Combining transcatheter arterial chemoembolization with percutaneous ethanol injection therapy for small size hepatocellular carcinoma

For patients with unresectable small size HCC, percutaneous ethanol injection therapy (PEIT) is used as a non-surgical treatment because it is difficult to achieve complete tumor necrosis by transcatheter arterial chemoembolization (TAE) alone. However, some small HCCs (<21 mm in diameter) are resistant to PEIT with incomplete tumor necrosis, which is associated with insufficient ethanol injection to the tumor. For more effective treatment for HCC, we performed a combination of TAE and PEIT on patients with small size HCC and evaluated the cumulative recurrence and survival rates. The recurrence rate in patients treated with the combination was less than that of TAE or PEIT alone. There were five patients without tumor recurrence during the follow-up period and three out of these underwent the combination treatment. The period of no recurrence was 33.4 months on average. In conclusion, we recommend combination therapy with TAE and PEIT for patients to accomplish more effective treatment of small size HCC.     

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.     

Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs

Somatostatin analogs and α-interferon induce good responses as single drugs in the treatment of endocrine pancreatic tumors. We examined the efficacy and tolerability of the combination of α-interferon and somatostatin analogs in 16 patients with metastatic endocrine pancreatic tumors. All patients except one had received prior treatment and were in a progressive state. Doses of α-interferon and somatostatin analogs were individually titrated. The α-interferon doses varied between 9 and 25 million units per week and were combined with 100–1500 μg of octreotide or 6000 μg of lanreotide daily. Radiological response was seen in 3 of 16 (19%) patients (median duration 23 mo). Biochemical response was seen in 10 of 16 (62.5%) patients (median duration 22 mo). All three patients previously progressing on both α-interferon and somatostatin analog as single drugs achieved a stabilization of the disease when treated with the combination (median duration 10 mo). Seven of eight (88%) patients previously progressing on α-interferon treatment benefited from the combination with biochemical partial response or stabilization. All six patients previously progressing during somatostatin analog treatment achieved biochemical partial response or stabilization. More than 80% of patients who progressed during previous treatment with either drug benefited from the combined treatment, which also was well tolerated. Thus, a combination of α-interferon and somatostatin analogs may be considered for patients previously progressing on treatment with α-interferon or somatostatin analogs. However, in this study, the value of sequential treatment has not been evaluated.     

The role of new agents in the treatment of colorectal cancer

New drugs improved efficacy or convenience of treatment in metastatic colorectal cancer. The oral fluoropyrimidines capecitabine and UFT are less toxic but equally efficacious relative to intravenous bolus 5-fluorouracil (5-FU)/folinic acid (FA). These agents might be beneficial for patients who unlikely benefit from the more intensive combination therapy with infusional 5-FU/FA and irinotecan or oxaliplatin. First-line therapy with irinotecan or oxaliplatin and 5-FU/FA induces an objective response in up to 50% of the patients and may allow neoadjuvant concepts in unresectable liver metastasis. The combination therapy increased progression-free survival and in the case of irinotecan/5-FU/FA also overall survival when compared to 5-FU/FA. Sequential treatment with infusional 5-FU/FA plus oxaliplatin followed by 5-FU/FA plus irinotecan or vice versa results in a median survival exceeding 20 months. Thus, patients in a good performance status and with favorable prognostic parameters should be offered first-line combination treatment of irinotecan or oxaliplatin with 5-FU/FA, whereby 5-FU is preferably administered as an infusion for combination therapy. New targets in the treatment of colorectal cancer are the EGF and VEGF receptor. The monoclonal EGF receptor antibody cetuximab alone and in combination with irinotecan is active in second-line treatment. The VEGF antibody bevacizumab prolongs survival when given in combination with 5-FU/FA and irinotecan.     

Preliminary trial of combination therapy with adriamycin and radiation in sarcomas and other malignant tumors

Based on reports of synergism between adriamycin and radiation therapy in experimental systems, a trial was initiated testing this combination in 53 adult patients with various advanced malignancies, especially sarcomas. Since studies have suggested a selective sensitization of hypoxic cells when this drug is given prior to radiation, an injection of low-dose adriamycin was given 90 min before radiation. This treatment was repeated every 7 days. The combination was most effective in the 30 patients with soft-tissue sarcomas, with 62% of these patients having partial or complete responses. Responses were less good in patients with gastric adenocarcinoma or with other tumors. The toxicity of the combined treatment was moderate. Further trials of this combination are warranted.     

Paclitaxel and carboplatin in pretreated advanced gastric cancer: a phase II study.

In the present study, the combination of paclitaxel and carboplatin was applied in the treatment of gastric carcinoma. This cytotoxic combination has been an effective regimen with acceptable toxicity in ovarian, lung and head and neck cancers. We evaluated 47 patients (37 male, 10 female), all with advanced disease and all having undergone prior chemotherapy treatment. All patients had disease progression or no response to the prior treatment. Forty-four patients had undergone a previous gastrectomy for gastric adenocarcinoma and 3 patients were inoperable at diagnosis. Paclitaxel 175 mg/m2 was administered as a three-hour infusion, followed by carboplatin 5 AUC infused for 90 min. Thirteen (27.66%) patients showed partial response with a median survival of 10 months; 3 (6.38%) patients showed minor response and 13 patients, stable disease with clinical benefit. The median survival of patients with minor response and disease stability was 6 months. Eighteen (38.29%) patients had disease progression with a median survival of 3 months. It appears that in advanced cancer patients, the paclitaxel-carboplatin combination is an effective second-line treatment, resulting in partial response and disease stability in 61% of patients as well as in a prolongation of median survival.     

Chemotherapy as treatment of primary and recurrent small cell lung cancer

Chemotherapy is the treatment of choice in metastatic stage of small-cell lung cancer (SCLC). Radiation therapy, surgery and other forms of therapy are only included in special treatment situations, particularly for different local problems. A wide range of chemotherapeutic agents have proven to be effective in SCLC, including carboplatin, cisplatin, cyclophosphamide, doxorubicin, epirubicin, etoposide, ifosfamide, teniposide and vincristine. However, treatment results could not be improved over the last 10 years and the median survival of patients with metastatic disease is limited to 7-10 months. New agents like docetaxel, gemcitabine, irinotecan, paclitaxel, topotecan and vinorelbine have shown promising results in phase-II investigations. Yet, no evidence is provided from randomized trials to employ these drugs in first line treatment. Clearly, polychemotherapy is superior to single agent treatment. Compared to the combination of cisplatin and etoposide, no other combination has clearly shown improved results in large phase-III randomised trials, yet. The combination of cisplatin and irinotecan has also shown promising results in a single randomised trial with the need to be confirmed in larger settings. Neither extending the initial treatment beyond the median number of six cycles, nor maintenance treatment have-so far-resulted in any increase in survival results for patients with metastasised SCLC. Nor has dose-intensification, which causes significantly higher toxicities in patients, shown a clear impact on the overall survival of these patients. Brain metastases represent a high frequent complication associated with SCLC. In these cases, the combination of chemotherapy and whole brain radiation therapy is advocated. Second-line treatment should always be considered in patients with relapse or failure to first-line therapy. In addition to a rechallenging with the prior drug combination or selecting a different potentially non-cross resistant one, monotherapy with topotecan proved to be effective as well. In summary, up to now, no standard chemotherapy combination exists for metastatic SCLC. The individual therapy strategy can only be selected by considering the clinically relevant conditions of the patient.     

Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison with regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.     

Piperacillin alone vs triple antibiotic combination in gynecological infections

Forty hospitalized adult patients with gynecological infections were randomly assigned to treatment either with piperacillin alone (22 patients) or with the combination of gentamicin, clindamycin and penicillin G (18 patients). The aim of the study was to investigate the possibility of replacing a triple combination therapy with a single-agent broad spectrum antibiotic. Penicillin G was added for the coverage of enterococci. The median duration of treatment was 8 days for both groups. The daily dose for the administered drugs was 12g for piperacillin, 4mg/kg for gentamicin, 1.8g for clindamycin and 20 million units for penicillin G. The cure-improvement rate in the single agent therapy group was 90.9% and in the combination therapy group 94.4%. These differences were not statistically significant. No side effects were reported. It is concluded that single agent piperacillin is as effective as the combination therapy used in this study for the treatment of hospitalized gynecological infections.     

Trastuzumab monotherapy versus combination therapy for treating recurrent breast cancer: time to progression and survival

Background HER2 expression is an important prognostic and predictive factor of treatment efficacy in breast cancer. Trastuzumab, in particular, is a key drug in the treatment of HER2-positive recurrent breast cancer. However, the difference in treatment efficacy between trastuzumab monotherapy and combination therapy with chemotherapy is unclear. In order to elucidate this point, both treatments were compared in terms of efficacy by metastatic site, time to progression (TTP), and survival. Patients and methods The subjects were 1,471 breast cancer patients who had been evaluated for HER2 expression between 1998 and March 2006; 74 of these had recurrent breast cancer that had been treated with trastuzumab. Of these 74 patients, 39 received trastuzumab alone and 45 trastuzumab in combination with chemotherapy. The items of investigation were clinical effect, TTP, survival, biological markers such as ER/PgR, proliferation (Ki67) or p53 overexpression, nuclear grade, performance status (PS), lymph node metastasis, and tumor size. Results The HER2-positive rate was 23.3%, and the degree of malignancy in these HER2-positive patients was high; postoperative disease-free survival (DFS) was low. However, this tendency was clear in patients with hormone-responsive breast cancer. In patients with hormone-non-responsive breast cancer, HER2 negativity had a significantly higher Ki67 value, and there was no difference in DFS between patients with HER2-positive and -negative tumors. Among the 74 patients with recurrent breast cancer, the response rate to trastuzumab was 64.9%; however, among patients who received the combination treatment, the response rate was 86%. In patients with liver metastasis, the effect of trastuzumab alone was low, but that of the combination treatment was significantly high. TTP was 5.7 months and 15.9 months with trastuzumab alone and the combination therapy, respectively. Furthermore, a significant difference was seen in post-treatment survival; however, there was no significant difference in survival after a recurrence. In the multivariate analysis on factors for TTP, PS, clinical effect, and combination treatment were significant. However, good PS and early treatment were the significant factors in post-treatment survival. Conclusions The effect of trastuzumab in patients with recurrent breast cancer who received the combination treatment was significantly high and TTP was long. However, this was not a significant factor in terms of overall survival. In particular, a good PS and early treatment were important in post-treatment survival. This article is based on a presentation delivered at Symposium 3, “Molecular target therapy: basics and clinical application,” held on 30 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.     

Absence of cross resistance between an irinotecan plus cisplatin combination and raltitrexed (ZD1694) in two patients with advanced colorectal cancer

Two patients with advanced colorectal cancer were consecutively administered two different chemotherapeutic regimens. The first patient showed an initial response to combination treatment with irinotecan plus cisplatin, but then progressed. He subsequently responded to treatment with a novel thymidylate synthase (TS) inhibitor, raltitrexed. The second patient, who progressed after exhibiting a response to raltitrexed, subsequently responded to irinotecan/cisplatin combination therapy. In conclusion, no clinical cross resistance between the regimens of irinotecan/cisplatin combination therapy and raltitrexed was observed in these patients with advanced colorectal cancer.     

The Impact of Sorafenib in Combination with Transarterial Chemoembolization on the Outcomes of Intermediate-Stage Hepatocellular Carcinoma

Background: We investigated the treatment outcomes and hepatic reserve of transarterial chemoembolization (TACE)-refractory patients with recurrent advanced hepatocellular carcinoma (HCC) treated with TACE plus sorafenib. Methods: Forty-one patients with intermediate-stage HCC defined as being TACE refractory on imaging were treated with sorafenib and TACE between 2009 and 2012 and comprised the combination treatment group. Twenty-nine patients who received repeated TACE after becoming refractory to TACE between 2005 and 2008 comprised the TACE continuation group. Results: Although the interval between successive rounds of TACE was significantly shorter before the patients developed TACE refractoriness, it was significantly longer after the development of TACE refractoriness, in the combination treatment group compared with the TACE continuation group. The appearance of extrahepatic spread and/or vascular invasion differed significantly between the two groups. The median overall survival was significantly longer in the combination treatment group than in the TACE continuation group (20.5 vs. 15.4 months, respectively; hazard ratio = 2.04; 95% confidence interval = 1.20–3.48). The 3-year overall survival rate was 33.4% in the combination treatment group and 3.5% in the TACE continuation group. Downstaging of the Child–Pugh class was significantly less frequent in the combination treatment group than in the TACE continuation group. In COX proportional hazards analyses, sorafenib plus TACE resulted in a better prognosis compared with repeated TACE. Conclusions: Treatment with sorafenib plus TACE in TACE-refractory patients with intermediate-stage HCC resulted in longer intervals between TACE rounds, better maintenance of hepatic reserve, and significantly longer OS compared with repeated TACE.     

Avastin in the treatment of breast cancer

Over the last decades, various new agents have been developed for the treatment of metastatic breast cancer and overall survival of these patients has increased. The role of chemotherapy in the treatment of metastatic breast cancer is well established. Bevacizumab is a potent antiangiogenic agent active in many solid tumors. Three randomised clinical trials (E2100, AVADO and RIBBON I) proved the benefit of chemotherapy, especially a combination of taxanes and bevacizumab, as the first line treatment of metastatic breast cancer. The combination improved patient progression-free survival in all trials with no impact on the known toxic effects of taxanes. This may be a potent treatment option particularly for patients with triple negative breast cancer, and a potentially less toxic alternative to combination chemotherapy.     

Mitomycin-C and vinblastine in advanced breast cancer

Forty-two patients with metastatic breast cancer refractory to first-line therapies were treated with combination chemotherapy with mitomycin-C and vinblastine. A response to treatment was observed in 11 of 34 evaluable patients (32.3%), with 3 complete remissions (8.8%) and 8 partial remissions (23.5%). The median duration of response was 185+ days. The 12-month survival was 78% for responders, 48% for patients with stable disease and 0% for patients with progressive disease. The toxicity was acceptable with 20 episodes of moderate myelosuppression (58.8%) and 2 cases with congestive heart failure that responded to medical treatment. The MMC-VBL combination is an active regime for advanced breast cancer previously treated with antracyclines. This combination may be regarded as a standard second-line treatment for this type of tumor.     

霍奇金淋巴瘤治疗研究进展

大多数霍奇金淋巴瘤（HL）可以治愈,目前的一线治疗通常采用ABVD方案（多柔比星、博来霉素、长春碱和达卡巴嗪）化疗或联合放疗。但是复发难治HL治疗依旧是一个巨大的挑战。大剂量化疗序贯自体造血干细胞移植对该类患者最为受益,同时维布妥昔单抗（BV）联合程序性死亡受体1单抗nivolumab、BV联合ICE（异环磷酰胺、卡铂、依托泊苷）、帕比司他（panobinotast）联合ICE等方案以及许多新药正在临床试验和研发中。第58届美国血液学会（ASH）年会对HL的最新治疗进展进行了深入报道。     

皮下植入中人氟安联合静滴亚砷酸治疗晚期肝癌临床研究

目的：探讨晚期肝癌新疗法皮下植入中人氟安联合静滴亚砷酸的疗效及毒副作用。方法：治疗组33例晚期肝癌和术后或介入术后复发的病例,一次皮下植入中人氟安400mg-480mg;静滴亚砷酸（三氧化二砷）每日10mg,连用14天为一疗程,每4周-6周重复,评价疗效、毒副反应、生存质量（KPS评分）、生存期等情况,与对症治疗组46例进行对比。结果：治疗组33例病例均能耐受,其中完成3疗程7例（21.21%）,2疗程14例（42.42%）,1疗程12例（36.36%）;出现胃肠道反应（腹胀或加重,或伴恶心、呕吐）12例（36.36%）;肝功能异常或黄疸加重10例（30.30%）;Ⅰ°-Ⅱ°骨髓抑制9例（27.27%）;植入区皮肤非感染性皮炎22例（66.67%）,其中并感染4例（12.12%）,KPS提高17例（51.52%）,稳定7例（21.21%）,下降9例（27.27%）;CT或MRI评价：CR0例,PR8例（24.24%）,NC13例（39.39%）,PD12例（36.36%）,临床获益（显效）（CR＋PR＋NC）21例（63.36%）,中位生存期6.7月,比对照组的3.4月长,P〈0.01。结论：初步临床研究表明,皮下植入中人氟安联合静滴亚砷酸治疗晚期肝癌有63%显效率,平均延长寿命3月余,两药有协同作用,毒副反应轻,能耐受,值得进一步扩大临床研究和加强机理探讨。     

Combination therapy with fludarabine and rituximab followed by alemtuzumab in the first-line treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase 2 trial of the Minnie Pearl Cancer Research Network

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of the combination of fludarabine and rituximab, followed by alemtuzumab, as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). METHODS: In a nonrandomized phase 2 trial, 41 patients who had previously untreated CLL or SLL and required treatment received 4 cycles of the fludarabine and rituximab combination followed 5 weeks later by 4 weeks (12 doses) of intravenous alemtuzumab therapy. The response to treatment was evaluated after completion of treatment with fludarabine and rituximab, and again after the completion of alemtuzumab consolidation. RESULTS: Initial treatment with the combination of fludarabine and rituximab was well tolerated, and produced a 71% overall response rate (13% complete response). Thirty-four patients began treatment with intravenous alemtuzumab, but this drug was relatively poorly tolerated when given at a short interval after fludarabine and rituximab, and only 20 patients (49% of total) were able to complete the prescribed course. Five patients had an improvement in their response with alemtuzumab; the final complete response rate was 21%. The median progression-free survival for the entire group was 42 months. Toxicity with alemtuzumab included infusion-related toxicity, myelosuppression, and opportunistic infections. CONCLUSIONS: The intravenous schedule of alemtuzumab employed in the trial was relatively poorly tolerated in this community-based trial. The relatively low complete response rates after treatment with the combination of fludarabine and rituximab and after the completion of treatment suggest that these abbreviated courses may compromise efficacy. The generalized use of alemtuzumab as consolidation therapy cannot yet be recommended for community practice. However, optimization of the route of administration, duration of treatment, and interval after completion of induction therapy may improve efficacy, and further investigation is ongoing.     

Long-term LHRH-agonist treatment in metastatic breast cancer as a single treatment and in combination with other additive endocrine treatments

Twenty-one premenopausal patients with metastatic breast cancer (unselected for receptor status) were treated during 3-14 months with the potent LHRH-agonist Buserelin (Hoe 766) as a first-line therapy. In one-third of 12 patients treated with Buserelin alone an objective tumour response was observed in the absence of side effects. The longest duration of response occurred in 2 patients with complete remissions (14+ and 13+ months). After addition and in combination with tamoxifen this LHRH-agonist treatment caused an objective response in about half (8/17) of the patients. A problem appears to be the great variation in hormonal response especially during the combination treatment with tamoxifen, which was not found during combination treatment with megestrol acetate in 4 patients. Ultimately, of the whole group of 21 patients, 9 patients (43%) showed an objective remission, 6 stable disease and 6 progression of tumour growth.     

A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer

Oral capecitabine has been shown to be a convenient and well tolerated alternative to intravenous 5-fluorouracil (5-FU) in the treatment of colorectal cancer. The question of whether capecitabine is an adequate and equally effective substitute for infusional 5-FU in combination with oxaliplatin for the treatment of advanced colorectal cancer has long been unanswered. On the basis of results from the randomized, phase III trial by Cassidy et al., capecitabine in combination with oxaliplatin has emerged as a valid treatment alternative to infusional 5-FU in combination with oxaliplatin in patients with advanced colorectal cancer. For patients treated in the US, however, questions about the most appropriate dosage and schedule of capecitabine have not yet been completely resolved. Oncologists will probably have to use a lower starting dose of capecitabine in combination therapies that include oxaliplatin, than that used in this study.     

Chemo/radiation with and without surgery in the thoracic esophagus: the Wayne State experience

Wayne State University was the site of one of the initial experiences with combination chemotherapy, radiation, and surgery for carcinoma of the thoracic esophagus. This review analyzes all the patients seen with thoracic esophageal carcinoma from 1980 to 1984 inclusive, plus an additional 22 patient pilot study. The great majority of patients seen were treated with combination radiation and chemotherapy, which may have a greater applicability than dose esophagectomy. Eighty-nine patients completed planned preoperative treatment consisting of (5-FU cisplatin and radiation therapy). Of these patients, 39 patients refused or were not offered surgery, and 4 patients are still alive and well several years from treatment initiation. Fifty patients underwent esophagectomy. Twelve of this patients were free of tumor at esophagectomy, and 4 of these are still alive and well several years from treatment. One patient with residual tumor in the esophagectomy specimen alone is still alive. Because of disappointing results and surgical mortality risk, 22 patients were entered on the pilot study, increasing the tumor dose of 5,000 cGy, and increasing chemotherapy to 4 courses. Six patients are still alive in this small series. Since the results of radiation and chemotherapy combination approximates that of best prior trials of radiation therapy alone, a randomized study has been initiated comparing these treatment plans to determine if the combination of radiation and chemotherapy is superior to radiation alone.