Systemic and skin toxicity in Cercopithecus aethiops sabaeus monkeys treated during 26 weeks with a high intravenous dose of the anti- epidermal growth factor receptor monoclonal antibody Nimotuzumab

Nimotuzumab (h-R3) is a humanized anti-epidermal growth factor receptor monoclonal antibody (mAb) registered for treating head and neck tumours. The present study was designed to evaluate the systemic and skin toxicity of chronic intravenous administration of the h-R3 in a relevant species demonstrated by comparing the h-R3 binding affinity constants (Kd) in microsomal placental fractions from Homo sapiens and Cercopithecus aethiops monkeys using an EGF-Receptor radioligand competition assay. The Kd obtained for Nimotuzumab were 9.1 x 10(-8) M for monkeys and 4.5 x 10(-8) M for humans. Monkeys (n = 18) were distributed into 3 groups with 3 animals of each sex in each group. Group I received saline; group II received 2.85 mg/kg of h-R3; and group III received 28.57 mg/kg of the h-R3, which represent 1 and 10 times the human dose, and they were weekly intravenously treated during 26 weeks. During the study there were no deaths. Electroneurophysiological, sanguine chemistry and haematological results did not evidence alterations. Areas of haematomas, probably related with the administration procedure, were observed at the administration zones of all animals. The electrocardiography study showed at the end of the study a slight increase in the cardiac frequency of four treated animals without other signs. Unexpectedly, skin biopsies and a detailed clinical inspection of the animals did not detect the presence of cutaneous rash or any other skin toxicity sign reported for the majority of the anti-EGF-R monoclonal antibodies. It is concluded that doses up to 28.5 mg/kg of h-R3, intravenously administered during 26 weeks to Cercopithecus aethiops monkeys, do not produce considerable toxic effects.     

h-R3联合放疗治疗局部晚期鼻咽癌的Ⅱ期临床研究

背景与目的:目前临床应用的抗表皮生长因子受体(epidermal growth factor receptor,EGFR)的单克隆抗体易产生人抗鼠抗体反应,影响治疗效果.本研究评估人源化的抗EGFR单克隆抗体h-R3联合放疗对局部晚期鼻咽癌的近、远期疗效及毒性反应.方法:将免疫组化证实有EGFR中、强度表达的Ⅲ～Ⅳb期(UICC 1997)鼻咽癌初诊患者随机分为单纯放疗组(单放组)和放疗联合h-R3组(联合组),两组的放疗剂量和技术基本相同,联合组在放疗期间每周一次静脉滴注h-R3 100 mg.用WHO标准评价两组的近期疗效,用Kaplan-Meier法估计两组的生存率.结果:本研究共纳入35例,单放组和联合组分别为17例和18例,其中联合组有1例于治疗中途退组.联合组于治疗结束时、治疗后5周及治疗后17周时的总CR率分别为72.2%、83.3%和83.3%,而单放组分别为35.3%、41.2%和47.1%(P＜0.05).中位随访时间31.9个月(4.2～40.7个月),单放组的3年局部区域控制率、无远处转移生存率分别为和总生存率93.8%、100%和88.2%,联合组分别为100%、88.2%和94.4%,两组间的差异无统计学意义(P＞0.05).联合组除1例出现Ⅱ级呕吐外,均无任何药物不良反应发生,两组的急性放射反应差异也无统计学意义(P＞0.05).结论:h-R3是一种安全性良好的药物,有助于增强局部晚期鼻咽癌的放射灭瘤效应,但对远期疗效似乎无明显影响.     

Induction of apoptosis in head and neck tumor-cell lines by anti-fas antibody

Programmed cell death, currently termed apoptosis plays a key role in the maintenance of the steady state in continuously renewing tissues. Since little is known of apoptosis in head and neck tumors, we studied morphological changes in head and neck tumor-derived cell lines (KB, KBrc, HSC-2,3,4), induced by anti-Fas antibody. Light and electron microscopic examinations were carried out after culturing these cell lines with the antibody for 1-2 days. The antitumor effect of anti-Fas antibody on tumor cells differed with the cell lines. Most of the cell lines that were sensitive to anti-Pas antibody showed evidence of enhanced apoptosis when the cells were pretreated with interferon-gamma. The results suggest that the strategy of induction of apoptosis by anti-Fas antibody may be considered in treatment of some tumors of head and neck.     

Simultaneous cis-platinum and radiotherapy in inoperable or locally advanced squamous cell carcinoma of the head and neck

A synergism between cis-platinum (CDDP) and radiotherapy (RT) has been demonstrated both in culture systems and in clinical studies. On the above basis, we planned, in patients with locally advanced or unresectable squamous cell carcinoma of the head and neck, a concomitant treatment with CDDP 80 mg/m2 i.v. every 3 weeks for three doses (days 1, 21 and 42) and RT in the primary and in the neck nodes bilaterally, for a total dose of 60-70 Gy. Thirty-five untreated patients with poor prognosis unresectable stage II and stages III-IV disease were entered in the study and 32 were evaluable. Complete response (CR) rate was 75% (24/32) with 95% confidence limits from 60 to 90% (+/- 15%): 8 cases (25%) achieved a partial response, for an overall response rate of 100%. A significantly higher CR rate and a longer survival rate was observed in patients with good performance status (PS = 90-100) and stages II-III. The overall estimated 2-year survival is 46%; 59% for patients who obtained a CR versus 0% for those who achieved only a partial response. Overall the treatment was well tolerated and gastrointestinal and hematologic toxicities were the most common side effects. In conclusion, the combination of CDDP plus RT is a very effective and safe treatment and we recommend such an approach in head and neck squamous cell carcinoma, particularly in those patients with good PS and with unresectable stage II or stage III disease.     

Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: report from a phase I/II trial

The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize the EGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosed high-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy. Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA) (12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated. No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypic response. Objective response-rate was 37.9% (17.2% complete response, 20.7% partial response) while stable disease occurred in 41.4% of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients.     

Combination of direct intratumoral administration of dendritic cells and irradiation induces strong systemic antitumor effect mediated by GRP94/gp96 against squamous cell carcinoma in mice

We tested a new therapeutic modality for head and neck and esophageal cancers, a combination of direct intratumoral (i.t.) administration of dendritic cells (DCs) and radiation therapy (RT) in mouse squamous cell carcinoma (SCC). We also evaluated the functions of gp96, which can enhance systemic antitumor activity, and the mechanism of the abscopal effect. Mouse SCC cells (1 x 10(5)), SCCVII, were inoculated into the left femur of C3H/He mice subcutaneously, and also similarly inoculated into chest subcutaneous tissue. Only the left femur tumor was exposed to 4 or 10 Gy of ionizing radiation, and then 1 x 10(6) DCs i.t. was injected only into the femur tumor. Following this procedure, tumor volumes of the femur and chest were measured. We evaluated whether gp96 could enhance the antitumor effect. With DCs i.t. and RT, tumor growth was markedly suppressed. Tumor growth of non-treated tumors were also suppressed, indicating that the combination therapy of DCs and RT evoked systemic antitumor activity. In vitro, the enhancement of gp96 expression was strongly detected by immunostaining after irradiation, DCs with gp96 induced strong cytotoxic activity in vitro, and tumor growth inhibition was observed by direct i.t. injection of gp96. A combination of DCs i.t. and RT can induce a strong antitumor effect not only against treated local tumor but also against non-treated distant tumor, indicating that this treatment can evoke a strong systemic antitumor effect. Gp96 is thought to be one of the target molecules to explain the abscopal effect.     

Dose scheduling of the dual VEGFR and EGFR tyrosine kinase inhibitor vandetanib (ZD6474, Zactima®) in combination with radiotherapy in EGFR-positive and EGFR-null human head and neck tumor xenografts

Purpose

Vandetanib (ZD6474, Zactima^®) is a novel, orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase activity with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. Vandetanib has demonstrated enhanced efficacy in combination with radiation therapy (RT) in human tumor models. This study aimed to evaluate the schedule-dependent interaction of clinically relevant dosing of vandetanib with RT in human head and neck cancer models that had been characterized as EGFR positive (EGFR⁺) or negative (EGFR^?) in order to begin differentiating vandetanib and RT interactions at the level of antitumor (EGFR) or antivascular (VEGFR2) activities.

Methods

The human head and neck squamous cell carcinoma (HNSCC) cell lines UMSCC2 (EGFR⁺) and UMSCC10 (EGFR^?) are sensitive and resistant to EGFR inhibitors, respectively, while having similar sensitivity to ionizing radiation. Nude mice with UMSCC2 or UMSCC10 tumor xenografts were treated with vandetanib or RT alone, or with combinations of concomitant and sequential therapy. Vandetanib was dosed at 30 mg kg^?1 day^?1 based on pharmacokinetic studies in nude mice showing that this dose results in drug exposure similar to that seen in humans at clinical doses. RT was dosed at 3 Gy twice a week for two consecutive weeks for a total dose of 12 Gy.

Results

Vandetanib alone caused regression in EGFR⁺ but not EGFR^? tumors and RT therapy alone was similar in both tumor types. Combinations of vandetanib and RT showed concomitant use of vandetanib and RT was superior to RT followed by vandetanib or visa versa in EGFR^? tumors. Therapeutic response of EGFR⁺ tumors was similar regardless of treatment sequencing.

Conclusions

The combination of vandetanib and RT is active in both EGFR⁺ and EGFR^? HNSCC tumor xenografts, however, vandetanib alone is only active in EGFR⁺ xenografts. EGFR⁺ tumor response to vandetanib and RT was independent of treatment sequencing, but concomitant treatment was superior to sequencing in EGFR^? tumors. These results suggest that the anti-VEGFR2 antitumor activity of vandetanib is enhanced by RT as presumably the activity seen in EGFR^? tumors is due to antiangiogenic activity, whereas the anti-EGFR antitumor activity dominates in EGFR⁺ tumors such that RT enhancement is not observed.     

Safety and potential increased risk of toxicity of radiotherapy combined immunotherapy strategy

Accumulating interest has emerged in exploring the toxicity profiles of the combination strategy of radiotherapy (RT) and immune checkpoint inhibitors (ICIs). Much remains unknown regarding safety and the potential increased risk of toxicity of a combined treatment. ICI prolongs survival but can induce immune-related adverse events as well. To increase awareness of adverse effect and support immediate and successful management, we go over the literature on the safety of RT combined immunotherapy strategy. Representative evidence relevant to RT combined with ICI in the brain, lung, head and neck, and pelvic malignance was reviewed respectively. Given radiation doses and fractionation, the irradiated volume, the timing of RT, and ICI would significantly affect the safety and efficiency of ICI+RT combination therapy, and no consensus had been reached about how to arrange RT delivery in the combined contexture, we went over the available literature and tried to address these challenges including the timing of RT, optimal dose and fractionations, RT target and target volume, and potential biomarkers to predict toxicity. We found even though RT+ICI combination therapy might augment toxicities, the majority of patients experienced grade 4 or 5 AE are relatively rare and no significant difference could be found between combination group and monotherapy group. Sometimes the acute toxicity with ICI is much less predictable and often life threatening and in some can give rise to permanent effects. Clinicians across disciplines should be aware of these uncommon lethal complications induced by ICI+RT. Early recognition is the key to successful treatment, reversibility of organ dysfunction, and in some cases even prevention of fatal outcome. If recognized early, managed properly, and no fatal AE occurs, the development of irAE indicates a good prognosis. It should be noted that nothing is known about potential late effects because very few studies have 5-year follow-up. The nature of irAE is the attack of activated immune cells on normal tissues. The nature of RT-induced AE is the DNA damage on normal tissue, which is related with the dose delivered and volume irradiated and the tolerance of surrounding normal tissues. The immune-modulating effect of SBRT may augment the damage on normal tissues. To maximize the antitumor immune response, 8–12 Gy/fraction is preferred when conducting RT. The available clinical evidence suggest RT of this dose/fractionated strategy combined with ICI have a tolerable AE profile, which need further validation by more clinical trials in the future. The combination strategy of RT with anti-PD1/PDL1 anti-body is supposed to be concurrent or RT followed by anti-PD1/PDL1 antibody. Although RT and ipilimumab combination sequence is controversial, ipilimumab prior to or concurrent with RT might be proper, which need more clinical validation. Under the concept of immunological dose painting, SBRT work as a trigger of immune response. It has been observed that SBRT of partially radiated tumors combined with ICI could induce similar tumor control compared with total tumor irradiation. The side effects of RT may be mitigated potentially due to the reduction of irradiated volume. The antitumor efficiency and safety profile of immunological RT dose painting+ICI deserve further investigation. Clinical predictive factors for irAE risk remain unclear, and more investigation deserves to be conducted about the irAE prediction.     

Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer

Overexpression of epidermal growth factor receptor (EGFR) in epithelial tumors, including head and neck, lung, breast, colon and other solid tumors, has frequently been correlated with poor prognosis, thus stimulating efforts to develop new cancer therapies that target EGFR. Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting EGFR are the most well-studied and hold substantial promise of success. Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors. This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments. Cetuximab (Erbitux) is being evaluated in combination with radiation or chemotherapy in Phase III trials. Other compounds such as h-R3, ABX-EGF, EMD-55900 and ICR-62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies. Tyrosine kinase inhibitors targeting the intracellular domain of EGFR, including ZD-1839 (gefitinib, Iressa), OSI-774 (Erlotinib/Tarceva), PD-153053, PD-168393 and CI-1033, have been studied in clinical setting alone or in combination with radiation or chemotherapy. ZD-1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer. EGFR targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy. The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy. Challenges of evaluating EGFR targeted agents exist in selecting the optimal dosages and determining long-term toxicity.     

Detection of anti-tumor antibody in virally induced tumors and its relationship to tumor growth.

The humoral antibody response to virally induced tumors insyngeneic hosts has been studied. The tumors include an SV40 tumor SVT2, the Friend virus-induced leukemias FBL-3 and FLC; and Moloney sarcoma virus-induced tumors. It was found that antitumor antibodies could be detected by the isotopic antiglobulin technique in these tumor systems at a relatively early stage of tumor growth. The kinetics of the antibody response in relation to the status of tumor growth varied between different tumors. In geneumor growth than in the regressors of tumor-free hosts. Reinoculation of tumor cells or recurrence of tumor growth produced elevation of antibody levels (secondary response). The specificity of the antibody reactions also varied in different tumor systems: some antibodies were truly tumor-specific and thus might produce a biological effect on in vivo tumor immunity, whereas others were not. These studies indicated that a sensitive antibody assay could be used for early detection of tumor growth. However, its usefulness in evaluation of the status of tumor growth should be carefully studied in each tumor system.     

Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).     

Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer

Overexpression of epidermal growth factor receptor (EGFR) in epithelial tumors, including head and neck, lung, breast, colon and other solid tumors, has frequently been correlated with poor prognosis, thus stimulating efforts to develop new cancer therapies that target EGFR. Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting EGFR are the most well-studied and hold substantial promise of success. Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors. This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments. Cetuximab (Erbitux^®) is being evaluated in combination with radiation or chemotherapy in Phase III trials. Other compounds such as h-R3, ABX-EGF, EMD-55900 and ICR-62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies. Tyrosine kinase inhibitors targeting the intracellular domain of EGFR, including ZD-1839 (gefitinib, Iressa^®), OSI-774 (Erlotinib/Tarceva^®), PD-153053, PD-168393 and CI-1033, have been studied in clinical setting alone or in combination with radiation or chemotherapy. ZD-1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer. EGFR targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy. The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy. Challenges of evaluating EGFR targeted agents exist in selecting the optimal dosages and determining long-term toxicity.     

肝动脉结扎加插管化疗结合外放射治疗肝癌25例

［目的］观察肝动脉结扎加插管化疗结合外放射（ＨＡＬ＋ ＨＡＩ＋ ＲＴ）治疗无法切除肝癌的疗效。［方法］２５例术中发现已无法切除的肝癌患者接受ＨＡＬ＋ＨＡＩ＋ＲＴ治疗。［结果］总有效率（ＣＲ＋ＰＲ）４８．０％,１、３、５年生存率分别为８０．０％、３３．２％、２４．３％。［结论］对于术中发现不能切除的肝癌,采用ＨＡＬ＋ＨＡＩ＋ＲＴ不失为一种较有效的治疗方法,值得推广与进一步研究。     

Feasibility study of single agent Cisplatin and concurrent radiotherapy in Japanese patients with squamous cell carcinoma of the head and neck: preliminary results

BACKGROUND: Concurrent chemoradiotherapy with the single agent cisplatin (CDDP + RT) has been recognized worldwide as the standard treatment for unresectable locally advanced SCCHN. The objective of this study was to clarify the feasibility of CDDP + RT in Japanese patients. Patients and methods Patients with unresectable squamous cell carcinoma of the head and neck were given single daily fractionated radiation (70 Gy at 2 Gy/day) and chemotherapy consisting of a 2 h infusion of CDDP 100 mg/m(2) on days 1, 22 and 43. The primary endpoint was the rate of completion of CDDP + RT. RESULTS: Between November 2005 and January 2007, 20 patients were enrolled, 19 males and one female with a median age of 61.5 years (range 50-74). One patient had recurrent unresectable disease after surgery and the remaining 19 had stage IV disease. No grade 4 hematologic toxicities were observed. The incidence of grade 3 mucositis was 55% and no treatment-related death occurred. Full-dose irradiation was performed in all patients, with a median duration of radiotherapy of 50 days (range 48-54). Although all patients received the first two administrations of CDDP, the third dose was administed in 17 patients (85%). The rate of completion of CDDP + RT was 85% and the dose intensity of CDDP was 28.9 mg/m(2)/week (relative dose intensity 89%). Overall complete response rate was 50% and the rate of primary complete response was 90%. CONCLUSION: Concurrent chemoradiation therapy with the standard dose of CDDP is feasible in Japanese patients. Treatment modification based on racial differences is not necessary.     

Concurrent chemoradiotherapy with low-dose cisplatin plus 5-fluorouracil for the treatment of patients with unresectable head and neck cancer

OBJECTIVE: The purpose of this study was to determine the efficacy of concurrent chemoradiotherapy using conventional radiotherapy combined with low-dose daily 5-fluorouracil (5FU) and cisplatin (CDDP) for the locally unresectable head and neck cancer patients. PATIENTS AND METHODS: From September 1996 through December 2000, we carried out a phase II study of concurrent chemoradiotherapy with low-dose CDDP plus 5FU for the treatment of patients with unresectable squamous cell carcinoma of the head and neck. Chemoradiotherapy consisted of irradiation with 1.6-2.0 Gy/day for 5 days per week up to a total dose 68 Gy and CDDP 3 mg/m2 by intravenous infusion over 1 h plus 5FU 150 mg/m2 by intravenous infusion over 24 h per day for 5 days per week. RESULTS: Ninety percent of the patients had stage IV disease, including 65% of patients with T4 disease. Thirty-three patients (83%) received the full treatment as planned; 39 (98%) received full-dose radiotherapy and 33 (83%) full-dose chemotherapy. Of the 40 patients evaluable for response, 20 (50%) achieved complete response (CR) and 12 (30%) partial response with an overall response rate of 80%. Among the 20 CR patients, 15 underwent endoscopic blind biopsies and 4 had positive lesions. The most frequently observed toxicity was mucositis. Ten patients developed grade III mucositis, and 3 patients required enteral nutritional support through a feeding tube. Grade III leukopenia, anemia and thrombocytopenia were observed in 28, 25 and 20% of the patients, respectively. The median duration of follow-up at the time of analysis was 18 months. The median survival time was 23 months. The responders survived longer (34 months) than the nonresponders (4 months; p < 0.05). CONCLUSION: This regimen is safe and efficacious in the treatment of patients with advanced unresectable head and neck cancer.     

Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model.

Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N(omega)-monomethyl-l-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N(omega)-monomethyl-l-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.     

抗表皮生长因子受体单克隆抗体h-R3联合放疗治疗晚期鼻咽癌的Ⅱ期临床研究

目的观察h-R3与放疗联合治疗晚期鼻咽癌的疗效和不良反应。方法采用随机对照设计,共7个治疗中心参加了这项研究。符合入组标准的晚期鼻咽癌患者随机分为单放组和联合治疗组,两组患者均接受单纯根治性放射治疗,总剂量70—76 Gy.联合治疗组同时给予h—R3治疗,剂量为100 mg/次,静脉滴注,每周给药1次。结果共137例患者入组,其中单放组67例,联合治疗组70例。联合治疗组治疗结束、治疗后第5周和第17周时的肿瘤完全缓解(CR)率,在全分析集(ITT集)分别为65.63%、87.50%和90.63%,在符合方案集(PP集)分别为67.21%、90.16%和93.44%,均显著高于单放组。联合治疗组治疗后第17周时,在ITT集和PP集的有效率均为100.00%,均显著高于单放组(90.91%和92.31%)。治疗前后两组间Karnofsky评分差异无统计学意义,联合治疗组患者体重恢复情况明显好于单放组。与h-R3相关的主要不良反应是发热(4.28%)、血压下降(2.86%)、恶心(1.43%)、头晕(2.86%)、皮疹(1.43%)。h-R3对血常规和生化指标无显著影响,并且未增加放疗的副作用。结论h-R3联合放疗可显著提高晚期鼻咽鳞癌患者的疗效,药物不良反应轻微,对治疗晚期鼻咽癌有很高的临床应用价值。     

Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Thalidomide has been shown to have antiangiogenic effects in preclinical models as well as a significant antitumor effect in hematologic tumors such as multiple myeloma. The authors performed this Phase II study to determine the activity, toxicity profile, and antiangiogenic effect of thalidomide in patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Twenty-one patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with single-agent thalidomide. All patients had received radiation therapy, and most had undergone surgery (95%) and/or chemotherapy (90%). Thalidomide was initiated at 200 mg;3>daily and increased to a target dose of 1000 mg daily. Patients continued treatment until disease progression, unacceptable toxicity, or death occurred. RESULTS: All 21 patients eventually developed progressive disease. Median time to progression was 50 days (95% confidence interval, 28-70), with median overall survival time of 194 days (95% lower confidence boundary, 151), similar to the progression and survival times reported for this patient group with other agents. Thalidomide was generally well tolerated, with few patients experiencing Grades 3 to 4 toxicities. Serum vascular endothelial growth factor and basic fibroblast growth factor levels increased in six of seven patients, for whom paired serum samples were available and all of whom had progressive disease. CONCLUSIONS: In this heavily pretreated population of patients with advanced squamous cell carcinoma of the head and neck, thalidomide does not appear to have single-agent antitumor activity. Further evaluation of the mechanism of action of thalidomide is indicated. Potentially, future evaluations of thalidomide may be performed in combination with other antiangiogenic or cytotoxic agents in patients with earlier stage disease or in patients with minimal residual disease.     

A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04)

A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity, oropharynx and hypopharynx. From June 1979 to February 1983, 42 patients were randomized with 40 patients available for analysis. In the radiotherapy (RT) only group, 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day, 5 days per week, to a total of 4400 to 5200 rad. In the radiotherapy plus misonidazole group (RT + MISO) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses. The observed side effects associated with misonidazole were: persistent numbness and paresthesia (1 patient), transient peripheral nerve paresis and persistent paresthesia (1 patient), and nausea and vomiting (2 patients). The treatment related morbidities were similar in both groups. Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group. Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue (1 in each group). Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group. The initial complete response rate in the RT group was 53%, versus 48% in the RT + MISO group. The estimated 2-year loco-regional control rates were 10% for RT alone and 17% for RT + MISO (no significancy). These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas. However, high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus, is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers.     

Combination chemotherapy with S-1 and carboplatin for head and neck cancers

Chemotherapy plays an important role in the treatment of head and neck cancer (HNC) patients with recurrent and/or metastatic unresectable disease. The standard regimen for HNC has been a combination of cisplatin (CDDP) and 5-fluorouracil (5-FU). We planned to develop a new outpatient regimen that could be carried out safely and had an antitumor activity equivalent to the regimen of CDDP plus 5-FU. For this purpose, we selected a combination of S-1 and carboplatin. The overall response rate of 40.9% in this study was almost equivalent to the study previously reported on 5-FU plus CDDP. This regimen of S-1 plus carboplatin has the possibility of yielding tumor responses equivalent to a conventional regimen of 5-FU combined with CDDP in patients with recurrent and/or metastatic head and neck carcinoma as a second-line palliative chemotherapy.