Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 ("Iressa") and trastuzumab ("Herceptin").

PURPOSE: The aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu. METHODS AND MATERIALS: The effects of inhibitors on the radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay. RESULTS: Radiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited the radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29. CONCLUSIONS: The present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

[Intensity Modulated Radiation Therapy (IMRT)].

Radiotherapy plays an important role in the management of cancer patients, and half of the patients with malignant tumors are treated with radiotherapy in the United States. In Japan, the necessity of radiation therapy has come to be widely acknowledged in cancer treatment, and more and more cancer patients are being treated with radiation. External beam radiation is the most-used radiotherapy at the present time. The advantage is that this treatment modality can be used in a short time, although the problem is that not only the cancer lesion but also the surrounding normal tissue is irradiated,causing an adverse effect on normal tissue. In order to solve this problem,treatments such as 3D-Conformal Radiation Therapy (3D-CRT), Intensity Modulated Radiation Therapy (IMRT), Stereotactic Radiation Surgery (SRS) and Stereotactic Radiation Therapy (SRT) are clinically used as an extremely precise radiotherapy, thanks to the advances in computer technology in recent years. Therefore, the purpose of these extremely precise radiation therapies is to administer a high dose to the tumor intensively, and to suppress quantities of magnetism to normal tissues. IMRT treatment results for prostate cancer patients and head and neck cancer patients are reportedly better than with other irradiation methods. In this chapter,we explain the external irradiation method with the focus on IMRT and the extremely precise radiotherapy preformed in the Tokyo Women's Medical University Hospital.

Assessment of psychological responses in patients about to receive radiotherapy.

PURPOSE: Radiotherapy is considered to be associated with psychological distress. We assessed the mental status, anxiety, and the factors associated with these in cancer patients about to receive radiotherapy. MATERIALS AND METHODS: Hospitalized patients about to receive radiotherapy participated. Psychological status was assessed by a psychiatrist, based on interview about the type of anxiety related to cancer or radiotherapy as well as self-rating questionnaires. RESULTS: Eligible data were collected from 94 patients. The incidence of mental disorders was 20%. The total mood disturbance scores were significantly higher in patients with poor performance status. The most common type of anxiety regarding radiotherapy was acute adverse effect, and the predictors were palliative treatment and living alone. CONCLUSION: Mental disorders, mood disturbance, and anxiety in patients cannot be neglected in radiation oncology practice. Especially careful attention should be paid to patients with these predictive factors.

Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process.

Cardiac glycosides such as digitoxin and ouabain have previously been shown to be selectively cytotoxic to tumor as opposed to normal cells. Moreover, this class of agents has also been shown to act as potent radiosensitizers. In the present study we explored the relative radiosensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzel that recently underwent a Phase I trial as a novel drug for anticancer therapy. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radiosensitization depended on duration of exposure of cells to drug prior to radiation treatment. While a radiosensitizing effect of oleandrin was evident with only 1h of cell exposure to drug, the effect greatly increased with 24h oleandrin pretreatment. Susceptibility of PC-3 cells to oleandrin and radiation-induced apoptosis was dependent on activation of caspase-3. Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.

Induction chemotherapy followed by hyperfractionated radiotherapy with concurrent chemotherapy for locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to improve tumor control, the survival rate and organ preservation for locally advanced head and neck cancer by using induction chemotherapy followed by hyperfractionated radiotherapy and concurrent chemotherapy. MATERIALS AND METHODS: Thirty-five patients with stage III-IVB head and neck cancer were treated with this protocol. Induction chemotherapy consisted of cisplatin and fluorouracil and concurrent chemotherapy consisted of carboplatin and doxifluridin. Radiotherapy was administered twice a day until a dose of 72 Gy was reached. RESULTS: Twenty-two (63%) and 13 patients (37%) achieved complete responses and partial responses, respectively. In terms of non-hematological toxicities, grade 3 mucositis was observed in 49% of the patients. The overall 5-year survival was 53.5% and the progression-free survival was 40.6%. CONCLUSION: Response to induction chemotherapy was useful as a predictive factor for ultimate outcome and organ conservation. More intensive regimen or other combination chemotherapy is needed to improve treatment outcome with hyperfractionated radiotherapy.

Radiotherapy with concurrent docetaxel for advanced and recurrent breast cancer.

BACKGROUND: Docetaxel has shown remarkable radiosensitizing properties in vitro. In this study we investigated whether the addition of docetaxel to radiotherapy enhanced tumor response in patients with advanced or recurrent breast cancer. METHODS: A total of 35 patients were enrolled in this study. Docetaxel was administered concurrently during radiotherapy. Radiation doses were 54 to 69 Gy (median 60 Gy). In those enrolled through January 2000, docetaxel 40 mg/m2 was administered biweekly (once every two weeks), with subsequent dose adjustments based on tolerance and bone marrow and liver function. Beginning in February 2000, a weekly docetaxel schedule was used instead. This new regimen was based on data suggesting reduced myelosuppression with this regimen. The weekly dose rate was 20 mg/m2, with dose reductions for impaired organ function. RESULTS: All patients were evaluated for toxicity and response and a total of 40 irradiated sites were evaluated for local response. The overall response rate of irradiated sites was 95% and the CR rate was 68%. CR and PR were achieved in 40%, 37% of patients, respectively. Acute toxicities were tolerated by most patients: 17% had Grade 3-4 neutropenia, 6% had Grade 3-4 radiation dermatitis, and 3% had Grade 3-4 pneumonitis. CONCLUSION: The combination of docetaxel with radiotherapy is an active and safe regimen in patients with inoperable advanced or recurrent breast cancer. We determined the recommended dose of docetaxel with concomitant radiotherapy to be 20 mg/m2 weekly for a Phase II study. Further study is necessary to assess the impact of this treatment on long-term outcome.

[A case of recurrent breast cancer with chronic renal failure treated on an outpatient basis].

We report a case of recurrent breast cancer with chronic renal failure in a 58-year-old female. She could be treated on an outpatient basis under good general condition for most of her remaining life by chemoradiotherapy in combination with hemodialysis. Modification of the chemoradiotherapy procedures and collaboration of medical staff including the doctor in charge of home medical care and her family was indispensable in keeping her hospital stay as short as possible.