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K K Ang

Publications and source records attributed to K K Ang.

At least 73 records · Page 4Linked to original sources
PubMed1996

Glioblastoma multiforme arising in the irradiated spinal cord of a rhesus monkey (Macaca mulatta).

An adult female rhesus monkey that had received 44.0 Gy of cobalt 60 radiation to 8 cm of the cervical and upper thoracic spinal cord approximately 2.8 years postirradiation developed a sudden onset of self-mutilation and loss of function of the right arm followed progressively by loss of function of the left arm and terminally bilateral paresis of the legs. Histopathologic examination of the cervical spinal cord revealed a glioblastoma multiforme that extended from the cervical medullary junction to the sixth cervical vertebrae. Because of the infrequent occurrence of spontaneous neoplasia in rhesus monkeys and the location in the radiation field, the glioblastoma is believed to be radiation induced.

Animals↗
PubMed1995

Base-of-tongue carcinoma: treatment results using concomitant boost radiotherapy.

PURPOSE: To evaluate the efficacy of accelerated fractionated radiotherapy using the concomitant boost schedule for patients with squamous cell carcinoma of the base of tongue. METHODS AND MATERIALS: Between September 1984 and July 1992, 54 patients with squamous carcinoma of the base of tongue were treated at The University of Texas M. D. Anderson Cancer Center using the concomitant boost schedule. The distribution of T and N stages was T1-4, T2-27, T3-22, and T4-1; N0-9, N1-11, N2-24, N3-7, and NX-3. American Joint Committee on Cancer (AJCC) stage groupings were II-6, III-14, and IV-34. Before radiation, nodal excision and neck dissection were done in 5 and 10 patients, respectively; 5 patients had neck dissections after radiotherapy. Standard on and off spinal cord fields were irradiated with 1.8 Gy fractions to 54 Gy given over 6 weeks. The boost was given concomitantly during the large field treatment as a second daily (1.5 Gy) fraction, with an interfraction interval of 4-6 h. The median dose to the primary tumor was 72 Gy (range, 66-74 Gy). The median treatment duration was 42 days (range, 39-48 days). Only three patients had treatment interrupted for more than one scheduled treatment day. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates were 59 and 65%, respectively, with a median follow-up of 41 months. The 5-year actuarial locoregional control rate was 76%. The actuarial local control rates achieved with radiotherapy at 5 years for T1, T2, and T3 primary tumors were 100%, 96%, and 67%, respectively; including surgical salvage, the local control rate of T3 primary tumors was 70%. Six patients had regional failures, which in three patients occurred in conjunction with primary tumor recurrence. Twenty-six patients with regional adenopathy were treated with radiation alone to full dose and had a complete clinical response in the neck; no planned neck dissections were performed in these patients. Only 2 of these 26 patients had subsequent regional failures. The 5-year actuarial risk of distant metastases in patients whose disease was controlled locoregionally was 21%. Grade 3 or 4 confluent acute mucositis occurred in 94% of patients. However, late complications were limited to two cases of transient mandibular exposure and three cases of self-limited mucosal ulcerations. CONCLUSION: The concomitant boost fractionation schedule is a very effective regimen for this disease when appropriately selected patients are treated with meticulous technique. The therapeutic ratio is favorable, with a high rate of disease control and no persistent severe late complications. Patients whose neck disease responds completely to treatment with this schedule do not appear to need a planned neck dissection.

Adult↗
PubMed1995

ASTRO Research Fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. American Society for Therapeutic Radiology and Oncology.

PURPOSE: Levels of apoptosis predict for tumor responsiveness to radiation in various animal systems. To investigate the potential role of apoptosis as a predictor of response in human tumors, a retrospective review was undertaken of patients with adenocarcinoma of the cervix whose primary lesion at presentation measured at least 4 cm and who underwent definitive radiation therapy. A previous report had indicated that roughly half this group of patients should have a long-term relapse free survival. METHODS AND MATERIALS: Pretreatment biopsy specimens of 44 patients with Stage IB adenocarcinoma of the cervix, whose primary lesion at presentation measured at least 4 cm in greatest dimension, were scored for apoptosis by two independent investigators without knowledge of the treatment outcome, and the results were averaged. Actuarial methods were used to assess overall survival, disease-free survival, determinate survival, and local control as a function of the baseline level of apoptosis. Patients ranged in age from 21 to 87 years and were treated with definitive radiotherapy between 1964 and 1989. Follow-up for the surviving patients ranged from 1 to 278 months, with a mean of 101 months. RESULTS: Patients whose tumors had a baseline level of apoptosis above the median value (2%) had a better overall survival than those with lower levels of apoptosis (p = 0.056). A similar trend for disease-free survival (p = 0.32) and determinate survival (p = 0.27) did not reach statistical significance, perhaps because of the small number of patients. Because only 6 of the 44 patients (13%) had a local tumor failure, it was not possible to establish a correlation between the pretreatment level of apoptosis and the local tumor control by radiation. CONCLUSION: The baseline level of apoptosis predicted for survival in patients with Stage IB cervical adenocarcinoma. Further investigation of the measurement of apoptosis as a potential predictive assay is warranted in other human tumor systems.

Adenocarcinoma↗
PubMed1995

Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma.

BACKGROUND: Because of a tendency for diffuse, clinically undetectable local spread, cutaneous angiosarcoma is difficult to treat with surgery alone. Radiation is a rational treatment modality for this disease, because a wide region of dermis can be treated, whereas the underlying normal tissues are spared. METHODS: The authors retrospectively studied 14 patients with dermal angiosarcoma of the head and neck who were treated with electron-beam radiation from 1970 to 1989. Primary tumors were located in the scalp and forehead (11 patients) and in the upper face (3 patients). Eleven patients presented with multiple foci of disease. Three patients were treated with radiotherapy alone; the other 11 were treated with chemotherapy (10 patients) and/or surgery (7 patients). Surgical excisions were limited procedures for patients whose disease readily could be encompassed; total scalp resections were not performed. Patients were irradiated with a multiple-field electron-beam technique. Six patients presented postoperatively for radiotherapy with no macroscopic disease in the treatment field and were given a median dose of 60 Gy (range, 50-66 Gy) over a median of 40 days (range, 37-43 days). Eight patients were irradiated with clinically evident disease; doses ranged from 55 to 75 Gy over a median of 44 days (range, 33-66 days). RESULTS: Five of the six patients irradiated without clinically detectable disease were controlled in the treatment field, but only two are currently disease free. Of the eight patients irradiated with macroscopic tumor, initial disease recurrence occurred in the radiation field in two patients and at the radiation field margin in three patients. The actuarial 5-year control rates above the clavicles for patients irradiated with and without clinical disease were 24% and 40%, respectively (P = 0.03). The 5-year actuarial incidence of distant metastases for all patients was 63%. The 5-year actuarial survival rate for patients irradiated with and without clinical disease was 13% and 50%, respectively (P = .04). CONCLUSIONS: Radiation is an effective modality for treating local disease, especially when used after surgical resection of macroscopic tumor. Our current strategy is to resect clinically evident tumor in patients presenting with focal, limited disease, and to follow this resection with moderate dose, very wide-field radiation. The survival outcome for patients presenting with diffuse multifocal disease is bleak, but some patients can be controlled infield with radiation. There must be continued efforts to develop effective systemic therapy.

Aged↗
PubMed1995

Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: results of RTOG 88-09.

PURPOSE: To establish the feasibility of performing split-course accelerated hyperfractionation (AHFX-S) and concomitant boost accelerated fractionation radiotherapy (AFX-C) for advanced head and neck cancer in a multi-institutional cooperative trial setting and to evaluate the tumor clearance rate and acute and late toxicity of these fractionation schedules. METHODS AND MATERIALS: Between February 1989 and January 1990, 75 patients with Stage III or IV squamous cell carcinoma of the head and neck were randomized to receive: (a) AHFX-S: 1.6 Gy/fraction, twice daily (6-h interval), 5 days/week, to a total dose of 67.2 Gy/42 fractions/6 weeks, with a 2-week rest after 38.4 Gy; or (b) AFX-C: 1.8 Gy/fraction/day, 5 daily fractions/week to 54 Gy/30 fractions/6 weeks to a large field and 1.5 Gy/fraction/day to a boost field, 6 h after large field treatment during the last 11 treatment days, to a total dose of 70.5 Gy/41 fractions/6 weeks. Acute and late toxicities were scored according to the RTOG normal tissue reaction scales and tumor clearance was evaluated at completion of therapy and at regular intervals thereafter. RESULTS: Of the 70 analyzable patients, 38 received AHFX-S and 32 received AFX-C. The two arms were balanced with respect to sex, age, T-stage, and Karnofsky Performance Status (KPS). However, the AHFX-S arm had a higher proportion of oropharyngeal primaries (63% vs. 44%), and Stage IV disease (82% vs. 50%) and lower proportion of oral cavity lesions (3% vs. 22%) and N0 disease (16% vs. 31%) than the AFX-C arm. The median follow-up was 2 years (range: 0.03-4.87 years). Tolerance of both variants of accelerated fractionated radiotherapy was satisfactory. There was no significant difference in local-regional control, disease-free survival, or survival between the two arms. The 2-year local-regional failure rate, survival, and disease-free survival was 50, 50, and 40%, respectively, for the entire group of patients. Acute radiation mucositis was increased in both arms. There was no significant difference in the incidence of grade 3 acute toxicities (63% vs. 56%) and grade 3 (14% vs. 14%) or grade 4 (6% vs. 17%) late toxicities. Permanent grade 4 late toxicity was observed in 6 and 7% of the patients, respectively. CONCLUSION: Results of this randomized Phase I/II trial showed that the two accelerated fractionated schedules studied can be successfully given in a multi-institutional cooperative trial. There was no significant difference in acute or late toxicities, local-regional control, disease-free survival, or survival in this small scale study. Therefore, a Phase III trial comparing the relative efficacy of these two accelerated fractionation schedules against standard fractionation and hyperfractionation has been activated.

Carcinoma, Squamous Cell↗
PubMed1995

The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation.

PURPOSE: Surgery is the primary treatment for adenoid cystic carcinomas arising from major and minor salivary glands of the head and neck. However, local recurrence is frequent because of the infiltrative growth pattern and perineural spread associated with these tumors. At UTMDACC, we have had a longstanding policy of using postoperative radiotherapy to reduce the risk of local recurrence and to avoid the need for radical surgery; this 30-year retrospective study analyzes the results of this combined modality approach. METHODS AND MATERIALS: Between 1962 and 1991, 198 patients ages 13-82 years, with adenoid cystic carcinomas of the head and neck, received postoperative radiotherapy for known or suspected microscopic residual disease following surgery. Distribution of primary sites was: parotid: 30 patients; submandibular/sublingual: 41 patients; lacrimal: 5 patients; and minor salivary glands: 122 patients. Eighty-three patients (42%) had microscopic positive margins and an additional 55 (28%) had close (< or = 5 mm) or uncertain margins. One hundred thirty-six patients (69%) had perineural spread with invasion of a major (named) nerve in 55 patients (28%). Using radiation techniques appropriate to the primary site, a median dose of 60 Gy (range 50-69 Gy) was delivered to the tumor bed. Follow-up ranged from 5-341 months (median, 93 months). All surviving patients had a minimum of 2 years follow-up. RESULTS: Twenty-three patients (12%) had local recurrences with 5-, 10-, and 15-year actuarial local control rates of 95%, 86%, and 79%, respectively. Fifteen of the 83 patients (18%) with positive margins developed local recurrences, compared to 5 of 55 patients (9%) with close or uncertain margins, and 3 of 60 patients (5%) with negative margins (p = 0.02). Patients with and without a major (named) nerve involved had crude failure rates of 18% (10 out of 55) and 9% (13 out of 143), respectively (p = 0.02). There was a trend toward better local control with increasing dose. This was significant in patients with positive margins, in whom crude control rates were 40 and 88% for doses of < 56 Gy and > or = 56 Gy, respectively (p = 0.006). Actuarial 5-, 10-, and 15-year freedom from relapse rates were 68%, 52%, and 45%, respectively. Base of skull and neck failures were uncommon with or without elective treatment, developing in 2 and 3% of patients, respectively. Distant metastases were the most common type of disease recurrence, developing in 74 patients (37%) of whom 62 (31%) were disease-free at the primary site. CONCLUSIONS: Excellent local control rates were obtained in this population using surgery and postoperative radiotherapy and we recommend this combined approach for most patients with adenoid cystic carcinomas of the head and neck. Perineural invasion was an adverse prognostic factor only when a major (named) nerve was involved. Microscopic positive margins was also an adverse prognostic factor, but even when present, local control was achieved in over 80% of our patients. We recommend a dose of 60 Gy to the tumor bed, supplemented to 66 Gy for patients with positive margins. Despite effective local therapy, one-third of patients fail systemically, and good treatment to address this problem is lacking.

Actuarial Analysis↗
PubMed1995

Postoperative radiation of free jejunal autografts in patients with advanced cancer of the head and neck.

BACKGROUND: Free jejunal autografts increasingly are being used to repair the pharynx after resections of head and neck carcinomas. Doses of greater than 45 Gy are generally considered to be above the tolerance of the small bowel, whereas the dose range for effective postoperative radiotherapy of advanced head and neck cancers is between 57.6 Gy and 63 Gy. Between July 1988, and December, 1992, 29 patients at the M. D. Anderson Cancer Center were treated with a combination of resection of the advanced head and neck cancer, reconstruction with free jejunal autograft, and postoperative radiation. Planned reductions in postoperative doses due to the presence of the jejunum within the field were not made. This retrospective study analyzes the outcome of these patients with attention to survival, local-regional control, and complications. METHODS: Twenty-seven of the 29 study patients had squamous cell carcinoma of the larynx or pharynx; 24 of these patients had Stage III or Stage IV disease. Two patients had recurrent papillary thyroid carcinoma. The median number of days from surgery to the start of radiation was 34. Radiation doses to the tumor bed ranged from 50 Gy to 72 Gy. The median doses to the tumor bed and the jejunal autograft were both 63 Gy. Surviving patients were followed from 12 to 68 months (median, 20 months) from the time of their surgery. RESULTS: The actuarial 2-year survival rate was 51%. Nine patients had local or regional recurrences above the clavicles. The 2-year local-regional control and freedom from relapse rates were 71 and 50%, respectively. The most severe complication during radiation was confluent mucositis in greater than 50% of the treated area, which developed in two patients. No patient developed a late complication related to the jejunal autograft. CONCLUSIONS: Postoperative radiation to free jejunal autografts used for pharyngeal reconstruction can be delivered safely. Doses in this setting of 57.6 Gy to 63 Gy depending on the anticipated risk of recurrence based on clinical, surgical, and pathologic findings are recommended. The presence of a free jejunal autograft did not require a reduction of the desired doses used for patients with postoperatively irradiated head and neck cancer.

Actuarial Analysis↗
PubMed1995

Radiation response of the central nervous system.

This report reviews the anatomical, pathophysiological, and clinical aspects of radiation injury to the central nervous system (CNS). Despite the lack of pathognomonic characteristics for CNS radiation lesions, demyelination and malacia are consistently the dominant morphological features of radiation myelopathy. In addition, cerebral atrophy is commonly observed in patients with neurological deficits related to chemotherapy and radiation, and neurocognitive deficits are associated with diffuse white matter changes. Clinical and experimental dose-response information have been evaluated and summarized into specific recommendations for the spinal cord and brain. The common spinal cord dose limit of 45 Gy in 22 to 25 fractions is conservative and can be relaxed if respecting this limit materially reduces the probability of tumor control. It is suggested that the 5% incidence of radiation myelopathy probably lies between 57 and 61 Gy to the spinal cord in the absence of dose modifying chemotherapy. A clinically detectable length effect for the spinal cord has not been observed. The effects of chemotherapy and altered fractionation are also discussed. Brain necrosis in adults is rarely noted below 60 Gy in conventional fractionation, with imaging and clinical changes being observed generally only above 50 Gy. However, neurocognitive effects are observed at lower doses, especially in children. A more pronounced volume effect is believed to exist in the brain than in the spinal cord. Tumor progression may be hard to distinguish from radiation and chemotherapy effects. Diffuse white matter injury can be attributed to radiation and associated with neurological deficits, but leukoencephalopathy is rarely observed in the absence of chemotherapy. Subjective, objective, management, and analytic (SOMA) parameters related to radiation spinal cord and brain injury have been developed and presented on ordinal scales.

Animals↗
PubMed1995

Radiation nephropathy in the rhesus monkey: morphometric analysis of glomerular and tubular alterations.

PURPOSE: The morphologic responses of the monkey kidney glomeruli and tubules to fractionated irradiation were assessed. METHODS AND MATERIALS: Both kidneys of adult female rhesus monkeys were irradiated with doses of gamma-rays ranging from 24 Gy in 12 fractions up to 36 Gy in 18 fractions. Serial renal biopsies were taken between 1 and 12 weeks after irradiation. The kidneys were removed at necropsy 16-23 weeks after irradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material, ectatic capillaries, thrombi, hemorrhage, adhesions, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, or tubules was determined using a Chalkley point grid. Tubules were further scored as being either normal or abnormal in appearance. RESULTS: Examination of the renal biopsies revealed that progressive glomerular lesions were evident within 4-12 weeks after irradiation. Tubular changes were mild and focal. Morphometric analysis of whole kidneys removed at necropsy demonstrated that numbers of glomeruli with ectatic capillaries, thrombi, and hemorrhage were significantly different from controls at 16-23 weeks after irradiation by all of the doses in the range of 24 to 36 Gy. A significant (p < 0.05) increase in the relative proportion of renal cortex occupied by glomeruli and interstitium was indicative of tubule loss. Further analysis of these tubular changes revealed a highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules. Thus following a dose of 24 Gy in 12 fractions, the ratio of abnormal: normal tubules was approximately 1:2; after 36 Gy in 18 fractions the ratio was 3:1. CONCLUSIONS: Glomeruli appeared to be very radiosensitive because after the clinically relevant dose of 24 Gy in 12 fractions essentially all glomeruli were altered in the irradiated kidneys as compared to controls. Thus, efforts aimed at increasing the threshold dose for development of radiation nephropathy should be directed primarily at preventing the glomerular lesions.

Animals↗
PubMed1995

Hyperfractionated radiation in the treatment of squamous cell carcinomas of the head and neck: a comparison of two fractionation schedules.

PURPOSE: In 1984 we began treating patients with squamous cell carcinomas of the larynx and hypopharynx with hyperfractionated radiotherapy. Patients received 76.8 Gy in 1.2 Gy fractions twice daily, with a 4 h interfraction interval. In 1988, this schedule was modified in patients treated with shrinking field techniques. The dose per fraction was slightly reduced (while not changing the total dose), and the interfraction interval was increased to 6 h. The goal was to decrease toxicity while maintaining satisfactory local-regional control. This retrospective study analyzes the results of this schedule modification. METHODS AND MATERIALS: Two hundred thirty-six patients were included in the analysis. Distribution of patients by primary site and T stage was as follows: supraglottic larynx, 120 patients; hypopharynx, 70; true vocal cord, 24; and oropharynx, 22; T1, 5 patients; T2, 118; T3, 93; T4, 19; and Tx, 1. Ninety-nine patients presented with cervical nodal disease. Seventy-eight patients (group A), including 16 treated with induction chemotherapy, were treated throughout with 1.2 Gy fractions twice daily and a 4-h interfraction interval. Subsequently, 158 patients (group B), 57 of whom received chemotherapy, received 1.1 Gy fractions to 55 Gy, and then 1.2 Gy fractions to their boost volumes to 76.6 Gy. The interfraction interval was 6 h. Median follow-up was 91 and 35 months for group A and B, respectively. RESULTS: Two-year actuarial survival, local control, and ultimate local rates were 70%, 75%, and 85%, respectively. Differences between survival rates for group A and group B were not statistically significant, with 2-year rates of 66% and 72%, respectively. Overall local control rates at 2 years were 77% and 74%, respectively, for groups A and B (p = 0.22). However, there was a trend toward inferior results in group B patients with T3 disease (67% at 2 years compared to 76% in group A, p = 0.13). Confluent mucositis and persistent mucositis developed in 52% and 14% of group A patients, but only 37% and 4% of group B patients (p = 0.02 and p < 0.01, respectively). There was a near significant trend toward fewer late complications in group B who developed an 8% complication rate at 3 years compared to 15% of group A patients (p = 0.07). CONCLUSIONS: The net effect of reducing the dose per fraction to 1.1 Gy twice daily for fields covering gross disease and subclinical sites, and increasing the interfraction interval to 6 h was to reduce the incidence of both acute and late complications. Excellent overall local control rates (85%) for T2 lesions were achieved with both hyperfractionation regimens and we, therefore, continue to treat patients with T2 tumors with the modified schedule. The overall results in selected patients with T3 lesions was also satisfactory (69%), but as there was a trend towards poorer local control in patients treated with 1.1 Gy fractions, we recommend using 1.2 Gy for the entire treatment of these patients, while maintaining the 6 h interfraction interval to reduce the risk of late complications.

Adult↗
PubMed1995

Effects of continuous hyperfractionated accelerated and conventionally fractionated radiotherapy on the parotid and submandibular salivary glands of rhesus monkeys.

Radiotherapy is a major treatment modality for head and neck cancer. It is often not possible to exclude the salivary glands from the treatment fields. The unique susceptibility of the serous cells of the salivary glands to irradiation often results in xerostomia with ensuing secondary complications and discomfort to the patients. Recent reports have suggested that continuous hyperfractionated accelerated radiotherapy (CHART) can lead to considerably less reduction in the parotid salivary gland than conventional radiotherapy. This study was undertaken to assess histologic changes of salivary glands induced by CHART and conventional radiation fractionation schedules. The parotid and submandibular salivary glands of adult rhesus monkeys were irradiated with cobalt-60 gamma radiation at 50 Gy/20 fractions/4 weeks, 55 Gy/25 fractions/5 weeks, or 54 Gy/36 fractions/12 days (CHART). Salivary tissues were harvested at 16 weeks following irradiation and evaluated histopathologically. Microscopically, the glands receiving 50 Gy, 55 Gy, or CHART were virtually indistinguishable. There was severe atrophy and fibrosis of all glands. Quantitative analysis revealed that 50 Gy, 55 Gy, and CHART induced a reduction of serous acini in parotid glands by 86.4%, 84.8%, and 88.8%, respectively. In submandibular glands, serous acini were reduced by 99.4%, 99.0%, and 100%, respectively. The corresponding reduction in mucous acini were 98.4%, 98.4%, and 99.2%, respectively. These histopathologic and quantitative morphologic studies show that the magnitude of serous gland atrophy in the parotid and submandibular salivary glands of rhesus monkeys was similar at 16 weeks after receiving 50 Gy in 20 fractions, 55 Gy in 25 fractions, or CHART.

Animals↗
PubMed1995

Effect of intra-peritoneal fludarabine on rat spinal cord tolerance to fractionated irradiation.

The effect of fludarabine (9-beta-D-arabinosyl-2-fluoroadenine-5'- monophosphate), an adenine nucleoside analogue, on the tolerance of the spinal cord to fractionated irradiation was studied in a rat model. Anesthetized female Fisher 344 rats received irradiation to 2 cm of the cervical spine with a telecobalt unit (dose rate 1.14 Gy/min). Radiation was administered in two, four or eight fractions spread over a 48-h period with or without fludarabine. Animals assigned to combined therapy received two daily intraperitoneal injections of fludarabine (150 mg/kg) given 3 h prior to the first daily radiation fraction. It was found that fludarabine reduced the iso-effect dose required to induce leg paresis at 9 months after irradiation for all fractionation schedules. Dose modification factors of 1.23, 1.29 and greater than 1.27 were obtained for two, four and eight fractions, respectively. Fitting the data with the direct analysis method of Thames et al. with an incomplete repair model [18] showed that the potentiating effect of fludarabine may be mediated through reduction in the number of 'tissue-rescuing units' (InK). Alpha and beta values were slightly but not significantly decreased, whereas the alpha/beta ratio was unchanged. These features suggest that fludarabine did not significantly inhibit cellular repair processes but rather reduced the spinal cord tolerance by a fixed additive toxic effect on the same target cells. In rodent models, the combination of fludarabine and fractionated radiation has previously been found to yield a therapeutic gain, i.e., the drug enhanced tumor response to a greater extent than it reduced normal tissue tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Postoperative radiotherapy for cutaneous melanoma of the head and neck region.

PURPOSE: To assess the efficacy and toxicity of elective-adjunctive radiotherapy given in five 6-Gy fractions to patients with cutaneous melanoma of the head and neck at high risk for local-regional relapse. METHODS AND MATERIALS: From 1983 to August 1992, 174 patients (132 men and 42 women) were enrolled. The ages ranged from 16 to 89 years (median: 54 years). One group (n = 79) received elective irradiation after wide local excision of lesions > or = 1.5 mm thick, or Clark's level IV-V, a second group (n = 32) received adjunctive irradiation after excision of primary lesions plus limited neck dissection, and a third group (n = 63) received irradiation after neck dissection for nodal relapse. Each group had a projected local-regional recurrence rate of approximately 50%. The radiotherapy consisted of five fractions of 6 Gy each, specified at Dmax, delivered twice a week, to a total dose of 30 Gy in 2.5 weeks. Electron beams of appropriate energies were used whenever possible. Junction lines between adjoining fields were moved twice to minimize dose heterogeneity. Patients were seen at regular intervals to assess disease status and therapy-related complications. Patients who relapsed were treated as indicated by the clinical status. RESULTS: With a median follow-up of 35 months, 111 of 174 patients were alive. The disease recurred above the clavicles only in six patients, at distant sites in 58 patients, and both local-regionally and at distant sites in nine patients. The actuarial 5-year local-regional control (LRC) and survival rates for the whole group were 88% and 47%, respectively. The thickness of the primary lesion, presence of more than three positive nodes, and extracapsular extension did not influence the LRC rate after radiotherapy (range: 85-92%). However, lesion thickness strongly affected the 5-year survival rate of group 1 patients (i.e., 100% for < or = 1.5 mm thick, but Clark's level IV, 72% for > 1.5-4 mm, and 30% for > 4 mm). In groups 2 and 3, the 5-year survival rate of patients with > three involved nodes was lower than that of patients with one to three positive nodes (23% vs. 39%). The acute tolerance to adjunctive radiotherapy was excellent. Late radiation complications were observed in only three patients. These were moderate neck fibrosis, mild ipsilateral hearing impairment, and transient exposure of external auditory canal cartilage. CONCLUSION: The safety of this hypofractionated radiotherapy regimen in the management of cutaneous melanoma was established in this study. The overall 5-year actuarial LRC rate of 88% was much higher than that of our historical group and that reported in the literature (50%). The survival rate of patients with lesion of 1.5-4 mm thickness was also higher than that observed in other series. Based on these results a prospective randomized study to further define the role of adjunctive postoperative radiotherapy is planned.

Adolescent↗
PubMed1994

Reemergence of apoptotic cells between fractionated doses in irradiated murine tumors.

PURPOSE: The purpose of this investigation was to follow up our previous studies on the development of apoptosis in irradiated murine tumors by testing whether an apoptotic subpopulation of cells reemerges between fractionated exposures. METHODS AND MATERIALS: Mice bearing a murine ovarian carcinoma, OCa-I, were treated in vivo with two fractionation protocols: two doses of 12.5 Gy separated by various times out to 5 days and multiple daily fractions of 2.5 Gy. Animals were killed 4 h after the last dose in each protocol, and the percent apoptosis was scored from stained histological sections made from the irradiated tumors according to the specific features characteristic of this mode of cell death. RESULTS: The 12.5 + 12.5 Gy protocol yielded a net total percent apoptosis of about 45% when the two doses were separated by 5 days (total dose = 25 Gy), whereas the 2.5 Gy per day protocol yielded about 50% net apoptotic cells when given for 5 days (total dose = 12.5 Gy). These values are to be compared to the value of 36% apoptotic cells that is yielded by large single doses (> 25 Gy). Thus, these results indicate that an apoptotic subpopulation of cells reemerged between the fractions in both protocols, but the kinetics appeared to be delayed in the 12.5 + 12.5 Gy vs. the multiple 2.5 Gy protocol. CONCLUSION: This reemergence of cells with the propensity for radiation-induced apoptosis between fractionated exposures is consistent with a role for this mode of cell death in the response of tumors to radiotherapy and may represent the priming of a new subpopulation of tumor cells for apoptosis as part of normal tumor homeostasis to counterbalance cell division.

Animals↗
PubMed1994

Radiation response of the monkey kidney following contralateral nephrectomy.

PURPOSE: The long-term functional and morphologic responses of the hypertrophied monkey kidney after unilateral nephrectomy to fractionated irradiation were assessed. METHODS AND MATERIALS: The right kidney of 13 adult female rhesus monkeys was removed. Twelve weeks after unilateral nephrectomy (UN) the remaining kidney received fractionated doses of gamma-rays ranging from 35.2 Gy/16 fractions (F) up to 44 Gy/20 F. Glomerular filtration rate, effective renal plasma flow, blood urea nitrogen, serum creatinine, and hematocrit values were measured up to 107 weeks postirradiation (PI). The monkeys were killed and the remaining kidneys were removed 107 weeks PI or earlier when end-stage renal failure was exhibited. Glomeruli were scored for the presence/absence of several pathologic features including increased intercapillary eosinophilic material (ICE), ectatic capillaries, and thrombi. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal tubules or abnormal tubules was determined using a Chalkley point grid. These quantal dose response data were analyzed using a logistic regression model. RESULTS: Irradiation of the remaining kidney in UN monkeys resulted in a dose-dependent reduction in renal function and anemia. Glomerular dysfunction preceded tubular dysfunction. Animals receiving 44 Gy all manifested progressive clinical renal failure. Conversely, those receiving < or = 39.6 Gy showed stable, albeit impaired, renal function for the duration of the observation period of 107 weeks. Morphologically, the incidence of ICE, ectatic glomerular capillaries, thrombi, and periglomerular fibrosis was significantly dose-related (p < 0.005). A significant (p < 0.001) dose-related increase in the relative proportion of renal cortex occupied by abnormal tubules was indicative of tubular injury. A highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules was also seen. CONCLUSION: The pathogenesis of radiation nephropathy is difficult to fully understand because of the complex and dynamic interactions among all components of the nephron that make discrimination between primary radiation effects and secondary pathophysiological consequences very difficult. Notwithstanding, the current experiment shows that the functional and morphological expressions of radiation injury in the kidney are dose dependent. Renal failure occurs when both the glomeruli and tubules are dysfunctional. In monkeys following UN, a total dose of 44 Gy to the remaining kidney damages all components of the nephron and causes renal failure in less than 45 weeks. With lower doses, changes to the glomeruli predominate and the animals survive. Kidney doses of up to 39.6 Gy/18 fractions of 2.2 Gy are compatible with survival for at least 2 years in primates.

Animals↗
PubMed1994

Postoperative radiation therapy for malignant tumors of minor salivary glands. Outcome and patterns of failure.

BACKGROUND: In the treatment of major salivary gland cancers, the addition of adjuvant postoperative radiation therapy for patients with high risk features has been shown to reduce the incidence of local failure. This retrospective study was done to determine the effectiveness of this approach for minor salivary gland cancers, to document patterns of failure, and to define prognostic variables for treatment outcome. METHODS: Between 1961 and 1990, 160 patients received postoperative radiation at the University of Texas M. D. Anderson Cancer Center (UTMDACC) after gross total removal of their tumors. These operations ranged from excisional biopsies to craniofacial resections with orbital exenterations depending on the original site and size of the tumor. The primary tumor site was in the oral cavity-oropharynx in 111 patients and in the nasal cavity or paranasal sinuses in 46 patients. The most prevalent histologic type was adenoid cystic carcinoma (71%). Microscopic positive margins were present in 64 (40%) patients. Half of the patients had pathologic evidence of perineural invasion. Radiation therapy techniques varied, depending on the site and extent of disease and the era of treatment. Doses ranged from 50 to 75 Gy (median, 60 Gy; mean 59.2 Gy). Follow-up for surviving patients ranged from 24 to 270 months (median, 110 months). RESULTS: Fifty-seven (36%) patients experienced disease relapse. Nineteen (12%) patients had a local recurrence: 6 within 5 years of treatment, 8 between 5 and 10 years, and 5 after 10 years. Regional failures occurred in 3 of 13 patients with initially node-positive disease but were uncommon (less than 5%) in patients with node-negative disease, regardless of elective neck treatments. Distant metastases developed in 43 patients, mostly (79%) within 5 years of treatment. Actuarial overall survival rates at 5, 10, and 15 years were 81%, 65%, and 43%, respectively. Complications occurred in 51 patients and were of three predominate types: hearing loss (26 patients), ocular injury (15 patients), and bone exposure/necrosis (12 patients). Improved techniques, including better immobilization, customized beam shaping, and treating multiple fields per day, have substantially reduced the risk of serious complications during the past decade. CONCLUSIONS: Postoperative radiation therapy is effective in preventing local recurrence in most patients with minor salivary gland tumors after gross total excision. When local failure occurs, it tends to be a late event. For most patients, the authors recommend a postoperative dose of 60 Gy in 30 fractions to the operative bed; if there is named nerve invasion, the path of the nerve is treated electively to its ganglion.

Adolescent↗
PubMed1994

Volume effects in rhesus monkey spinal cord.

PURPOSE: An experiment was conducted to test for the existence of a volume effect in radiation myelopathy using Rhesus monkeys treated with clinically relevant field sizes and fractionation schedules. METHODS AND MATERIALS: Five groups of Rhesus monkeys were irradiated using 2.2 Gy per fraction to their spinal cords. Three groups were irradiated with 8 cm fields to total doses of 70.4, 77, and 83.6 Gy. Two additional groups were irradiated to 70.4 Gy using 4 and 16 cm fields. The incidence of paresis expressed within 2 years following the completion of treatment was determined for each group. Maximum likelihood estimation was used to determine parameters of a logistic dose response function. The volume effect was modeled using the probability model in which the probability of producing a lesion in an irradiated volume is governed by the probability of the occurrence of independent events. This is a two parameter model requiring only the estimates of the parameters of the dose-response function for the reference volume, but not needing any additional parameters for describing the volume effect. RESULTS: The probability model using a logistic dose-response function fits the data well with the D50 = 75.8 Gy for the 8-cm field. No evidence was seen for a difference in sensitivities for different anatomical levels of the spinal cord. Most lesions were type 3, combined white matter parenchymal and vascular lesions. Latent periods did not differ significantly from those of type 3 lesions in humans. CONCLUSION: The spinal cord exhibits a volume effect that is well described by the probability model. Because the dose response function for radiation myelopathy is steep, the volume effect is modest. The Rhesus monkey remains the animal model most similar to humans in dose response, histopathology, and latency for radiation myelopathy.

Animals↗