High-dose intra-arterial cisplatin therapy followed by radiation therapy for advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To assess the effectiveness of a protocol consisting of 4 cycles of high-dose intra-arterial cisplatin infusions followed by radiation therapy for improving chemotherapy response rates, organ preservation, and survival in patients with advanced-stage untreated and previously treated squamous cell carcinoma of the head and neck. DESIGN AND SETTING: A prospective study of sequentially enrolled patients treated in an academic medical center. The Kaplan-Meier method was used for survival analysis. PATIENTS: Fifty-eight nonpregnant adults, 18 years of age or older, with measurable untreated or recurrent advanced biopsy-proven squamous cell carcinoma of the head and neck. MAIN OUTCOME MEASURES: Response rate to targeted intra-arterial cisplatin infusions, organ preservation, and survival. RESULTS: Fifty-eight patients (44 men and 14 women) were followed up for at least 2 years (median duration of follow-up, 27 months). Twenty-nine (67%) of the 43 previously untreated patients had a complete response to intra-arterial cisplatin therapy. Of the untreated patients, 28 are alive and disease free after a median follow-up time of 30 months. Five of the patients with recurrent disease had a complete response to intra-arterial cisplatin therapy. There were 4 survivors after a median follow-up time of 17.5 months. Of note, there were no deaths or serious complications related to the treatment in either group. CONCLUSIONS: High-dose intra-arterial cisplatin therapy provides a high complete and partial response rate (91%). The combination of high-dose intra-arterial cisplatin and radiation therapy is effective in improving survival and organ preservation rates in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. This treatment protocol is much less effective for recurrent disease.

Dosimetric considerations in radiation therapy of coin lesions of the lung.

PURPOSE: The dose distribution in small lung lesions (coin lesions) is determined by the combined effects of reduced attenuation and electronic disequilibrium. The magnitude of the dose delivered also depends on the algorithm used to correct for reduced lung density. These effects are investigated experimentally and computationally for 10 MV photons. METHODS AND MATERIALS: Using a polystyrene miniphantom embedded in cork or cedar, thermoluminescent dosimetry and film dosimetry was performed to investigate interface effects and the central dose per monitor unit (MU). Three frequently applied calculation techniques--no density correction, ratio of tissue maximum ratios (TMRs), and the Batho correction--were also used to calculate the dose per MU. The measurements and calculations were compared with a one-dimensional phenomenological theory with parameters taken from the literature. RESULTS: The measurements at the entrance surface and center of the miniphantom agreed well with the predictions of the phenomenological theory. The interface regions are usually thin enough (2-3 mm) to be clinically unimportant for 10 MV. Depending on the algorithm used to correct for decreased lung density, the lesion dose may be larger or smaller than the prescribed dose by as much as 20% in extreme cases. A clinical example is presented. CONCLUSIONS: In comparing clinical results of treatments of small lung lesions, it is important to be aware of the density correction used.

Healing impairment of open wounds by skin irradiation.

BACKGROUND: Ionizing radiation is frequently used for the treatment of malignancy. Sequelae of therapeutic radiation frequently present clinical problems in the form of poor wound healing and easy injury of treated tissue in response to mild trauma. OBJECTIVE: We describe a radiation-impaired wound healing model in guinea pigs, developed to determine the effect of cutaneous irradiation on wound contraction. METHODS: Guinea pigs were anesthetized and a flap of skin was isolated and treated with x-rays to 18 Gy. Circular wounds of identical size were made in irradiated and control skin, and average wound size was recorded. RESULTS: Our results demonstrate that a statistically significant wound healing deficit is produced in open wounds by surface irradiation of skin. CONCLUSION: Radiation of skin results in slower healing of open wounds, and provides an in vivo system for evaluation of topical dressings and growth factors in radiation-impaired wounds.

Collagen gene expression and wound strength in normal and radiation-impaired wounds. A model of radiation-impaired wound healing.

BACKGROUND: Poorly healing wounds result in significant morbidity postoperatively. Numerous attempts have been made to study wound healing in vivo to understand better the normal healing process and factors that impair healing. Animal models of wound healing have been developed to evaluate wound healing in a systematic and controlled setting. Incisional wounds are created in animals to mimic the surgical patient. They may then be evaluated by a variety of methods for degree of healing. OBJECTIVE: To give insight into the mechanisms of wound healing impairment, we developed a model of impaired wound healing in guinea pigs using radiation applied to the skin surfaces only. METHODS: Wound bursting strength, a direct measure of the force required to burst apart healing linear incisions, was measured. Collagen content, measured indirectly as collagen gene expression, was measured. RESULTS: Significant reductions in wound bursting strength were noted after radiation administration. Collagen gene expression was decreased in wounds 7 days after radiation, but recovered to control levels 14 days after irradiation. Our model enables the inclusion of irradiated and unirradiated skin flaps within the same animal, thus eliminating intra-animal variation when comparing impaired and normal wounds. CONCLUSION: Wound bursting strength analysis, combined with techniques aimed at elucidating changes at the molecular level, provides a useful tool for the study of factors that impair healing and potential treatments for resulting healing deficits.

Transforming growth factor-beta improves healing of radiation-impaired wounds.

Exogenously applied TGF-beta 1 has been shown to increase wound strength in incisional wounds early in the healing process. An impaired wound healing model was first established in guinea pigs by isolating flaps of skin and irradiating the flaps to 15 Gray in one fraction using a 4-MeV linear accelerator. Incisions made 2 d after irradiation were excised 7 d later, and showed decreased linear wound bursting strength (WBS) as compared to non-irradiated control wounds on the contralateral side of each animal (p = 0.001). The effect of TGF-beta on healing of radiation-impaired wounds was studied using this model. Skin on both left and right sides of guinea pigs was irradiated as above. A linear incision was made in each side. Collagen with either 1, 5, or 20 micrograms of TGF-beta was applied to one side prior to closure with staples, whereas the contralateral side received saline in collagen. Wounds given either 1 or 5 micrograms of TGF-beta were found to be stronger than controls at 7 d (p less than 0.05), whereas those receiving the higher 20-micrograms dose were weaker than controls (p less than 0.05). Thus, TGF-beta in lower doses improved healing at 7 d but very large amounts of the growth factor actually impaired healing. In situ hybridization done on wound samples showed increased type I collagen gene expression by fibroblasts in wounds treated with 1 micrograms TGF-beta over control wounds. These results indicate that TGF-beta improved wound healing as demonstrated by increased WBS. This improvement is accompanied by an up-regulation of collagen gene expression by resident fibroblasts.

Glioblastoma oncometry.

A prospective study of 20 patients was conducted to determine changes in the computed tomography appearance of glioblastomas seen at the completion of radiation therapy. An interval CT was obtained after 4000 to 4500 cGy to the whole brain and was compared to a similar baseline study. The tumor volume increased in twelve patients by 13 to 878% (mean 126%) and decreased in seven by 13 to 73% (mean 37%). It remained unchanged in one patient. A broadening or thinning of the enhancing rim frequently accompanied the increased or decreased tumor, respectively. Volume change immediately after whole brain radiotherapy was no prognostic indicator. The volume increase seen in 60% of the patients had implications for treatment planning of the boost field. It translated into a potential field size increase of up to 5.6 cm (mean 3.5 cm) and could contribute to a geographic miss. It is concluded that following whole brain radiation therapy, a repeat CT scan or magnetic resonance imaging, depending on the initial exam, is necessary for optimal planning of the reduced radiation field.

Unresectable gliomas in children: tumor-volume response to radiation therapy.

Serial tumor volume measurements were performed on computed tomographic (CT) scans or magnetic resonance (MR) images of 12 children treated with radiation therapy for high-grade (three children) or low-grade (nine children) astrocytomas of the optic nerve, thalamus, hypothalamus, cerebellar-pontine angle, and pons. Three types of initial tumor response were observed: Tumor volume increased in four children, remained unchanged in one, and decreased immediately after completion of radiation therapy in the others. High-grade tumors regressed maximally within 6 months and low-grade tumors within 10-25 months. All high-grade tumors recurred within 12 months. Three low-grade tumors recurred 3, 6 1/2, and 10 years after diagnosis, respectively. The tumor-volume halving time was 60-78 days for high-grade tumors and 108-330 days for low-grade tumors. The tumor doubling time was 48-60 days for high-grade tumors. The posttreatment increase in tumor volume has implications for radiation treatment planning. It did not indicate a poor prognosis.

CT-assisted assessment of bladder and rectum dose in gynecological implants.

Eight patients who received gynecological implants with Fletcher-Suit type applicators were involved in this study. An orthogonal pair of films and computed tomographic scans were obtained for each patient. In the CT study, judicious use of contrast materials and selective window and level settings permitted clear delineation of the bladder and the rectum boundaries relative to the implanted applicators. In comparison to reference organ doses derived from the orthogonal film pair method, the maximum organ doses estimated from the CT-assisted evaluation were considerably higher, by approximately twofold on the average. The differences between the values estimated from the two methods vary from patient to patient, being highly dependent on the individual anatomy and the geometry of the implanted sources. These preliminary results point to the inaccuracy of the conventional method of estimating organ doses. CT-assisted evaluation may be necessary to accurately calculate organ doses in gynecological applications.

Paraaortic lymph node irradiation in cervical carcinoma without prior lymphadenectomy.

A study of complications associated with paraaortic irradiation was undertaken in patients with uterine cervical cancer who had not undergone prior lymphadenectomy. Between 1975 and 1984, 29 highly selected patients received paraaortic irradiation as part of their definitive treatment for cervical carcinoma. Paraaortic fields were irradiated to a total dose of 4,200-5,000 rad (42-50 Gy), in fractions of 150-180 rad (1.5-1.8 Gy). An anteroposterior-posteroanterior technique was generally used. All fields were treated every day. There were no instances of small-bowel obstruction or other major complications, surgical procedures, or deaths caused by paraaortic irradiation. Eleven patients (38%) have no evidence of recurrent disease 23-120 months after completion of therapy. Paraaortic irradiation was well tolerated in this patient group without prior staging lymphadenectomy. Thus, in selected patients and with appropriate techniques, paraaortic irradiation for cervical carcinoma may be used with relative safety.

Irradiation of bilateral orbital lymphoma: a non-coplanar technique with case reports.

Bilateral synchronous involvement of the orbits by lymphoma is an uncommon event. Therefore, the irradiation techniques for this disease are not well refined. Depending on the technique used, one has to decide between underdosing the anterior segment of the orbit and the frequently involved lacrimal glands or to tolerate shield related in homogeneities in the range of 40 to 50% as well as higher doses to the midline structures, e.g. the optic chiasma. To avoid the above shortcomings we developed a technique by which half the prescribed dose is delivered by pairs of beams angulated in the transverse plane and the other half by pairs of beams angulated in the sagittal plane. Film dosimetry in a phantom confirms that the entire orbit, including its anterior portion, is well covered, the lens is protected, and the dose to the mid-sagittal structures is not increased. The dose inhomogeneity is in the range of 20% which represents a substantial improvement over alternative methods. Two irradiated patients with bilateral orbital lymphoma are presented with local control and no ophthalmic or other side effects as of last follow-up.

Orbital tumor irradiation using non-coplanar beams.

Irradiation of the orbit is often associated with substantial dose inhomogeneity resulting from the insertion of lens blocks. We postulated that such dose inhomogeneity, which often exceeds 40%, could be halved by the use of two pairs of wedged beams, one angled in the sagittal plane and the other in the commonly employed transverse plane. The sagittal plane is obtained by turning the treatment couch 90 degrees. All beams carried a central-axis lens block and were angled 30 degrees relative to the vertical. Verification of dose distribution was obtained by film dosimetry in a head phantom for central- and off-axis planes. These measurements indicate that significant improvement in dose homogeneity over alternate methods can be achieved with this technique.

An atypical endocrine tumor of the lung responsive to radiation therapy and 5-fluorouracil-streptozotocin.

A case is reported of a patient who presented with a peripheral left upper-lobe lung mass, a thyroid nodule, and multiple enlarged cervical and supraclavicular lymph nodes. Fine-needle aspiration cytology of the lung lesion, the thyroid nodule, and several of the lymph nodes was interpreted as small cell cancer of the lung (SCCL). The patient was treated with Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and vincristine (CAV), alternating with VP-16 + cisplatin. When progressive disease was documented after three cycles of chemotherapy, an involved cervical lymph node was biopsied. By light microscopy (LM) the tumor appeared to be a poorly differentiated adenocarcinoma, but by transmission electron microscopy (TEM) it was found to have both neuroendocrine and glandular features. Biochemical analysis of the biopsy specimen revealed immunoreactive bombesin, and on immunoperoxidase staining many tumor cells contained neuron-specific enolase. The tumor was therefore classified as an atypical endocrine tumor of the lung (AETL), a recently described morphologic variant for which no therapy has yet been established. The patient was treated with radiation therapy (RT) followed by chemotherapy including 5-fluorouracil (5-FU) (500 mg/m2 IV, d 1-5) and streptozotocin (STZ) (500 mg/m2 IV, d 1-5) every 5-6 weeks, with objective evidence of tumor regression following each modality. This report illustrates the importance of ultrastructural study in the characterization of lung cancer, and indicates the need for the further evaluation of RT and 5FU + STZ in the treatment of neuroendocrine tumors of the lung.

The role of radiation therapy in the management of metastatic renal cell carcinoma.

From 1965 to 1980, 35 patients were treated by radiation for palliation of symptoms related to metastatic renal cell carcinoma. The male:female ratio was 1.9:1. Eighty-six percent (30/35) of the patients were over 40 years of age at initial presentation. Sixty-three percent (22/35) of the patients showed symptoms of metastatic disease within three years of diagnosis of the primary malignancy. Sixty sites were irradiated in the 35 patients: 36 sites of metastatic bone pain, 14 obstructing and/or palpable masses, and ten sites treated for symptoms due to central nervous system (CNS) metastases. Efficacy of treatment was assessed at serial follow-up visits beginning one month after completion of radiotherapy. Bone pain responded at 77% of the treated sites. Mass effect responded in 64%. Disappointing results were obtained with CNS metastases. There was only a 30% response of brain and spinal cord lesions within the dose range that these patients were treated. No correlation between TDF equivalent dose of radiation administered and frequency of palliative response was found. In those sites where a response of bone pain to radiation was observed, 86% of the responses lasted the remainder of the patient's life. No correlation was found between TDF equivalent dose of radiation administered and duration of response. Radiation may be a useful palliative tool for bone pain and mass effect from metastatic renal cell carcinoma. Inordinately high doses need not be used to achieve the desired effect.

Cerebellar hemangioblastomas.

Between 1950 and 1976, 24 patients with cerebellar hemangioblastomas received postoperative radiation therapy. In retrospect, the low-dose radiotherapy that was practiced in the 1950s and early 1960s has been associated with inferior survival rates. Since 1963 and with increased awareness of the effects of radiotherapy, patients receiving high-dose irradiation postoperatively have generally survived longer. Postoperative radiotherapy is used whenever the neoplasm has not been totally excised. This more likely to occur with solid hemangioblastoma and neoplasms arising in the brain stem. In addition, radiotherapy should be used when the tumor recurs after total excision. The recommended dose is in the range of 4500--5000 rads in 4 1/2--5 weeks.

Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids.

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Oncogenic transformation and hyperthermia.

The potential of hyperthermia for producing oncogenic transformation in vitro was assessed using C3H/10T 1/2 mouse embryo cells. Temperatures in the range of 40 degrees to 45 degrees C caused no transformations, whether or not the heat treatment was associated with significant cell killing. In addition modest hyperthermia appreciably reduced the transformation frequencies associated with X-ray doses. The findings suggest an additional benefit in combining ionizing radiations with hyperthermia.

Transverse axial film tomography with a therapy simulator.

A tomographic attachment was designed and developed that attaches to our existing simulator. The film tomograms obtained with the aid of this device exhibit very low geometrical distortion and good contrast and resolution for the objects used in this investigation. In addition, our results to date show that adjacent areas with densities differing by as little as 5% can be distinguished on film.