T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors.

The fact that progressing tumors contain a significant infiltrate of T-cells brings into question the competency of the infiltrating T-lymphocytes (T-TIL). We have examined the role of the T-cell receptor/CD3 complex and/or the interleukin 2 receptor (IL2R) in responsiveness of T-cells that infiltrate human renal cell carcinoma. T-TIL display a poor proliferative response to interleukin 2 (IL2) alone, IL2 in combination with antibody to CD3, or mitogen stimulation. The proliferative unresponsiveness was not related to low expression of CD3 or IL2R beta as the percentage of T-cells expressing CD3 and IL2R beta were comparable in both T-TIL and peripheral blood T-cells obtained from the same patient. In contrast to the lack of proliferative activity, stimulation of T-TIL or peripheral blood lymphocytes with phytohemagglutinin or anti-CD3 resulted in comparable levels of both IL2 and gamma-interferon mRNA and protein expression. While levels of IL2R alpha were low in unstimulated T-TIL and peripheral blood lymphocytes, anti-CD3 antibody or IL2 were capable of inducing surface expression of this protein in both cell populations. IL2R alpha mRNA levels were comparable in T-cells from the tumor and peripheral blood although in some experiments both the percentage of IL2R alpha-positive cells and the density of surface expression per cell were reduced in T-TIL. This reduced IL2R alpha expression on T-TIL was not responsible for the proliferative unresponsiveness since T-TIL that expressed both IL2R alpha and/or IL2R beta still failed to respond to high doses of IL2. Thus T-TIL display a selective loss of response to at least two well defined extracellular stimuli. While T-TIL exhibit a poor proliferative response regardless of the form of stimulation these cells remain sensitive to both anti-CD3 and IL2 in terms of IL2 and gamma-interferon or IL2R alpha expression, respectively. The fact that proliferative unresponsiveness exists even though T-TIL can produce IL2 and express IL2R alpha/beta suggests that T-TIL have a selective loss of a common intracellular signaling pathway which is requisite to proliferation but not other aspects of response to antigenic stimulation.

Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.

PURPOSE: Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated. PATIENTS AND METHODS: rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy. RESULTS: The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy. CONCLUSION: rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.

Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer.

Because tamoxifen and all-trans-retinoic acid (ATRA) have additive antitumor effects in preclinical systems, we performed a Phase I/II clinical trial of this combination in patients with advanced breast cancer. Patients with potentially hormone-responsive advanced breast cancer were enrolled. All received 20 mg of tamoxifen by mouth daily. Consecutive cohorts of 3-6 patients were treated on odd-numbered weeks with ATRA at doses of 70, 110, 150, 190, or 230 mg/m2/day. Twenty-six patients were entered in this trial; 25 were evaluable. A dose of 230 mg/m2 ATRA produced unacceptable headache and dermatological toxicity, but doses < or = 190 mg/m2 were tolerable. Two of 7 patients with measurable disease responded. Seven of 18 patients with evaluable, nonmeasurable disease achieved disease stability for more than 6 months. Plasma AUCs on day 1 of successive weeks of treatment were stable over time. A nonsignificant decrease in serum insulin-like growth factor I levels was noted during treatment, but this trend was similar to that observed in three "control" patients treated with tamoxifen alone. When given with daily tamoxifen, the maximum tolerated dose of ATRA that could be given on alternate weeks was 190 mg/m2/day. This schedule of ATRA resulted in repeated periods of exposure to potentially therapeutic concentrations of ATRA. Declines in the serum insulin-like growth factor I concentrations observed in patients treated with tamoxifen and ATRA were similar to those observed in patients treated with tamoxifen alone. Objective responses were observed, some in patients who had previously progressed while receiving tamoxifen, suggesting that further studies would be of interest.

Phase I trial of subcutaneous interleukin 3 in patients with refractory malignancy: hematological, immunological, and pharmacodynamic findings.

We conducted a Phase I trial of s.c. recombinant human interleukin 3 (rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokinetics, and in vivo biological effects of this cytokine. Thirty-one patients with refractory cancer were entered into the study between November 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 days administered to cohorts of three to nine patients at dose levels of 60-4000 microgram/m2/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per patient) and the maximal tolerated dose was 2000 microgram/m2/day. Toxicity was moderate, with most patients developing chills, fever, and myalgia. Dose-limiting toxicity consisted of diarrhea (two patients) and headache (one patient). Hematological effects of rhIL-3 included significant dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte numbers also increased. Various CD3(+) lymphocyte subsets increased; however, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced. Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-induced lymphocyte proliferation also was increased variably. Pharmacokinetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dose levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhIL-3 is well tolerated when administered s.c. and has reproducible hematological and immunological effects. The pleiotropic effects of this cytokine on various in vivo biological parameters were demonstrated clearly. Further studies of its immunoregulatory effects are warranted.

Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carmustine (BCNU).

STUDY OBJECTIVE: To determine pretreatment factors that predict for pulmonary toxic reactions after high-dose chemotherapy containing carmustine (BCNU) and to determine the utility of prednisone in preventing pulmonary toxic reactions. DESIGN: Retrospective review. SETTING: Tertiary care referral center. PATIENTS: Forty-five patients with relapsed or refractory lymphoma and 27 patients with breast cancer with normal cardiopulmonary function were treated with one of two high-dose combination chemotherapeutic regimens containing the same dose of BCNU. MEASUREMENTS: Recorded pretreatment patient characteristics included previous chemotherapy or radiation therapy, history of pulmonary metastases, history of chronic obstructive pulmonary disease, and history of smoking. Spirometry and single-breath carbon monoxide diffusing capacity (DCO) were obtained before and after high-dose chemotherapy. INTERVENTIONS: Patients were treated with prednisone for a 5% or more drop in postchemotherapy DCO whether or not symptoms were present. RESULTS: Fifty-nine patients were evaluable. No pretreatment characteristic predicted for declines in pulmonary function postchemotherapy. The FEV1/FVC ratio did not change significantly after high-dose chemotherapy, but the DCO decreased 12.1% (p < 0.001). Of the 59 evaluable patients, 30 were treated with prednisone for declines in postchemotherapy DCO. Sixteen (53%) of these 30 patients were asymptomatic. The DCO increased 10.3% in patients treated with prednisone compared with a decrease of 2.3% in patients not treated (p = 0.017). There was no statistically significant difference in FEV1/FVC in patients treated with prednisone compared with those not treated. Regression analysis of pretreatment characteristics, type of high-dose chemotherapy received, and treatment with prednisone identified only treatment with prednisone as a significant variable in predicting an increase in DCO (p = 0.03; regression coefficient = +11.5%, SE = +/- 5.2%) after high-dose chemotherapy containing BCNU. CONCLUSIONS: High-dose BCNU-containing chemotherapeutic regimens cause decreases in DCO that are often asymptomatic and likely represent subclinical pulmonary toxic reactions. Pretreatment clinical parameters cannot predict which patients will manifest pulmonary toxic reactions after high-dose chemotherapy. Empiric treatment with prednisone will reverse chemotherapy-induced decreases in DCO. Earlier institution of glucocorticoids for evidence of pulmonary dysfunction is recommended.

Impact of bladder neck preservation during radical prostatectomy on continence and cancer control.

OBJECTIVES: To assess the effect of preservation of the bladder neck and other factors on the rate of postoperative urinary continence and cancer control after radical prostatectomy. METHODS: Prospective analysis of clinical and pathologic findings in 206 consecutive patients undergoing radical prostatectomy with a surgical technique that emphasizes preservation of periurethral supporting tissue, urethral length, incorporation of the posterior periurethral fascia into the vesicourethral anastomosis, and preservation of the bladder neck. RESULTS: Uni- and multivariate statistical analysis demonstrated that patient age (p = 0.033) and vesical neck contracture (p = 0.047) were predictive of incomplete return of urinary control. Preservation of the vesical neck had no impact on return of continence, but was associated with a trend to a lower incidence of vesical neck contractures. A positive bladder neck margin occurred in 6.8% of surgical specimens and was associated with a higher grade, more advanced local stage, and other positive margins in all cases. The rate of local recurrence or prostate-specific antigen (PSA)-only failure was similarly independent of whether the vesical neck was preserved or resected and reconstructed. CONCLUSIONS: Age greater than 65 and occurrence of a vesical neck contracture are adverse predictors for return of urinary continence after radical prostatectomy. Preservation of the bladder neck does not have an impact on return of urinary control but may be associated with a lower risk of vesical neck contracture. Preservation of the bladder neck does not compromise cancer control as assessed by local or PSA-only failure rates.

Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy.

OBJECTIVES: Positive margins predict an adverse outcome after radical retropubic prostatectomy (RRP). The effect of initial incision of the lateral pelvic fascia prior to urethral transection on positive margins rates is assessed. METHODS: The rate of positive margins in 350 consecutive RRPs is compared in two groups without hormonal pretreatment. In group 1 (n = 198), RRP was performed in standard fashion with apical dissection and urethral transection preceding dissection of the lateral pelvic fascia and mobilization of the prostate from the anterior rectal surface. In group 2 (n = 1 52), the initial step consisted of incision of the lateral pelvic fascia along the perirectal surface with prostatic mobilization off the rectum prior to urethral transection. The bladder neck and seminal vesicle dissection was identical in both groups. Specimens were step-sectioned for histologic analysis. Differences in rates of positive margins were analyzed by Fisher's exact test and logistic regression. RESULTS: The rate of positive margins was reduced from 37.4% in group 1 to 15.8% in group 2. In the logistic regression model, surgical technique, Gleason sum, serum prostate-specific antigen (PSA), and the presence of extracapsular extension were independent predictors of margin status, with group 1 being more than twice as likely to have positive margins than group 2 (P = 0.0076; odds ratio 2.198; 95% confidence interval 1.23 to 3.92). The rate of positive margins was reduced from 45.5% in group 1 to 16.7% in group 2 (P = 0.0046) for non-nerve-sparing RRP and from 33.3% to 15.5% (P = 0.0012) for nerve-sparing RRP. There were no differences in functional outcomes between groups and no rectal injuries in group 2. CONCLUSIONS: Initial dissection of the lateral pelvic fascia during RRP results in a lower rate of positive margins independent of tumor grade, clinical stage, extracapsular extension, and preoperative PSA level.

High-dose busulfan and cyclophosphamide followed by autologous bone marrow transplantation and/or peripheral blood progenitor cell rescue for metastatic breast cancer.

High doses of combination alkylating agents have shown promise in the treatment of breast cancer but are complicated by significant toxicity. Busulfan and cyclophosphamide (BuCy) is a high-dose combination alkylating agent regimen that is well-tolerated when given for hematologic malignancy. We prospectively studied the effects of BuCy followed by autologous bone marrow transplant (ABMT) or peripheral blood progenitor cell (PBPC) rescue in 21 patients with metastatic breast cancer who had responded to either standard chemotherapy or radiotherapy. The mean patient age was 44 years. Nine patients were either estrogen- or progesterone-receptor positive, ten were negative, and two were unknown. Fourteen patients had local recurrence, ten had bone metastases, six had visceral disease, and two had a nonlocal soft tissue recurrence. Busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BuCy2) was given and followed by either ABMT, PBPC rescue, or both. Grade III to IV extramyeloid toxicity occurred in 6 (29%) patients. One patient died of hepatic venoocclusive disease but there was no other treatment-related mortality. Pulmonary infiltrates with hypoxia of uncertain origin developed in 2 patients after discharge. Of the 10 patients with measurable disease, 4 had complete responses, and 3 had partial responses to high-dose therapy for a total response rate of 70%. The estimated 2-year disease-free survival is 25% (95% CI = 6% to 44%). Our study found BuCy to be a well-tolerated preparative regimen for ABMT in the treatment of patients with metastatic breast cancer.

HIV infection among Brazilian transvestites in a prison population.

Eighty-two male transvestites imprisoned in Casa de Detenção (São Paulo, Brazil) were tested for HIV antibodies, and completed a questionnaire investigating their demographics, arrest and imprisonment records, sexual practices, and drug use. Data were then analyzed to evaluate the incidence of HIV infection and its association with various behavioral and other factors. Sixty-four of 82 (78%, 95% confidence interval [CI], 67-87%) transvestites were positive for HIV infection. The factors associated with significant differences in positivity among these individuals were the time spent in prison and the number of sexual partners during the previous year. It appears that the high rate of infection in this group obscured the importance of other risk factors and behavioral patterns potentially associated with infection. Given the social environment and the high rate of HIV infection among imprisoned transvestites, their role as "vectors" for dissemination of HIV in urban areas of Brazil may be significant.

Radical hysterectomy for cervical cancer: the effect of shorter length of stay on outcome.

BACKGROUND: The surgical treatment for limited cervical cancer (radical hysterectomy and pelvic lymph node dissection) has remained essentially the same for 40 years, but economic pressures have resulted in shorter length of hospital stay, and precautions against infectious diseases have resulted in less use of blood products. PURPOSE: To determine if recent changes in hospital practices have affected outcomes, and if obese patients are at greater risk of complications. METHODS: Retrospective review of 100 surgical cases grouped by time period (1981 through 1987 and 1988 through 1993) and by patient weight (< 80 kg and > or = 80 kg). RESULTS: Comparing the two time periods, the mean operative time remained the same (199 minutes), but use of blood products declined (mean 2.1 vs 1.5 units; P < .01), as did the mean length of hospital stay (10.6 vs 7.4 days, P < .01). The rate of postoperative complications decreased significantly (P < .01), and the 5-year survival rate remained 91%. Obese patients received more blood transfusions than did nonobese patients (2.6 vs 1.6 units; P = .02), but their mean operative time and hospital stay did not significantly differ. The rate of postoperative and long-term complications did not differ significantly between the two weight groups. CONCLUSIONS: Surgical treatment of limited cervical carcinoma continues to be safe and effective.

Histologic correlates of progression-free interval and survival in ovarian clear cell adenocarcinoma.

Unlike other ovarian epithelial cancers, histologic measures of differentiation of ovarian clear cell adenocarcinoma have not been found to be reliable predictors of progression-free interval and survival. Forty-two consecutively treated patients with pure ovarian clear cell adenocarcinoma were identified and all histologic materials were reviewed. The following histologic features were assessed: architectural pattern (tubular/tubulocystic, papillary, solid, and mixed), average and maximal mitotic activity per 10 high-power fields (hpf's), percentage of cells with clear cytoplasm, and nuclear grading (both Fuhrman et al.'s (Am. J. Surg. Pathol. 6, 655-663, 1982) and Christopherson et al.'s (Cancer 49, 1511-1523, 1982) methods). Surgical stage was most predictive of survival (P < 0.01) and subsequent comparisons using Cox proportional hazards modeling were adjusted for Stages III and IV. Greater than six mitotic figures per 10 hpf's predicted a poorer survival (P = 0.05) but was not predictive of progression-free interval (P = 0.28). Survival and progression-free interval in patients with tumors of mixed architectural pattern tended to be shorter than those for patients where one type did predominate, but this was not statistically significant (P = 0.06). The tubulocystic pattern was not predictive of patient outcome nor was either method of nuclear grading. Stage and average mitotic activity seem to be the best predictors of survival for patients with ovarian clear cell adnocarcinoma, while architectural pattern and nuclear grading are not as reliable.

Results of the clinical evaluation of atypical glandular cells of undetermined significance (AGCUS) detected on cervical cytology screening.

OBJECTIVE: To determine the clinical significance of and underlying pathology among patients with atypical glandular cells of undetermined significance (AGCUS) identified on cervical Pap smear screening. METHODS: The computerized files of the Cleveland Clinic Foundation cytology laboratory were searched from 1990 to 1994 to identify all patients with AGCUS. Patients with other significant cytologic diagnoses were considered separately from patients whose only significant finding was reported to be AGCUS. Retrospective chart review was completed to identify associated conditions and to record the results of the clinical evaluations of these patients. RESULTS: One hundred thirty-six patients were identified among the 68,368 (0.2%) specimens from this 5-year period in contrast to 3078 (4.5%) patients with atypical squamous cells (ASCUS). Mean patient age was 43.7 years (range 20-78). Among 77 patients without other significant cytologic findings in addition to AGCUS, without prior gynecologic cancer and who had a recorded gynecologic evaluation, 13 patients (17%) were diagnosed with the following lesions: two (3%) invasive cervical adenocarcinomas, three cervical adenocarcinomas in situ (4%), three grade 1 cervical intraepithelial neoplasms (CIN) (4%), four grade 2-3 CIN (5%), and one (1%) endometrial adenocarcinoma. Additionally, in subsequent follow-up examinations two patients were diagnosed with cervical adenocarcinoma in situ, one with invasive adenocarcinoma of the cervix and one with diffusely metastatic pancreatic cancer. CONCLUSIONS: AGCUS on cervical cytologic screening, even in the absence of other associated cytologic findings, is associated with substantial underlying uterine pathology including at least 4% (95% confidence interval (CI) 0.8%, 11.0%) invasive cancers and 13% (95% CI 6.4%, 22.6%) precancerous lesions. Cervical colposcopy, endocervical curettage, and endometrial biopsy are recommended for the complete evaluation of AGCUS.

Partial mastectomy and breast reconstruction. A comparison of their effects on psychosocial adjustment, body image, and sexuality.

BACKGROUND: This retrospective study compared psychosocial adjustment, body image, and sexual function in women who had either breast conservation or reconstruction for early stage disease. METHODS: Questionnaires were completed at a mean of 4 years after surgery by 72 women who had partial mastectomy and 146 women who had immediate breast reconstruction after mastectomy. RESULTS: In general, fewer than 20% of women reported poor adjustment on the domains measured. The two groups did not differ in overall psychosocial adjustment to illness, body image, or satisfaction with relationships or sexual life. There was a specific advantage of partial mastectomy over breast reconstruction in terms of maintaining pleasure and frequency of breast caressing during sexual activity. Women who had undergone chemotherapy had more sexual dysfunction, poorer body image, and more psychological distress. Hormonal therapy and radiation therapy, however, did not measurably affect quality of life. Factors predictive of greater psychosocial distress included a troubled marriage, a poor body image, sexual dissatisfaction, less education, and treatment with chemotherapy. CONCLUSIONS: The choice of local treatment had little psychosexual impact, whereas chemotherapy was associated with long term impairments.

Phase I trial of cisplatin, WR-2721, and the murine monoclonal antibody R24 in patients with metastatic melanoma: clinical and biologic effects.

The therapeutic and biologic effects of murine monoclonal antibodies in patients with malignancies have been widely investigated. Attempts to enhance results by combining these agents with cytotoxic drugs are now under study. A Phase I trial was performed to assess the toxicity and biologic effects of escalating doses of R24 (0-40 mg/m2/day 1-5, 8-12), an antibody that binds to the ganglioside GD3 present on melanoma cells, administered in combination with cisplatin (120 mg/m2) and WR-2721 (740 mg/m2) on day 1. Twenty-three patients with metastatic malignant melanoma were treated and are evaluable. The true maximum tolerated dose of R24 given as part of this combination was not reached. The toxicity of the regimen was moderate and included fever and urticaria, which were attributed to R24. Severe but reversible renal failure was noted in six patients in subsequent (two or more) treatment cycles, but when cisplatin was administered in 3% saline, this toxicity was not seen. Responses were seen in 2 of 19 patients receiving all three agents and in 1 of 4 patients receiving only cisplatin and WR-2721. No significant enhancement of natural killer, lymphokine-activated killer, and antibody-dependent cellular cytotoxicity lytic activity or significant changes from baseline in lymphocyte subsets secondary to R24 were seen. In 4 of 10 patients tumor localization of mouse monoclonal antibody was found and appeared greatest at higher R24 doses and during week 1 of therapy. Human anti-mouse antibody responses developed by day 22 in 17 of 19 patients treated with R24, and the coadministration of cisplatin did not appear to abrogate this response. Finally, the half-life and Cmax of cisplatin were not affected by R24. In summary, the combination was well tolerated, responses were few, and significant biologic interactions or immunomodulation were not observed.

Characterization of tumor-infiltrating lymphocyte subsets from human renal cell carcinoma: specific reactivity defined by cytotoxicity, interferon-gamma secretion, and proliferation.

The detection of T cells with specificity for human renal cell carcinoma (RCC) has been difficult to document. In an attempt to improve our identification of RCC-reactive T cells, tumor-infiltrating lymphocytes (TIL) were expanded in interleukin-2/interleukin-4 (IL-2/IL-4) and then separated into CD4+ and CD8+ subsets using antibody-coated biomagnetic beads. TIL grown in IL-2/IL-4 expanded to greater numbers than TIL grown in IL-2 alone. From 16 patients in whom subset separation was performed, three CD4+ and three CD8+ TIL consistently had specificity for RCC that was detected by cytotoxicity, proliferation, or interferon-gamma (IFN-gamma) production. Four of the six lines were derived from the IL-2/IL-4 cultures. Two CD8+ TIL lines displayed specific lytic activity, lysing the autologous tumor but not allogeneic RCC or nonrenal tumors. Moreover, the lytic activity of these lines was blocked by anti-CD3 antibody, suggesting that tumor recognition was through the TCR/CD3 complex. Two additional TIL lines showed preferential lysis of RCC because they were cytotoxic for autologous tumor and one or more allogeneic RCC but not other tumor types. Two nonlytic CD4+ lines as well as the two CD8+ lines that were specifically lytic also produced IFN-gamma in response to the autologous tumor but not allogeneic RCC. Although these TIL lines produce IFN-gamma when stimulated with tumor alone, the addition of 5 U/ml of IL-2 significantly enhanced IFN-gamma secretion. The four TIL lines that showed specificity for RCC in terms of IFN-gamma production also had enhanced proliferation to the autologous RCC plus IL-2 but not to multiple allogeneic RCC plus IL-2. These studies demonstrate that TIL from RCC patients contain both CD4+ and CD8+ T cells that have specificity for RCC. In addition to cytotoxicity, specificity to RCC can be defined by IFN-gamma production and proliferation.

A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results.

BACKGROUND: A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous-course radiotherapy was performed at the Cleveland Clinic Foundation. METHODS: Between March 1990 and June 1995, 100 patients with resectable stage III and IV squamous cell head and neck cancer were randomized to either Arm A: radiotherapy alone, 68-72 Gy at 1.8-2.0 Gy per day; or to Arm B: the identical radiotherapy with concurrent chemotherapy. Chemotherapy consisted of 5-fluorouracil, 1000 mg/m2/day, and cisplatin 20 mg/m2/ day, both given as continuous intravenous infusions over 4 days beginning on day 1 and day 22 of the radiotherapy. At 50-55 Gy, patients were clinically reassessed. If a response was evident, radiotherapy was completed. In non-responding patients, however, radiotherapy was terminated and surgery recommended. After completion of all treatment, salvage surgery was performed, if possible, for any residual primary or nodal disease or for any subsequent locoregional recurrence. RESULTS: Except for an overrepresentation of T1 patients on Arm A, the treatment arms were equivalent. Toxicity was greater in the patients on Arm B with a higher incidence of grade III and IV neutropenia, thrombocytopenia, cutaneous reaction, and mucositis. Feeding tubes were also required more often, and weight loss was greater on the chemotherapy arm. No toxic deaths occurred. With a median follow-up of 36 months, the Kaplan-Meier 3-year projections of relapse-free survival are 52% for Arm A and 67% for Arm B (p = .03), and the likelihood of developing hematogenous metastases is 21% for Arm A and 10% for Arm B (p = .04). Although overall survival is not significantly different, overall survival with successful primary site preservation was 35% for Arm A and 57% for Arm B (p = .02). This difference remains statistically significant in the subsets of patients with laryngeal and hypopharyngeal primaries but not in patients with oropharyngeal primaries. CONCLUSIONS: Continuous-course radiotherapy and concurrent combination chemotherapy is an intensive, toxic but tolerable treatment regimen, which, when compared with radio therapy alone, can produce an improvement in relapse-free survival, a decrease in distant metastases, and an improvement in overall survival with successful primary site preservation.

Phase II trial of subcutaneously administered granulocyte-macrophage colony-stimulating factor in patients with metastatic renal cell carcinoma.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is involved in the differentiation and proliferation of various hematopoietic precursors. It also has been reported to enhance the antitumor activity of various mature effector cells. Previous reports have noted preclinical antitumor activity in a murine model utilizing genetically engineered tumor cells and instances of tumor regression in patients with solid tumors receiving GM-CSF. In the present study, a Phase II trial of human recombinant GM-CSF (GM-CSFrh) in patients with metastatic renal cell carcinoma (RCC) was conducted to investigate further the potential antitumor activity of this cytokine. METHODS: Twenty-six eligible patients with metastatic RCC received 3 microgram/kg of GM-CSFrh subcutaneously for 14 days, with cycles repeated every 28 days. RESULTS: Two of 26 patients (8%; 95% confidence interval 1-25%) demonstrated partial tumor responses during GM-CSFrh therapy. Both individuals who responded had received prior therapy. A median of three cycles per patient were administered, and toxicity was mild. CONCLUSIONS: GM-CSFrh may mediate tumor regression in patients with metastatic RCC; however, the level of activity in previously treated patients is low.

Phase II trial of interleukin-2 and interferon-alpha in patients with renal cell carcinoma: clinical results and immunologic correlates of response.

A phase II trial was conducted in patients with metastatic renal cell carcinoma, to assess the clinical efficacy and immunoregulatory effects of continuous-infusion recombinant interleukin-2 (rIL-2) (9.0 x 10(6) IU/m2/day on days 1-5, 8-12, 15-19, and 22-26) and subcutaneously administered recombinant human interferon-alpha 2b (rHuIFN alpha 2b) (10.0 x 10(6) U/m2/day TIW). Thirty-six patients with metastatic renal cell carcinoma, performance status of 0-1, and measurable disease who had not received prior rIL-2, rHuIFN alpha 2b, or chemotherapy were treated. Patients with CNS metastases, active infections, history of another malignancy within 3 years, and those requiring corticosteroids were ineligible. Cycles of rIL-2 and rHuIFN alpha 2b were administered in the outpatient department every 6-8 weeks in stable or responding patients until patient tolerance or a complete response were reached. Doses were modified for grade III or IV toxicity. Ancillary studies included three-color immunocytometric analysis of peripheral blood lymphocytes, repetitive tumor biopsies for immunohistologic analysis of infiltrating cells and proliferative responses of tumor infiltrating lymphocytes, and preliminary studies of changes in peripheral blood T-lymphocyte signal transduction molecules [T-cell receptor (TCR)-zeta, p56ick, p59fyn]. Thirty-six eligible patients were treated, with 6 of 36 patients (17%, 95% confidence interval 6-33%) responding (3 complete response, 3 partial response). In two of the partial responders, and in an additional three patients with either minimal tumor regression (one patient) or stable disease (two patients), surgical removal of residual disease was undertaken. The median survival of all patients was 14 months. The toxicity of this regimen was severe, but outpatient administration was possible in most instances. Immunoregulatory effects on T-cell subsets included increases in various CD3+ CD25+/- HLADr+/- subsets unrelated to response. Tumor biopsies before and/or during therapy were obtained in 17 patients, and no consistent alterations in the degree of T-lymphocyte or macrophage infiltrates could be detected. In a subset of patients, tumor infiltrating lymphocyte proliferative responses and levels of peripheral blood T-cell signal transduction molecules (TCR-zeta, p56lck, p59fyn) were investigated. Abnormalities were found in selected patients, which improved during rIL-2/rHuIFN alpha 2b therapy. This cytokine combination produces tumor regression in selected patients with metastatic renal cell carcinoma. Surrogate immunologic markers associated with response were not identified; however, preliminary studies demonstrate investigation of immune defects and their reversal with cytokine therapy is possible.

Immunomodulatory effects of interleukin-2 and interleukin-4 in patients with malignancy.

A phase I trial of simultaneously administered recombinant interleukin-2 (rIL-2) and recombinant human IL-4 (rHuIL-4) was conducted to evaluate the toxicity and the clinical and immunologic effects of this cytokine combination. Thirty-nine eligible patients with refractory malignancy were treated at eight different dose levels (1A to 3B): 1-3 of rIL-2 [3.0, 12.0, and 48.0 x 10(6) IU/m(2) i.v. three times weekly (TIW)] and A-C of rHuIL-4 (40, 120, and 400 mu g/m(2) s.c. TIW). The toxicity of these two cytokines was moderate and was comparable with that seen with rIL-2 alone. The maximal tolerated dose (MTD) of the combination was not reached because of lack of sufficient rHuIL-4 but is at least 48.0 x 10(6) IU/m(2) of rIL-2 and 120 mu g/m(2) of rHuIL-4. Two patients with melanoma had partial responses. The immunologic effects included increases in absolute lymphocyte numbers, and the CD3- /CD56+/ CD2+, total CD56+, CD8+, and CD16c+ lymphocyte subsets with increasing rIL-2 dose levels, but not with rHuIL-4. This increase in natural killer (NK) cells in the peripheral blood was accompanied by an increase over baseline in NK lytic activity against K562 targets; however, concomitant increases in lymphokine-activated killer (LAK) activity (Daudi targets) were not seen. The CD3+, CD4+, and CD3+/CD25+/HLA-Dr+ T-cell subsets also increased, and these increases were related to both increasing rIL-2 and rRuIL-4 doses. Finally, in four of six patients, serial tumor biopsies demonstrated increases in major histocompatibility complex (MHC) class I or II antigen expression on tumor cells or increasing T-cell infiltrates during cytokine therapy or both. This trial demonstrated that rIL-2 and rHuIL-4 can be administered simultaneously with acceptable toxicity. The immunologic findings demonstrated the expected rIL-2-associated increases of CD56+ and CD16c+ lymphocytes and NK activity, and interestingly, no development of LAK activity. These findings suggest regulatory effects of rHuIL-4 on rIL-2-related effects in vivo.