Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients

Radiation therapy is an important curative modality in the treatment of patients with head and neck cancer. However, radiation-induced changes in the oral cavity, such as xerostomia and mucositis, are among the most debilitating treatment sequelae experienced by patients undergoing radiation therapy, and attempts at ameliorating these side effects have been poor at best. Pilocarpine has been approved for post-radiation xerostomia, and the effect of its use during radiation therapy on salivary flow, xerostomia, mucositis, and quality of life (QOL) was assessed in a phase III study conducted by the Radiation Therapy Oncology Group (RTOG 97-09). In total, 245 evaluable patients were randomized to pilocarpine or placebo. Selected patients were required to have > or = 50% of the volume of the major salivary glands receive > or = 50Gy; to agree to provide stimulated and unstimulated samples of saliva (measured in g) before treatment, at the end of treatment, and 3 and 6 months after completion of radiation therapy; and to complete the University of Washington Head and Neck Symptom Scale. Following the completion of radiation therapy, the average unstimulated salivary flow was statistically greater in the pilocarpine group, whereas no difference was noted following parotid stimulation. There was no effect on the amelioration of mucositis. The results of the QOL scales did not reveal any significant difference between the pilocarpine and placebo groups with regard to xerostomia and mucositis. The significant difference in unstimulated salivary flow supports the concomitant use of oral pilocarpine to decrease radiation-associated xerostomia. However, the absent correlation between improved salivary flow and QOL scores is of some concern (though not a new finding) and may be related to the existence of comorbidities and the lack of effect on mucositis.     

Hyperthermia in combination with definitive radiation therapy: results of a Phase I/II RTOG Study

Between August 1981 and April 1986, 133 patients with superficial malignant tumors not previously treated with radiotherapy were entered on a Phase I/II RTOG study evaluating hyperthermia plus definitive radiotherapy. Eligible patients included those with superficial epithelial or mesenchymal tumors less than 4 cm in depth. Protocol radiotherapy specified a tumor dose of 60 Gy delivered in 1.8-2.0 Gy fractions 5 times/week with a boost of 5-10 Gy through reduced portals to residual tumor. Protocol hyperthermia, delivered twice weekly, was to start within 15 minutes following irradiation and to consist of 60 minutes of heat to a tumor temperature of 43 degrees C. Sixteen patients were excluded. Of the 117 eligible patients, the treated lesions had site/histologies which were 35% head & neck/squamous, 46% breast/adenocarcinoma, and 19% other site/histologies. Lesions were 3 cm or larger for 77% of patients. Of the 41 patients with head & neck/squamous lesions, skin or subcutaneous necrosis occurred within 6 months for 2% of the patients; 12% experienced thermal blisters. Fourteen patients were followed for 6 months or more following start of treatment; none of these experienced late toxicities more severe than telangiectasis. Complete responses were observed in 51% of these patients. Of the 54 patients with breast/adenocarcinoma lesions, skin or subcutaneous necrosis occurred within 6 months for 13% of the patients; 17% experienced thermal blisters. Thirty-seven patients were followed for 6 months or more following start of treatment; complications observed during this period included 13% with ulceration and one case of skin necrosis. Complete responses were observed in 85% of these patients. Local control was maintained at nearly this level for at least 2 years. Logistic regression analyses showed site/histology, greatest tumor diameter and average tumor temperature to be significantly related to response. Based on these promising findings, the RTOG has instituted a randomized Phase III study evaluating radiation therapy with or without hyperthermia in this patient population.     

Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31

PURPOSE: Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. RESULTS: Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. CONCLUSION: In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10.     

Fast neutron irradiation of metastatic cervical adenopathy: the results of a randomized RTOG study

Between 1977 and 1982, 199 evaluable patients with measurable cervical adenopathy were entered on a prospective, randomized RTOG study evaluating the use of fast neutrons in treatment of advanced, inoperable squamous cell carcinomas of the head and neck region. One hundred-eleven patients were randomized to receive mixed beam radiation therapy, and 88 were randomized to the photon control treatment. The complete response rates were 86% for mixed beam vs 75% for photons for Stage N1 nodes, 62% for mixed beam vs 48% for photons for Stage N2 nodes, and 63% for mixed beam vs 53% for photons for N3 nodes. The percents of patients remaining free of their adenopathy for two years were 78% for mixed beam vs 55% for photons for Stage N1 nodes, 39% for both mixed beam and photons for N2 nodes and 24% for mixed beam vs 13% for photons for N3 nodes. The median disease-free status was 20.3 months for mixed beam treated patients and 6.4 months for photon-treated patients. Patients who had clearance of cervical adenopathy survived significantly longer than those who did not.     

Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study

We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n=366) or MA 40 mg four times daily (160 mg daily; n=403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete response (CR)+partial response (PR) (15.0% vs. 12.4%) and of CR+PR+stable disease (SD)=24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR+PR+SD=24 weeks (60.1 vs. 49.1 weeks; P=0.025), time to tumor progression (20.3 vs. 16.6 weeks; P=0.037), time to treatment failure (16.3 vs. 15.7 weeks; P=0.042), and overall survival (not reached vs. 123.4 weeks; P=0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P=0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.     

Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial

Intraperitoneal treatment with interferon-gamma (IFN-gamma) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic-Illc ovarian cancer. In the control arm women received 100 mg/m(-2) cisplatin and 600 mg/m(-2) cyclophosphamide, the experimental arm included the above regimen with IFN-gamma 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P= 0.031, relative risk of progression 0.48, confidence interval 0.28-0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-gamma versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-gamma. Thus, with acceptable toxicity, the inclusion of IFN-gamm in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival.     

Long term results of radium therapy in cervical cancer

This paper reviews 649 patients with invasive cervical carcinomas; they were selected from among the overall number of patients who were treated from January 1959 to December 1970 and who for various reasons, received exclusively local treatment of the primary tumor with endocavitary curietherapy alone. The analysis was carried out with the intention of giving the long-term results of endocavitary curietherapy alone in the treatment of invasive cervical carcinoma. It also offers a contribution towards solution of the queries which still exist concerning the indications for endocavitary treatment in cervical cancer, and the questions connected with the optimal sequence of endocavitary irradiation with respect to external irradiation. To this end the following types of cases were excluded: carcinomas “in situ”; those with early stromatic invasion (≤ 0.3 cm); patients who were treated for relapse of the disease; patients who had surgery and/or external irradiation in association with endocavitary curietherapy; those few patients whose disease was initially at Stage IV. The endocavitary curietherapy adopted in these cases is a technique without rigid applicators that uses conventional ²²⁶Ra sources; an average of 7,500 nigh were administered in a single and continuous application with an average duration of 7 days. These were reduced to an average of 6,700 nigh in the case of cervical stump cancer. The crude 5-year survival rate, i.e. not corrected for natural mortality, calculated by the actuarial method, was 82.6% in Stage Ib “occ,” i.e. clinically undetectable, 64.8% in Stage Ib, 50.3% for Stage II and 29.8% in Stage III. In $\text{155}\text{601}$ patients with adequate follow-up the endocavitary treatment did not achieve local success (25.8% ). Local relapses, either alone or in association with pelvic relapse and/or a metastases in the medium and lower third of the vagina, comprised 43.9% of the overall failure causes found in relapsed patients. For lesions with a diameter greater than 6 cm it is unrealistic to expect a full-dose with endocavitary treatment in order to maximize the probability of controlling the primary tumor, since the primary lesion extends beyond the treatment isodose. This also applies to carcinomas of the cervical stump where the overall activity applicable is reduced and there are less favorable arrangement possibilities for the radioactive sources. In the Stage Ib “occ” cases, a conservative therapeutic approach can be proposed. In fact local treatment alone produces favorable results and nodal metastases are infrequent. In Stage III the physical examination alone often leads to errors when patients are classified; examination under general anesthesia should be considered compulsory.     

A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results

The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.     

A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118)

PURPOSE: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. PATIENTS AND METHODS: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints included overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. RESULTS: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. CONCLUSION: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.     

Vaccination therapy for non-small-cell lung cancer: review of agents in phase III development

The historical results of cancer vaccination for non-small-cell lung cancer (NSCLC) were disappointing. In the current decade, however, new insights in the interaction between tumours and the immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Modern NSCLC vaccine strategies rely on better identification of antigenic targets, addition of strong immunoadjuvants, and use of more efficient delivery systems. These treatments have convincingly demonstrated to elicit potent immune responses and have shown promising efficacy signals and excellent tolerability in phase II randomised studies. This-together with recent positive phase III data in indications other than NSCLC-has helped to establish the proof of principle for cancer vaccination. In NSCLC, ongoing phase III trials are investigating this approach in different treatment settings: the Melanoma AntiGEn A3 vaccine in resected early-stage NSCLC, the L-BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy, and belagenpumatucel-L, the epidermal growth factor and the TG4010 vaccine in advanced stage, either as an adjunct to chemotherapy or as maintenance after completion of chemotherapy. Mode of action, development, available clinical data, and currently ongoing phase III studies are reviewed.     

Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.     

Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: updated results of a phase III randomized trial

PURPOSE: The aim of this study was to compare the toxicity and efficacy of radiation therapy (RT) for localized carcinoma of the prostate, using a hypofractionated (55 Gy/20 fractions/4 weeks) vs. a conventionally fractionated (64 Gy/32 fractions/6.5 weeks) dose schedule. METHODS AND MATERIALS: A total of 217 patients were randomized to either the hypofractionated (108 patients) or the conventional (109 patients) dose schedule, with planning with two-dimensional (2D) CT scan planning methodology in the majority of cases. All patients were followed for a median of 48 (6-108) months. Gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated before RT and after its completion using modified late effects of normal tissue-subjective, objective, management, analytic (LENT-SOMA) scales and the European Organization for Research and Treatment of Cancer sexual function questionnaire. Efficacy of RT based on clinical, radiologic, and prostate-specific antigen data were also evaluated at baseline and after RT. RESULTS: Gastrointestinal and GU toxicity persisted 5 years after RT and did not differ between the two dose schedules other than in regard to urgency of defecation. However, 1-month GI toxicity was not only worse in patients with the hypofractionated RT schedule but also adversely affected daily activities. Nadir prostate-specific antigen values occurred at a median of 18.0 (3.0-54.0) months after RT. A total of 76 biochemical relapses, with or without clinical relapses, have occurred since; of these, 37 were in the hypofractionated and 39 in the conventional schedule. The 5-year biochemical +/- clinical relapse-free and overall survival was 55.9% and 85.3% respectively for all patients, and did not differ between the two schedules. CONCLUSIONS: Radiation therapy for prostate carcinoma causes persistent GI toxicity that is largely independent of the two dose schedules. The hypofractionated schedule is equivalent in efficacy to the conventional schedule.     

Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate

The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.     

Carbon ion radiation therapy for prostate cancer: results of a prospective phase II study.

BACKGROUND AND PURPOSE: To determine the efficacy and feasibility of carbon ion radiotherapy (C-ion RT) for prostate cancer. PATIENTS AND METHODS: Between April 2000 and November 2003, 175 patients received C-ion RT using a recommended dose fractionation (66.0 GyE/20 fractions) established from prior studies. C-ion RT alone was performed for 33 patients constituting a low-risk group (Stage < or =T2a and PSA <20 ng/ml and Gleason score < or =6); the remaining 142 high-risk patients received an additional androgen deprivation therapy (ADT). RESULTS: The 4-year overall survival and bNED rates were 91% and 87%, respectively. Local control was achieved in all but one patient. The 4-year bNED rates were 87% in the low-risk group and 88% in the high-risk group. In very advanced diseases (Stage > or= T3a or PSA > or= 20 ng/ml or Gleason score > or =8), there was significant difference in the bNED rate according to period of ADT administration (ADT > or =24 months: 93%, ADT <24 months: 73%, p<0.01). Grade 2 late toxicities developed in 4 patients (2%) for the rectum and 9 patients (5%) for the genitourinary system but no Grade 3 or higher toxicity was observed. CONCLUSIONS: The effectiveness of C-ion RT for prostate cancer has been well confirmed. Based on these results, new study of a C-ion RT modified for the administration strategy of ADT according to the patient risk has been started by dividing patients into 3 groups, high-risk, intermediate-risk, and low-risk.