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Objective: Observations indicate that the acute toxicity of chemoradiation for squamous cell carcinoma (SCC) of the head and neck is not the same as that which occurs with radiation therapy alone. Thus, the specific aim of this pilot study was to estimate the reliability and validity of a modified version of a symptom distress scale used to assess the qualitative difference in symptom distress between the 2 populations., Methods: Over a period of 4 months a consecutive sample of 56 patients with head and neck cancer were recruited from the Department of Radiation Oncology to take part in our pilot study. The Cancer Disease and Treatment Concern Scale (CDTCS) was modified by adding 15 additional items and called the Head and Neck Distress Scale (HNDS). All dimensions were interrogated with at least four questions and a domain score was generated. In addition, the Head and Neck Radiotherapy Questionnaire (HNRQ), an established 22-item multidimensional questionnaire was also administered by interview after completion of the HNDS., Results: Fifty-six patients, 32 chemoradiation patients (mean age 64 years) completed the HNDS, taking 8 to 10 minutes to complete. The HNDS scores correlated well with the HNRQ scores (r = 0.835), demonstrating an acceptable level of content and concurrent validity. There was a significant difference in the overall HNDS scores between the chemoradiation group and the radiation therapy group (ANOVA, P = 0.001)., Conclusion: The HNDS is a valid measure of acute symptom distress and appears able to discriminate between the chemoradiation and radiation alone patients. There is considerable variation in symptoms that cause these patients distress.

Recent data show that accelerated radiotherapy (XRT) improves local-regional control (LRC) over standard-fractionation XRT. Concurrent chemoradiotherapy improves LRC and survival over XRT alone. This study assesses the feasibility, toxicity, and preliminary efficacy of concurrent 96-hour paclitaxel infusion with accelerated XRT. Eligible patients had stage IV squamous cell carcinoma of the head and neck, exclusive of nasopharynx cancer. Tumor had to be considered technically unresectable after evaluation by our multidisciplinary head/neck tumor board. XRT was given continuous course using an accelerated regimen with twice a day fractionation for the cone down (70-72 Gy/6 weeks). Chemotherapy consisted of 2 cycles of paclitaxel via 96-hour infusion during weeks 1 and 5 of XRT. The first 10 patients received doses of 40-120 mg/m2/cycle, and the subsequent 13 patients received 100 mg/m2/cycle. Twenty-three patients were studied. Median follow-up was 20.4 months (44.4 months for the 10 long-term survivors). Most (19/23) patients had reversible grade 3 acute mucositis. Median treatment time was 44 days, and all but 1 patient received both cycles of paclitaxel at their planned dose. The 3- and 4-year actuarial survival was 37%. Three- and 4-year LRC was 50%. Four patients (18%) developed distant metastases. Two patients (9%) developed severe esophageal strictures requiring permanent gastrostomy/tracheostomy, and 2 patients developed other late grade 3+ toxicities. Accelerated XRT plus concurrent 96-hour infusional paclitaxel as given in this study has intense but acceptable toxicity and is feasible. LRC and survival compare favorably with other aggressive regimens for this poor-prognosis population. Further study of accelerated XRT with concurrent chemotherapy is indicated.

Purpose: Radiation therapy has a high success rate in the treatment of early glottic carcinoma. Excellent outcomes have been reported from centers using cobalt-60 or relatively low-energy (< or = 4 MV) radiation therapy to achieve these results. Whether similar outcomes can be achieved with a 6 MV linear accelerator has been less rigorously evaluated. This study assesses the efficacy of 6 MV radiation therapy for early stage glottic cancer and identifies prognostic factors for local control and overall survival in this common disease., Materials and Methods: One hundred twenty-eight consecutive cases of Tis, T1, and T2 squamous cell carcinomas of the glottis from 1982 to 1996 were retrospectively analyzed with regard to local control and survival. All patients were treated with definitive radiation therapy with a 6-MV linear accelerator. Potential prognostic factors for local control and survival were evaluated with univariate and multivariate models. Median follow-up of locally controlled patients was 65 months., Results: The overall 3-year actuarial local control rates for T1 and T2 carcinomas were 86% and 68%, respectively. Patients with lesions involving the posterior third of the vocal cord had significantly worse 3-year local control (76% vs. 86%, P =.038). Radiation therapy technique and overall treatment time did not significantly affect local control. For patients with Tis and T1 lesions, factors associated with significantly worse local control included cordectomy-ineligible disease (P =.024), dose less than 6,600 cGy (P =.024), and lesions limited to the posterior third of the vocal cord (P =.004). Three-year local control was 76%, with doses less than 6,600 cGy and 90% with higher doses. High rates of second primary malignancies were observed and represented the major cause of death. Five-year overall survival was 84%., Conclusions: The use of 6-MV photons for treatment of early glottic cancer seems to achieve local control similar to that reported with lower-energy photons. However, patients with posterior third involvement had a poorer local control rate with standard radiation therapy, thereby suggesting that alternative approaches be considered.

Purpose: To examine the variation in the anatomy of parotid glands discerned by magnetic resonance imaging., Methods: Head and neck magnetic resonance scans of 16 patients (representing 32 glands) whose studies consisted of 5 mm contiguous sections were selected at random. The T1 weighted scans were thresholded and outlined to only encompass the parotid tissue. A volumetric analysis program (ISG Technologies, Inc.) was used to compute the parotid volume in cubic millimeters. Each of the 32 glands was measured independently by two observers., Results: The difference between observers averaged 4.8%. The median volume was 25,262 mm3, range 9225-54,080 mm3. In four patients there were considerable differences in the volumes of the right and left parotid glands, with variations of 9, 10, 14 and 29%. In nine patients, (18 glands) the depth from the medial edge of the gland to the spinal cord ranged from 19-32 mm. However, the maximum variation between the two sides in a single patient was 4 mm. Observations made include: (1) parotid glands extending anterior to the masseter muscle, or posterior to the posterior margin of this muscle; (2) parotid glandular tissue extending above the zygoma and the external auditory canal; (3) parotid tissue extending posteriorly to overlap the spinal cord; (4) parotid glands extending below or remaining above the angle of the mandible; and (5) wide variation of the transverse dimension of the parotid glands, with one measuring 4.8 cm., Discussion: To ensure that the entire parotid is or is not in a treatment field a computerized tomography or magnetic resonance scan is necessary. If a specific portion of the gland must be in the field a volume histiogram must be available.

Purpose: To determine the maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy schedule for the definitive treatment of advanced (nonmetastatic) unresectable squamous cell carcinoma of the head and neck (SCCHN)., Methods and Materials: Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70-72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed by 1.6 Gy b.i.d. for 2 weeks, with no planned interruptions. Paclitaxel was administered over a 96-hour continuous infusion during Weeks 1 and 5 of radiotherapy at the following dose levels: Dose Level 1: 40 mg/m(2)/96-hours (3 patients); Dose Level 2: 80 mg/m(2)/96-hrs (5 patients); Dose Level 3: 120 mg/m(2)/96-hours (2 patients); and Dose Level 2A: 100 mg/m(2)/96-hours (3 patients)., Results: The MTD of Paclitaxel was 100 mg/m(2)/96-hours. All but one patient (who experienced progressive disease after receiving 61 Gy and both cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity occurred in both patients enrolled at Dose Level 3, with one patient experiencing Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4 mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis occurred at all paclitaxel dose levels. There were no treatment-related deaths. All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8 of 13 patients, 4 patients achieved partial responses, and 1 patient had no response/progressive disease., Conclusions: Infusional paclitaxel over 96 hours during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The MTD of paclitaxel in this protocol was 100 mg/m(2)/96-hours. Dose-limiting toxicities were primarily enhanced epithelial reactions, but febrile neutropenia also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal reactions, reflecting the high treatment intensity. This regimen merits further investigation.

Tumors of the head and neck are primary sites for radiation treatment. In combination with surgery, the role of radiation is further expanded; however, localization of the primary tumor and its metastases, actual or potential, and the relationship to critical structures are quintessential to the application of radiation. In this process, the information made available by appropriate imaging studies as interpreted by the diagnostic radiologist is a requirement for cancer management.

Purpose: To determine whether midline mucosa-sparing blocks (MSBs) protecting the aerodigestive tract can statistically significantly reduce acute toxicity during radiation therapy for carcinoma of the head and neck, without compromising tumor control., Materials and Methods: Radiation records and simulation films were reviewed in 125 patients with carcinoma of the oral cavity, oropharynx, or nasopharynx. Patients with and without MSBs were compared. Measures of acute toxicity during radiation therapy were weight loss (> or = 5%), hospitalization for nutritional support, and unplanned treatment interruptions (> or = 5 days). Actuarial local-regional tumor control was compared., Results: Patients with MSBs had significantly less weight loss (26 of 50 vs 37 of 47 patients, P = .006), fewer hospitalizations for nutritional support (one of 61 vs seven of 64 patients, P = .04), and a trend toward fewer treatment interruptions (10 of 61 vs 19 of 64 patients, P = .07) than patients without MSBs. The 3-year actuarial tumor control rates in the neck were similar., Conclusion: Midline MSBs decrease acute toxicity during radiation therapy for carcinoma of the oral cavity, oropharynx, and nasopharynx without compromising tumor control.

Clinical studies have been initiated in conformal radiotherapy using a computer controlled multi-leaf collimator. Quantitative dosimetry and treatment planning studies comparing field shaping by lead alloy blocks and the multi-leaf collimator demonstrate the clinical acceptability of the multi-leaf collimator. Sixteen patients with tumors in multiple sites have received some part of their treatments with both blocking systems. Studies of dosimetry and field shaping show that the multi-leaf collimator produces clinically acceptable blocking for most field shapes and disease sites. The 80-20% penumbra was characterized for a wide range of shaped beams. For straight edges perpendicular to the leaf travel, the penumbra of measured dose distributions from the multi-leaf collimator is equal to conventional divergent blocking. When the multi-leaf collimator leaves approach a contour at an angle, the penumbra increases. At forty-five degrees, the maximum angle of approach, the penumbra is approximately 4 mm wider than that for divergent blocks. Three-dimensional treatment planning demonstrates that equivalent dose distributions can be obtained from the two field shaping systems. The multi-leaf collimator can be used effectively and efficiently to treat a variety of disease sites. Its optimal utility may be in treating complex fields--five or more shaped coplanar or non-coplanar beams. It is well suited for conformal therapy applications.

One hundred patients with inoperable, unresectable, or recurrent adenocarcinoma of the rectum were stratified and randomized to WR-2721 plus radiation therapy (WR + RT) or radiation therapy (RT) only treatment arms. The protector, WR-2721, was administered at a dose of 340 mg/m2 15 minutes before RT, 4 days a week for 5 weeks. The entire pelvis received 225 cGy per fraction for a total of 4500 cGy. The RT only group received the same treatment schedule. After this, both groups received a conedown of 720 cGy in 4 fractions. Inoperable and unresectable cases received a second conedown of 720 cGy. No moderate or severe pelvic normal tissue late effects were seen in the 34 evaluable patients in the combination group. However, in the RT only group, 5 of 37 evaluable patients exhibited late effects of moderate or severe degree. This difference was statistically significant (P = 0.03). There was no evidence of tumor protection by WR-2721. Sixteen percent of patients randomized to the WR + RT group had a complete response compared with 10% in the RT only group. The conditions of 12 patients of 100 became operable and 8 were resected. Seven of these patients remain free of recurrence.

The objectives of this randomized trial are to define the maximum tolerated dose of radiation therapy, at curative dose levels, that can be delivered following WR-2721, and to observe the anti-tumor effects and normal tissue responses. One hundred patients with inoperable, unresectable, or recurrent rectal cancer were stratified and randomized to radiation only, or WR-2721 and radiation. The entire pelvis is treated with 4 portals 4 times a week to a total of 4500 cGy (first level dose) in 5 weeks. WR-2721, 340 mg/m2 was given 15 minutes before radiation to the combination group. Subsequently, both groups received a conedown of 720 cGy in 4 days to 144(2) cm portals APPA, and if originally inoperable or unresectable 720 cGy in four days to second conedown of 64(2) cm. Patients were observed from 3 to 18 months (median = 12 months). No significant hypotension or hematologic toxicity occurred in the WR-2721 treated group. Mild to moderate emesis occurred in 80% of the courses. (No antiemetics were used.) Moderate or severe acute toxicities to normal tissues were observed less frequently in the WR-2721 arm. No moderate or severe late toxicities to the skin, mucous membrane, urinary bladder or intestine was observed in the WR-2721 group, however, 5 patients treated with radiation alone experienced moderate or severe late toxicity to these organs. No evidence of tumor protection was observed.

We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy. Sixteen patients with advanced cancers had serial measurements of serum calcium and other studies of blood chemistry before and after taking the compound. In all 16 patients (18 courses) the mean serum calcium level fell from 2.33 to 1.90 mmol per liter (9.33 to 7.62 mg per deciliter, P less than 0.001) after WR-2721, and in all 8 patients from whom data were obtained, serum calcium levels remained depressed at 24 hours. In 12 patients, ionized calcium levels dropped from 0.98 to 0.80 mmol per liter (P less than 0.01). Serum magnesium values fell from 0.96 to 0.74 mmol per liter (1.91 to 1.48 mg per deciliter, P less than 0.001). There were no changes in arterial pH or serum phosphate concentrations. In nine patients urinary calcium excretion rose from 3.96 to 10.68 mumol per minute (P less than 0.01) after WR-2721. Despite hypocalcemia, parathyroid hormone levels fell in all subjects. WR-2721 also inhibited the release of parathyroid hormone from bovine parathyroid cells incubated in vitro in low (0.5 mM) concentrations of calcium. We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia.

The underlying considerations necessary for selecting a CT scanner for radiation therapy treatment planning are analyzed and discussed. To obtain best value for funds expended it is desirable to compare CT scanner mechanical characteristics, data quality, and data handling capabilities. Specifications can be written to ensure prompt delivery of a unit containing all essential features without adding to the cost or complexity of the unit.

Forty-one patients with a total of 86 tumors were treated with negative pimesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) through December 31, 1977. An additional 30 tumors in the total patient population were treated with 100 kVp x-rays to assess comparative effects on skin nodules and 8 patients received additive photon or electron radiation to pion-treated portals. Of 52 evaluable tumors in 20 patients treated with pions only and followed for 3 to 22 months, 81% (42 tumors) completely regressed; 6% (3 tumors) partially regressed; and 13% (7 tumors) did not respond, although 5 of the 7 have shown no growth for 10 months. Of eight tumors in seven patients treated with a combination of pions and conventional radiation, three tumors showed complete response and five tumors showed partial response, though the resected specimens in two (one with complete and one with partial response) revealed no tumor microscopically. Reactions in normal tissues have been mild, with some patients exhibiting no normal tissue reaction, as compared with relatively marked tumor response.

Cultured human kidney T-1 cells were irradiated in flasks or on coverslips at different depths in a water phantom using the Los Alamos Meson Physics Facility Biomedical negative pion beam. Postirradiation colony formation and cell multiplication were assayed. Maximum cell inactivation occurred in the vicinity of maximum pion dose. Comparison of dose-survival curves with those found following x irradiation indicated RBE = 1.4 plus or minus 0.3 for colony formation and approximately 1.5 for growth delay. Delivery of 400 pion rads in four fractions resulted in higher survival than did delivery of 400 rads in a single fraction.

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematologic toxicity. Fifteen patients received WR-2721 (450-1100 mg/m2) prior to cyclophosphamide (1200-1800 mg/m2) and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. The mean WBC increased from 1800/mm3 on cyclophosphamide alone to 2700/mm3 with WR-2721 + cyclophosphamide (p = 0.008). In 11 patients who had nadir differential counts performed, 7 (64%) demonstrated improved nadir granulocyte counts with WR-2721. The mean granulocyte count increased from 765/mm3 on cyclophosphamide to 1274/mm3 with WR-2721 + cyclophosphamide (p = 0.05). In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide (1200-1800 mg/m2) alone, followed 4 weeks later by WR-2721 (450-1100 mg/m2) prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. The mean WBC increased from 1550/mm3 on cyclophosphamide alone to 1850/mm3 with WR-2721 + cyclophosphamide (p = 0.02), while the nadir granulocyte count increased from 449/mm3 to 844/mm3 (p = 0.001). No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. One patient developed mild thrombocytopenia. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m2 administered over 15 minutes.

Preliminary measurements of the biological effects of negative pions on cells in culture are reported. Cell survival as a function of depth was obtained by using gelatin to suspend the cells. The results indicate that the effects are more pronounced at the peak portion of negative pions. Cell-survival curves were also obtained under oxygenated and hypoxic conditions. The biological effectiveness at the peak was found to be a factor of 2.0 higher than at the plateau. The oxygen enhancement ratio was 1.5 at the peak. No significant differences in biological effects were observed above 14 mm in the peak region.

Irradiation of humans with negative pions requires a knowledge of the absorbed dose and radiation quality outside the primary pion beam. In conjunction with early clinical trials at LAMPF, experimental data have been obtained with microdosimetric techniques and multiwire proportional counters. Theoretical calculations have been made for the neutron contribution to the dose and are consistent with these data. Measurements were made with in 40 cm x 51 cm x 76 cm water phantom for a negative pion beam of initial momentum of 170 MeV/c, deltap = +/- 3MeV/c. The absorbed dose outside the treatment volume is the result of: (1) neutrons and photons from the pion interactions,(2) treatment room background and (3) peripheral muons, electrons and pions in the primary beam. The first two components are nearly isotropic and are congruent to 0.02% of the peak dose at a distance of 24 cm from the treatment volume; the third component is anisotropic and varies from 0.01 to 0.1% of the peak dose. Collimation of the bean increases the dose outside the treatment volume typically by 50%.

High-linear energy transfer radiation (neutrons, heavy ions, and pions) have a greater relative biological effectiveness than low-linear energy transfer radiation by depositing a high density of ionization in irradiated cells. This overcomes the protective effect of oxygen; decreases the variation in sensitivity among the several stages of the cell cycles; and, inhibits the repair of sublethal damage as compared to x-rays, gamma rays, electrons and protons. Negative pi mesons (pions), appear particularly suited for radiation therapy as their penetration and depth-dose profile lend themselves to shaping the high dose area to the tumor size and location. Preliminary biological experiments with pions produced at the Los Alamos Meson Physics Facility studied cell survival at various radiation depths and cell cycle sensitivity. Histologic study of data from the first human experiments indicated severe tumor cell destruction by pions as compared to x-rays in treating malignant melanoma skin nodules, without increased effects on dermal elements.

Seventeen patients with esophageal carcinoma treated by radiation therapy (RT) at our hospital between 1981 and 1984 had initial diagnostic esophagrams and 1 or more repeat esophagrams after completing RT. Total regression of the tumor was observed radiographically in 10 patients (59%) with a normal esophagus (24%) or benign-appearing residual stricture (35%) at the site of the previous lesion. Partial regression was observed in 4 patients, and progression of the tumor in 3. No correlation was found between the size, stage, or morphology of the lesion and its response to therapy. Although local recurrences were relatively uncommon, patient survival was often limited by the development of distant metastases. Fourteen of 15 patients with clinical follow-up initially had significant relief from dysphagia as the tumor regressed. However, 9 of those patients had recurrent or increased dysphagia over a subsequent 3-9-month period. Exacerbation of symptoms did not necessarily indicate recurrent carcinoma; it also resulted from benign radiation strictures, opportunistic esophagitis, or other complications of RT detected on esophagography.

A system is described for comparing various modalities and fractionation schedules of radiation by means of their long-term morphologic effects upon the mouse kidney. The comparison system utilizes a grading scale for histopathologic changes in which a given histologic grade depends upon meeting defined threshold criteria, rather than quantitation of a particular measurement. Renal tubular alterations served as the basis for comparison, since they appeared more reliably defined than glomerular changes. The radiation dose that induced a specific threshold effect in kidneys from 50% of the animals at 6 months was defined as the effective dose-50%, or ED50.ED50 was found for x-rays and negative pimesons administered in 1, 2, or 5 fractions. From these data, the relative biologic effectiveness (RBE) of negative pi-mesons with respect to x-rays was determined for each fractionation schedule.

The pharmacokinetic properties of WR-2721 were investigated in 13 cancer patients given a 150 mg/M2 intravenous bolus dose of the drug. An average plasma clearance value of 2.17 L/min was obtained. Very little of the drug or the two metabolites, WR-1065 and WR-33278, were excreted in urine obtained after the blood collection schedule. Plasma concentrations of WR-2721 decreased by 94% within 6 minutes of drug administration. The mean value of 6.44 L obtained for the steady-state volume of distribution indicates that the extravascular space occupied by the drug is small. These observations suggest that in human cancer patients, WR-2721 is rapidly taken up by tissues and converted to metabolites.

Irradiation treatment portals of the upper abdomen must limit the dose to the kidneys. Sparing one-third of the parenchyma of each kidney will prevent late clinical sequelae. One hundred CT scans of the abdomen were studied to evaluate using the vertebrae as landmark for treatment planning. In lateral fields, using the anterior border of the vertebral column as a landmark for the posterior high isodose line will limit treatment to less than 60% (mean 22%) of a single kidney. Placing the edge of an anterior/posterior field 2 cm lateral to the vertebral column will limit the dose to less than 44% of a single kidney (mean 11%).

Given the limitations of available material and methods for measuring skin response, the relative biological effectivenss (RBE) for the development and healing of skin reaction to pions in this experiment is 1.43. This is based on data obtained from a patient with malignant melanoma, in whom multiple skin nodules and the surrounding normal skin were randomized into three dose levels for pions and x-rays. The RBE for skin reaction was obtained while the skin tumor nodules appeared to regress at least as rapidly with pion therapy as with x-rays. Without benefit of adequate observation of time required for nodule regrowth, any estimate of tumor RBE is speculative.

The radioprotector with clinical potential, S-2-(3 aminopropylamino)-ethylphosphorothioic acid (WR-2721) is undergoing two Phase I trials. The objectives of these trials are 1) to determine the maximum tolerated dose (MTD) of WR-2721 in a single dose and 2) to determine the highest dose of WR-2721 that can be tolerated daily in the greatest number of fractions per week. A total of 65 patients have been treated. The single maximum tolerated dose has not yet been reached, though 740 mg/m2 is well tolerated. A single dose of 910 mg/m2 has been successfully administered to one patient. The multiple dose MTD is at an early stage with patients currently receiving 170 mg/m2 four times a week. Among the toxicities noted in both trials are hypotension, hypertension, emesis and somnolence. In addition, in the multiple dose trial there have been three patients who have had allergic reactions including one which was life-threatening. Phase II studies are planned and will begin when the maximum tolerated dose is established from each Phase I trial.

Two hundred forty-three patients have received WR-2721 in Phase I-II studies. Separate studies were conducted in which patients with advanced malignancies received WR-2721 before single or multiple doses of radiotherapy or in single doses prior to cyclophosphamide, nitrogen mustard or cis-platinum. Single doses were escalated from 25 to 1330 mg/m2. An Acceptable Tolerated Dose (ATD) of 740 mg/m2 infused in 15 minutes has been established and is currently used in Phase II studies. Significant persistent hypotension (greater than 20 torr systolic) as a dose-limiting toxicity has occurred in 5% of patients in the single dose study. Fifty-five patients have been entered in the multiple dose trial. Dose levels of 340 mg/m2, four times a week for three weeks, and 250 mg/m2, four times a week for six weeks have been reached. There were five idiosynchratic reactions (fever, chills, rash, hypotension), one of which was severe. Some patients withdrew from the multiple dose study because of vomiting after each injection, or fear. No deaths nor any long-term untoward effects were observed. There is no suggestion of tumor protection.