Enhanced Tumor Control Research Articles

Intensity Modulated Radiotherapy (IMRT) Decreases Treatment-Related Morbidity and Potentially Enhances Tumor Control

Intensity modulated radiation therapy (IMRT), a new form of three-dimensional conformal radiation therapy (3DCRT), optimizes the concept of computer-controlled radiation deposition in tumor (target) while sparing adjacent normal structures. A retrospective review was done on the initial 185 patients with tumors in different sites including prostate cancer, head and neck cancer, pediatric tumors, adult brain tumors, and previously irradiated recurrent tumors treated with IMRT.Preliminary findings indicate that IMRT is a new clinically feasible tool in radiation oncology. Treatment-related morbidity profile was favorable. Tumor response, local control, and the ability to palliate previously irradiated patients are encouraging. Intensity modulated radiation therapy will allow dose escalation, leading to better tumor control.

Prostate cancer: Multimodality approaches with docetaxel

The trend toward earlier diagnosis of prostate cancer and technological advances in radiotherapeutics (eg, imaging enhancement, planning optimization, refinement of calculation algorithms, and computerized delivery systems) have led to increased use of radiation therapy (RT) as primary treatment for presumed localized disease. However, monomodal local therapy fails to achieve consistently successful long-term disease control, especially in patients with intermediateand high-grade risk factors. Local-regional factors, such as absolute and relative resistance mechanisms, epigenetic influences, and clonogenic heterogeneity, and probable micrometastatic disease require consideration, evaluation, and potentially the implementation of combined modality approaches. Patients receiving combined RT and androgen suppression (AS) in various sequences (AS → AS + RT, AS + RT, AS → AS + RT → AS, and RT → AS) have shown enhanced diseasefree survival, increased pathologic local control related to the duration of AS treatment, and improved overall survival with prolonged AS. Furthermore, limited but provocative trials suggest that multimodality chemoradiotherapy may also enhance tumor control in patients with locally advanced disease with acceptable toxicity. Several new trials that will test the efficacy and safety of docetaxel combined with radiotherapy as well as biologic modifiers are described.

A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model II. improved tumor control at clinically achievable temperatures

Purpose: To assess the therapeutic gain (at the TCD 50 level) that can be obtained by boosting thermoradiotherapy with intravenous glucose infusion at different temperatures. This completes our series of studies to determine the optimal conditions and the effectiveness of glucose administration at clinically achievable glucose levels and treatment temperatures. Methods and Materials: Subcutaneous rat rhabdomyosarcoma BA1112 was irradiated with graded single doses of 300-kV X-rays (dose range 0–60 Gy). Fifteen minutes after irradiation, a 100-min intravenous infusion was started, consisting of either glucose (20% solution, 2.4–3 g/kg/h) or saline as a control. Then heat was applied to the tumors at 42°C or 43°C (water bath) during a subsequent 100-min period of infusion. Tumor control was scored as the absence of palpable growth at 100 days after treatment. Results: Glucose infusion enhanced tumor control independent of temperature in the range 42–43°C. At 42°C, the TCD 50 for X-irradiation decreased by 5.9 Gy (SEM 1.8 Gy), from 41.6 (1.6) to 35.7 (1.5) Gy, and at 43°C from 33.3 (1.6) to 27.3 (1.5) Gy, representing a glucose enhancement ratio of approximately 1.2. At doses corresponding to the TCD 50 at either 42 or 43°C, the addition of glucose increased tumor control from 50% to 70%. An enhancement ratio of 2.1 was found for the combination of irradiation, glucose infusion, and heating at 43°C, with respect to irradiation alone (TCD 50 56.3 Gy, reanalyzed earlier data). The contribution of combined heat and glucose to tumor control represented an additive effect, probably on the hypoxic cell population. Conclusion: Moderate glucose administration (blood concentration 300 mg/100 mL) sizably improves experimental tumor control after combined X-irradiation and hyperthermia under clinically feasible conditions. Clinical treatment should benefit from this additional modality, in particular if unsatisfactory local control rates are due to insufficient heating. The therapeutic gain has to be evaluated further in clinical studies.

Isolated limb perfusion for local gene delivery: efficient and targeted adenovirus-mediated gene transfer into soft tissue sarcomas.

To evaluate the potential of isolated limb perfusion (ILP) for efficient and tumor-specific adenovirus-mediated gene transfer in sarcoma-bearing rats. A major concern in adenovirus-mediated gene therapy in cancer is the transfer of genes to organs other than the tumor, especially organs with a rapid cell turnover. Adjustment of the vector delivery route might be an option creating tumor specificity in therapeutic gene expression. Rat hind limb sarcomas (5-10 mm) were transfected with recombinant adenoviruses. Intratumoral luciferase expression after ILP was compared with systemic administration, regional infusion, or intratumoral injection using a similar dose of adenoviruses carrying the luciferase marker gene. Localization studies using lacZ as a marker gene were performed to evaluate the intratumoral distribution of transfected cells after both ILP and intratumoral injection. Intratumoral luciferase activity after ILP or intratumoral administration was significantly higher compared with regional infusion or systemic administration. After ILP, luciferase gene expression was minimal in extratumoral organs, whether outside or inside the isolated circuit. Localization studies demonstrated that transfection was confined to tumor cells lying along the needle track after intratumoral injection, whereas after ILP, lacZ expression was found in viable tumor cells and in the tumor-associated vasculature. Using ILP, efficient and tumor-specific gene transfection can be achieved. The ILP technique might be useful for the delivery of recombinant adenoviruses carrying therapeutic gene constructs to enhance tumor control.

Applications of brachytherapy in head and neck cancer.

Brachytherapy offers the radiation oncologist the opportunity to deliver high doses of radiation to the tumor, with minimal doses to the surrounding normal tissue. This combination enhances the therapeutic ratio. It allows for enhanced tumor control, with minimal toxicity. When utilized, it often allows for tumor control without the need for resection. This is especially important in the head and neck. Resection of organs such as the lip, oral tongue, base-of-tongue, and other sites can cause significant functional and cosmetic morbidity. The ability to save these structures, using radiation therapy instead of surgery, can provide excellent tumor control and optimal quality-of-life outcome. In situations of recurrent disease, especially when prior radiation has been given, brachytherapy is often the only way to re-irradiate certain areas. This can be done alone, or in combination with surgery. Therefore, brachytherapy becomes an important component of the treatment of recurrent disease. This broad overview of the use of brachytherapy in head and neck cancer will include applications in the primary as well as the recurrent disease setting.

137 Enhanced tumor control of human glioblastoma multiforme xenografts with the concomitant use of radiotherapy and an attentuated herpes simplex-1 virus (ASTRO Research Fellowship)

Purpose: Glioblastoma Multifonne remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-l virus alone. We have chosen a replication competent, non-neurovimlent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft.

Circadian rhythms and cancer chemotherapy.

Temporal coordination of biologic processes with an approximately 24-h cycle (circadian) is common throughout the animal and plant kingdom and even in some prokaryotic organisms. In all organisms studied, the capability to keep biologic time is an inherited characteristic located intracellularly. These biological clocks anticipate and get the organism ready for regular environmental changes. This indicates both the ubiquity and the weight of the selective environmental pressure to keep time accurately. Several molecular strategies for biologic time keeping have apparently arisen independently several times throughout evolution. The anatomic, biochemical, and molecular mechanisms of the clock are in the process of being defined. This temporal organization at the cellular, organ, and organismic levels results in predictable differences in the capacity of plants, animals, and human beings to respond to therapeutic interventions administered at different times throughout important biologic cycles (e.g., circadian timed therapy). In the treatment of the cancer bearing host, circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, enhanced tumor control, and improved host survival. The routine clinical application of such principles is facilitated by the availability of programmable drug delivery devices. Rhythm frequency ranges other than 24-h (e.g., low frequency: menstrual; high frequency: 10 to 120 min) may also be important to understanding health and disease and to designing successful therapy in diseases as diverse as cancer, infertility, and diabetes.

Modulation of hematoporphyrin derivative-sensitized phototherapy with corynebacterium parvum in murine transitional cell carcinoma

The interaction of photodynamic therapy (PDT) with hematoporphyrin derivative (Hpd) and immunotherapy with Corynebacterium parvum (CP) was studied in a murine transitional cell carcinoma (MBT-2) model. C3H/He mice were transplanted subcutaneously in the hind limb with 2.5 × 10 5 tumor cells. One day after transplantation, mice were randomized into groups to receive saline (control), PDT, CP 25 μg, CP 250 μg, CP 25 μg + PDT, and CP 250 μg + PDT. PDT was administered by intraperitoneal (IP) injection of Hpd (12.5 μg/g body weight), followed twenty-four hours later by photoirradiation. CP was given intralesionally at the same time as IP injection of Hpd (24 hours before photoirradiation). A low dose of CP (25 μg) was shown to enhance the effect of PDT while PDT reduced the benefit obtained with high dose of CP (250 μg). In a second series of experiments, CP (250 μg) treatment after photoirradiation was shown to give significantly greater benefit than CP treatment before photoirradiation. The study thus indicates that the effectiveness of combined immunophototherapy is dependent on the sequence of the combination and its intricate relationship with the dosage of CP. The enhancement of PDT by low dose of CP in this model suggests the usefulness of this combined immunophototherapy in enhancing tumor control and in lessening deleterious side effects.

Improved control of bulky prostate carcinoma with sequential estrogen and radiation therapy

Patients with bulky prostate cancer have usually been treated by palliative measures because the likelihood of tumor control with definitive irradiation has been low and the development of distant metastases high. The addition of estrogen to irradiation has not been shown to be of value. However, we believe the method of estrogen administration may have been the cause for the apparent lack of benefit. Estrogen had been started either concurrent with irradiation or had been used for palliation and was given for long and unscheduled time periods prior to irradiation. We have used estrogen for two months prior to and concurrent with irradiation. We postulated that in those patients with estrogen responsive cancer, the reduced tumor burden prior to irradiation could enhance tumor control and survival. Between 1975 and 1980, 25 patients with bulky prostate cancer received sequential estrogen and irradiation, 12 patients irradiation alone and six patients irradiation after having become refractory to longterm estrogen use. One patient was lost to follow-up. Eighteen of 25 (72%) treated by sequential estrogen and irradiation, 14/17 (82%) with estrogen responsive cancer and 4/8 (50%) with estrogen resistant cancer had a complete tumor response. Six of 11 (55%) patients treated by irradiation alone and 2/6 (33%) treated by irradiation for estrogen refractory cancer had a complete tumor response. Disease-free survival was observed in 13/25 (52%) treated by sequential estrogen and irradiation, and 8/17 patients (47%) with irradiation. It is also possible the improved survival in the estrogen responsive group was a direct result of improved local control. Persistent local disease can act as a source for distant metastases. Distant metastases was observed in 15% of patients when the primary tumor was controlled and 30% when there was persistent or recurrent local disease. Also, progressive local disease can be an important cause of death. This was most evident in our patients with estrogen refractory cancer. Almost all patients in this group had progressive local disease that caused serious urinary bleeding and urinary infection that were considered the major cause of death. Our results suggest bulky prostate cancer should be aggressively treated when first diagnosed. The value of adjunct estrogen is unproven. Our results with the use of estrogen prior to and concurrent with irradiation is encouraging. Estrogen may shrink the cancer and allow for a more favorable geometry for external irradiation. Tumor control and survival may be thereby improved. The lower frequency of tumor control and survival of patients with estrogen resistant cancer indicates the need to explore other therapeutic approaches for this group of patients. A higher dose of external irradiation or the addition of chemotherapy prior to irradiation may be of value.

Enhanced tumor control following sequential treatments of photodynamic therapy (PDT) and localized microwave hyperthermia in vivo

Photodynamic therapy (PDT), or photoradiation therapy (PRT), utilizing hematoporphyrin derivative (HPD) as photosensitizer and an argon-dye laser system as the light source, was used alone and in combination with localized microwave hyperthermia (2450 MHz) to treat axillary tumors of the SMT-F mammary carcinoma in mice. Thirty-minute heat treatments were applied either immediately before or immediately after a standard PDT treatment of 630 nm light at 75 mW/cm2 for 30 min (135 J/cm2) given 24 hr post-7.5 mg/kg HPD, intraperitoneally (i.p.). Tumor control as judged by lack of tumor regrowth 35 days or longer after the combined treatments was compared to that following each treatment when given alone. Little or no enhancement of tumor control was seen when sublethal temperatures of 37.5, 38.5, and 39.5 degrees C were applied for 30 min immediately following the PDT treatment. However, increasing levels of enhancement were seen when heat treatments of 40.5 and 41.5 degrees C or 44.5 degrees C, given for 30 min, were applied immediately before or after the photodynamic treatment.

Skin Radioprotection by 5-Thio-D-Glucose

The radioprotective effect of 5-thio-D-glucose on mouse skin was studied. Intraperitoneal injection of A/J mice with 1.5 g/kg of 5-thio-D-glucose 2 hr prior to X irradiation of the foot reduced early foot skin damage through Day 40 postirradiation by a dose modification factor of 1.3 +/- 0.1. Similarly, late foot deformity during Days 60-90 postirradiation was reduced by a factor of 1.2 +/- 0.1. The radioprotective effect of 5-thio-D-glucose was also compared with that of WR-2721, an aminothiol radioprotector, in CDF1 mice. An intraperitoneal injection of 1.5 g/kg of 5-thio-D-glucose reduced early radiation-induced skin damage by a dose modification factor of 1.2 +/- 0.1 as compared to that of 1.5 +/- 0.2 by 0.65 g/kg of WR-2721 in this strain of mice. 5-Thio-D-glucose is also known to specifically kill and radiosensitize hypoxic tumor cells. Consequently, this drug may be a useful radiotherapy adjuvant, reducing normal tissue damage and enhancing tumor control by minimizing hypoxic protection.