 顺铂80㎎/㎡,d2。对临床疗效和毒副反应进行对比观察。结果 有效率DG组为46.2%,DP组为45%,两组差异无统计学意义（P﹥0.05）。DG组和DP组中位生存期分别为12.4月和11.7月,一年生存率为50.8%和46.7%,均无统计学差异（P >0.05）。毒副反应均以骨髓抑制、胃肠反应为主,可耐受。DP组Ⅲ~Ⅳ度白细胞下降、恶心/呕吐、腹泻较DG组严重（P﹤0.05）。其他毒副反应相似。结论 DG方案和DP方案治疗晚期NSCLC均具有较好的耐受性和疗效,毒副反应可以耐受。DG方案毒副反应较DP方案更少、更轻,可作为晚期NSCLC较理想的化疗方法之一。     

多西紫杉醇在非小细胞肺癌二线治疗中疗效及剂量的研究

目的观察多西紫杉醇在非小细胞肺癌二线治疗中的疗效和安全性,并探讨安全使用剂量的范围。方法选取26例在2009年1月至2011年2月26日期间于福建省肿瘤医院肿瘤内科进行治疗且经病理证实符合入选标准的晚期非小细胞肺癌患者,对他们进行多西紫杉醇75mg/m2单药化疗,并根据骨髓毒性来调整剂量。每化疗2个周期后按照实体瘤疗效评价标准（RECIST1.0版）评价疗效和中位肿瘤进展时间,按照化疗药物毒副反应判定标准（NCICTC3.0版）评价毒性反应。结果 1例不能耐受其不良反应出组,1例化疗1周期后出现进展,25例病例可评价疗效。总体情况是0例CR、6例PR、13例SD、6例PD,客观有效率（RR）为24%（6/25）,疾病控制率（DCR）为76%（19/25）;中位PFS为4个月,本组中位OS为10个月。毒性主要表现为粒细胞下降及疲乏,100%粒细胞下降,其中Ⅲ/Ⅳ粒细胞下降为84.6%（22/26）;粒缺伴发热为26.9%（7/26）;Ⅲ疲乏的发生率为23.1%（6/22）。调整多西紫杉醇剂量,安全剂量浓度平均为60.84mg/m2。结论多西紫杉醇75mg/m2二线治疗晚期非小细胞肺癌骨髓毒性大,合适剂量为60mg/m2。在该剂量下,能够延长晚期非小细胞肺癌患者生存期,同时改善生活质量。     

Chemotherapy and immunotherapy combination in advanced prostate cancer

In prostate cancer, there is considerable evidence that tumors promote immune tolerance starting early in the disease. By suppressing tumors and activating immune system homeostatic mechanisms, chemotherapy may help overcome this tumor-induced immune tolerance. As such, chemotherapy may therefore support improved results from novel immune-modulating therapies. Prostate cancer is particularly suited for active immunotherapy because prostate tumor cells express a number of distinctive surface antigens. Sipuleucel-T, which has recently been approved in the United States, is an active immunotherapy that triggers T-cell responses against prostate cancer. An exploratory analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, VITAL-2, a phase III trial investigating a prostate cancer therapeutic vaccine plus concurrent docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed lower overall survival with the vaccine regimen. This trial highlights major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy. Patient characteristics, prostate cancer disease stage, and treatment history also may influence the response to combined therapy. Advances in biomarker validation and trial design are needed to efficiently investigate these issues.     

Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma

OBJECTIVE: To evaluate the efficacy and safety of adding thalidomide to the pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone (DVd) regimen for multiple myeloma. PATIENTS AND METHODS: Patients newly diagnosed as having active multiple myeloma and those with relapsed-refractory disease were studied between August 2001 and October 2003. Patients received DVd as previously described. Thalidomide was given at 50 mg/d orally and the dose increased slowly to a maximum of 400 mg/d. At the time of best response, patients received maintenance prednisone, 50 mg orally every other day, and daily thalidomide at the maximum tolerated dose for each patient. The primary end point was the rate of complete responses plus very good partial responses as defined by the European Group for Blood and Marrow Transplantation criteria and the Intergroupe Fran?ais du Myélome, respectively. RESULTS: Of 102 eligible patients, 53 were newly diagnosed as having multiple myeloma, and 49 had been previously treated for multiple myeloma. The complete response plus very good partial response rate was 49% and 45%, with an overall response rate of 87% and 90% for patients with newly diagnosed and previously treated multiple myeloma, respectively. Furthermore, better responses were associated with improved progression-free and overall survival. The most common grade 3 and 4 adverse events were thromboembolic events (25%), peripheral neuropathy (22%), and neutropenia (14%). CONCLUSIONS: The addition of thalidomide to the DVd regimen significantly improves the response rate and quality of responses compared with the DVd regimen alone. This improvement is associated with longer progression-free and overall survival. The rate of observed quality responses is comparable to responses seen with high-dose therapy.     

Defining the immunogram of breast cancer: a focus on clinical trials

In phase III ImPassion130 trial, the addition of immunotherapy to chemotherapy improved overall survival in metastatic triple-negative breast cancer patients. This benefit was significant only in patients harboring PD-L1-positive tumors, suggesting that stratification according to response biomarkers is needed to achieve consistent responses. Besides PD-L1 expression, a variety of potential biomarkers are under investigation for predicting immunotherapy efficacy in breast cancer, such as tumor-infiltrating lymphocytes, gene signatures, tumor mutational burden, microsatellite instability, and gut microbiome. Enriching future trials through these biomarkers could help identifying the population of responders, realizing what has been called precision immunotherapy.     

Adoptive immunotherapy: novel applications of blood cell separators

Animal models have demonstrated that syngeneic lymphocytes activated ex vivo and infused into animals with experimentally induced tumors can mediate tumor regression. This "adoptive immunotherapy" has been applied to patients with end-stage malignancy refractory to standard therapy. Lymphocytes are collected with the blood cell separator, expanded in culture under the influence of cytokines such as interleukin-2 (IL-2), and reinfused into the patient under conditions similar to those used in the animal models. Studies from several centers using lymphokine-activated killer (LAK) cells, involving more than 300 patients, have shown an overall response rate of greater than 15% and a complete response rate of approximately 10%. Renal cell carcinoma, melanoma, and lymphoma appear to be the cell types that respond best to such therapy. Toxicity in these phase 1 studies has been substantial, related primarily to high doses of intravenous IL-2, and treatment-related deaths have been reported. Adoptive immunotherapy using lymphocytes derived from surgically excised tumors, tumor-infiltrating lymphocytes (TIL), is in the early stages of clinical trials, but this appears to offer a potentially more potent and specific approach than does LAK cell therapy. TIL have been shown to traffic to tumor sites and mediate tumor regression. The mechanisms of adoptive immunotherapy are poorly understood, but blood cell separators and storage technology are playing a critical role in the collection and processing of cells for these research applications.     

Dramatic response to immunotherapy in an epidermal growth factor receptor-mutant non-small cell lung cancer: A case report

BACKGROUNDThe advent of immune checkpoint inhibitors (ICIs) has revolutionized the management of several types of solid cancers, including lung cancer, by boosting the body''s natural tumor killing response. However, it is undeniable that only a small proportion of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can achieve long-term responses and benefit from immunotherapy.CASE SUMMARYHerein, we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval. In this case report, we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy.CONCLUSIONWe suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression (defined as ≥ 25%), the L858R mutation, smoking history, or pemetrexed pretreatment may benefit from immunotherapy.