Mild Acute Toxicity Research Articles

Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma

Background: The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma.Study Design: Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence–free interval, and survival.Results: Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-α (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent–free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent–free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p = 0.14, respectively).Conclusions: More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.

Treatment of A2-B2 prostatic cancer: results of a hormonoradiotherapy combination in the PSA era

Prospective analysis of results of combined neoadjuvant hormonetherapy and external beam radiation therapy in A2-B2 prostate adenocarcinoma. Between 1986 and 1994, 36 patients with clinical stage A2 (five patients), B1 (12 patients) and B2 (19 patients) N0 adenocarcinoma of the prostate declined for radical surgery, underwent a brief neoadjuvant hormonal therapy before external beam radiotherapy at our radiation therapy department. They all had a PSA determination before the combined treatment and no evidence of local extension or metastatic spread. They were followed clinically and with serial PSA levels for a median time of 58 months. Relapse was defined by a PSA level > or = 2.5 ng/mL. Median pre-treatment PSA level was 16.5 ng/mL; 16 patients had less than 15 ng/mL. Combined treatment was very well tolerated. After 3 months of neoadjuvant hormonetherapy, digital rectal examination was normalized in 27 cases with a PSA value < or = 1 ng/mL in 23. Only four tumors have relapsed (one local failure, two metastases and one PSA failure). The single factor that predicted biochemical relapse was pre-treatment PSA level: the 5-year actuarial rate of PSA failure when PSA level < 15 ng/mL was 0% and 27.5% if it was > or = 15 ng/mL (p = 0.05). During follow-up, only two patients suffered grade 2 rectitis and seven complained a total impotency. This limited study advocates hormonal neoadjuvant therapy and radiotherapy association in intracapsular prostatic carcinoma in patients declined for surgery or when pre-treatment PSA is above 15 ng/mL, with mild acute and late toxicity.

Radiosensitivity of Kock ileal reservoir

To acquire preliminary information on the radiosensitivity of the Koch ileal reservoir by reviewing acute and late toxicity incurred by nine patients who received pelvic radiotherapy after cystoprostatectomy with lower urinary reconstruction utilizing a Koch ileal reservoir with bilateral uretero-ileal-urethrostomy. All patients were irradiated because of synchronous locally advanced prostate cancer (pT3). A fourfield box technique at 100 cm source-axis-distance (SAD) with all fields treated every day at 1.8 Gy daily fractions, to a total dose of 45-50.40 Gy was used. The average AP portal dimension was 11 x 11 cm, and the average lateral was 7 x 8 cm. All portals were shaped using custom shields to optimize protection of normal tissues not suspected of tumor involvement (small bowel, posterior rectal wall). No attempt was made to shield the Koch ileal reservoir. For each patient, comparison of the treatment portals with the Kochgram radiography (gravity cystogram) confirmed the inclusion of the majority of the Koch ileal reservoir within the radiation fields. Acute and late morbidity was measured by RTOG toxicity criteria by retrospectively reviewing the patients' records. Only mild acute toxicity was reported by the patients: Six patients experienced grade 1 acute urinary toxicity and one suffered Grade 2 acute urinary toxicity. In four patients Grade 1 acute gastrointestinal toxicity occurred and in two patients Grade 2 toxicity occurred. With a median follow-up of 50 months late toxicity consisted mainly of microscopic hematuria in six patients and persistent frequency in two patients (with spontaneous improvement respectively at 4 and 6 months after radiation). No patients experienced acute or late Grade 3 or 4 genitourinary or gastrointestinal toxicity. The use of moderate doses of pelvic radiotherapy (45-50.40 Gy) at standard fractionation was well tolerated among nine patients who received pelvic radiation for invasive prostate cancer detected at the time of cystectomy and Koch ileal reservoir diversion. These preliminary data support the evidence that patients with a Koch ileal reservoir could safely undergo postoperative pelvic radiotherapy in these dose ranges and fractionation.

Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable nonsmall cell lung carcinoma: A multicenter randomized clinical trial

Lonidamine (LND) is an indazol-carboxylic acid derivative that selectively inhibits the energy metabolism of neoplastic cells, and increases the permeability of cell membranes. In vitro studies have demonstrated that LND can potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the acquired multidrug resistance of neoplastic cells. Some clinical trials have suggested a synergism of LND with alkylating agents, cisplatin, and anthracyclines in various solid tumors. From June 1990 to June 1993, 158 previously untreated patients with Stage IIIB and IV nonsmall cell lung cancer (NSCLC) were enrolled into a multicentric randomized trial to evaluate the addition of LND to a cisplatin-epirubicin-vindesine regimen. Eighty patients in the control arm (A) received cisplatin, 60 mg/m2 intravenously (i.v.); epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. (PEV), on Day 1 every 4 weeks, whereas 78 patients in the experimental arm (B) received the same regimen with the addition of LND from 75 mg orally three times on Day 1 to 150 mg orally three times on Day 7+ until tumor progression occurred. The experimental treatment achieved a significantly higher proportion of major responses in comparison with the control regimen (43% vs. 24%; P=0.02). The addition of LND apparently potentiated the activity of this cytotoxic treatment, particularly in patients with metastatic disease (overall response rate, 39% vs. 17%). The median time to progression (5 vs. 8 months; P=0.0007) and the median survival time (7.6 vs. 11 months; P=0.0013) were also statistically improved in Arm B. The acute toxicity of the 2 treatments was low: only 6% of patients in Arm A and 4% of patients in Arm B had to withdraw from treatment due to Grade 4 World Health Organization toxicity. The main additional side effects related to the administration of LND were epigastralgia, myalgia, asthenia, and orchialgia. However, these symptoms were mild and controlled by the concomitant administration of low doses of steroids. The mild acute toxicity of the PEV regimen and the acceptable and nonoverlapping additional side effects of LND render our experimental therapy worthy of consideration for the management of NSCLC patients with poor performance status or low tolerance to more aggressive therapeutic approaches.

Transrectal hyperthermia as palliative treatment for advanced adenocarcinoma of prostate and studies of cell-mediated immunity

During a fifteen-month period, 15 patients with progressive adenocarcinoma of the prostate (CaP) were treated with transrectal microwave hyperthermia (TRHT). There were 5 Stage T4 and 11 Stage T 3 patients including 6 patients with skeletal metastases. Nine of the patients had severe and 6 had moderately severe signs and symptoms of CaP. TRHT was given six times at 2,450 MHz with temperature controlled at 43.5° for thirty minutes. Cell-mediated immunity tests were performed before TRHT and at two, four, and six months post-therapy. The results of these tests were compared with those of 15 patients with benign prostatic hyperplasia (BPH) treated with the same TRHT and with 30 untreated normal volunteers. TRHT was well tolerated with mild acute toxicity noted in 3 patients (20 %). Of the 15 patients treated, 2 (13 % ) showed scintigraphic evidence of regression of bone metastases. Five patients survived more than five years since treatment, and in 3 patients there was no evidence of CaP. A decrease of marked or moderate degree in signs and symptoms of CaP was noted in 8 patients (53 %). The results of cell-mediated immunity tests were of interest. The 15 CaP patients prior to TRHT had lower OKT 4/OKT 8 ratio, lower PHA transformation index, and lower Con-A induced T-cell suppressor activity as compared with the 15 BPH patients and 30 healthy volunteers, who had normal immune parameters (p < 0.01). Following TRHT there was a significant increase in the monitored immune parameters noted in the 15 CaP patients (p<0.01). This immune stimulation peaked at two months and gradually decreased to near pretreatment levels at six months. In the 15 BPH patients post- TRHT changes in immune tests were less apparent. The results of this small study, if confirmed, could be of clinical importance in patients with advanced prostate cancer.

A Comparison of Transurethral and Transrectal Microwave Hyperthermia in Poor Surgical Risk Benign Prostatic Hyperplasia Patients

From 1987 to 1989, 36 poor surgical risk patients with benign prostatic hyperplasia (BPH) were treated with transrectal or transurethral microwave hyperthermia. Most of the 36 patients treated (85%) had severe signs and symptoms of urinary outflow obstruction. Of the patients 22 (61%) underwent transrectal and 14 (39%) underwent transurethral hyperthermia. Followup ranged from 10 to 28 months (mean 19 months) for the transrectal hyperthermia group and 7 to 16 months (mean 10 months) for the transurethral hyperthermia group. The patients were given 6 hyperthermia sessions of 30 minutes each with the temperature controlled on the rectal or urethral surface at 45C. Hyperthermia was well tolerated with mild acute toxicity and no late complications were observed. In the important subjective and objective parameters, major improvement was noted more frequently in the 14 transurethral than in the 22 transrectal hyperthermia treated patients (p < 0.05). The Food and Drug Administration severity score, prostate volume, post-voiding residual volume and urethral flow showed substantial improvement in 79, 86, 79 and 79%, respectively, of the 14 transurethral hyperthermia treated patients compared to 41, 45, 82 and 82%, respectively, for the 22 transrectal hyperthermia treated patients. A prospective randomized trial comparing transrectal and transurethral hyperthermia is required to define the role of each treatment mode in patients with BPH.

Leishmania donovani: Oral efficacy and toxicity of formycin B in the infected hamster

Formycin B, a structural analog of inosine, was evaluated as an orally administrable antileishmanial agent. Against Leishmania donovani in hamsters, it achieved an 85–92% reduction in numbers of parasites in livers of infected animals after oral administration at 13 mg/kg/day for 4 days. Its efficacy by oral administration was approximately four to eight times that by intramuscular administration and four times that of the positive control drug Glucantime by intramuscular administration. The levels of formycin B in serum after the final oral administration of 26 mg/kg/day were 1.4 μg/ml at 1 hr and 0.3 μg/ml at 2 hr. The concentration in liver was greater (9.0 μg/ml at 1 hr) and declined more slowly. With this latter dosage or with 104 mg/kg/day there was no acute toxicity of formycin B to bone marrow or formed elements of the blood. The only statistically significant toxicity to the liver was a doubling of serum total bilirubin levels. Comparison of the in vivo efficacy of formycin B against L. donovani to the mild acute toxicity of the drug suggests that formycin B has potential as an oral agent against visceral leishmaniasis.

Chlordane contamination of a municipal water system

On March 24, 1976, a section of the public water system of Chattanooga, Tennessee, supplying 105 people was contaminated with chlordane, a chlorinated hydrocarbon pesticide. In a door-to-door health survey of the 71 residents affected, 13 (18%) were noted to have symptoms or signs compatible with mild acute chlordane toxicity. Serum levels of chlordane metabolites measured shortly after the incident did not correlate with the recorded symptomatology. Retesting of the symptomatic residents 2 months later revealed a possible rise in oxychlordane levels, suggestive of an acute exposure in the past. None of the residents have had prolonged sequelae from chlordane exposure; further followup is recommended.