- [Show abstract] [Hide abstract] ABSTRACT: To investigate influence of various pretreatment prognostic factors in patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone. One hundred and sixteen patients were treated with tumor doses of 69.6 Gy, 1.2-Gy, twice-daily fractionation. There were 49 patients with Stage I and 67 patients with Stage II. Eighty patients had Karnofsky performance status (KPS) 90-100 and 95 patients had <5% weight loss. Peripheral tumors were observed in 57 patients. Squamous histology was observed in 70 patients and the majority of patients had concomitant disease (n=72). The median survival time for all patients was 29 months; 5-year survival was 29%. The median time to local progression and the distant metastasis were not achieved, whereas 5-year local progression-free and distant metastasis-free survivals were 50% and 72%, respectively. Multivariate analysis identified KPS, weight loss, location, histology, and the reason for not undergoing surgery as prognostic factors for survival. KPS, location, and histology influenced local progression-free survival, whereas only KPS and weight loss influenced distant metastasis-free survival. This retrospective analysis identified KPS and weight loss as the most important prognostic factors of outcome in patients with early-stage NSCLC treated with hyperfractionation radiation therapy.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the influence of interfraction interval (IFI) on treatment outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (Hfx RT) with or without concurrent chemotherapy (CHT). During 3 randomized phase III and 1 phase II study, a total of 536 patients were treated with Hfx RT alone or with concurrent carboplatin/etoposide. Two hundred eighty-five patients were treated with IFI of 4.5-5.0 hours, while 251 patients were treated with IFI of 5.5-6.0 hours. "Shorter" (4.5-5.0 hours) IFI led to better overall survival (OS) (P = 0.0000) and local recurrence-free survival (LRFS) (P = 0.0000). Multivariate analyses showed IFI to be an independent prognosticator of both OS and LRFS. These results were confirmed when we separated all patients (n = 536) into those treated with Hfx RT only (n = 127) and those treated with concurrent RT/CHT (n = 409). Various RT-related high-grade acute toxicity was not different between the 2 IFI, but patients treated with shorter IFI had a significantly higher incidence of hematological toxicity (P = 0.002). None of the late high-grade toxicities were different between the 2 interfraction intervals. Using regression analysis, it was shown that IFI was not a significant predictor of any of acute or late high-grade (> or =3) toxicity. IFI is an important prognosticator of OS and LRFS in patients with stage III NSCLC treated with Hfx RT with or without concurrent carboplatin/etoposide. IFI led to higher incidence only of hematological toxicity, but was not predictive of any acute or late high-grade (> or =3) toxicity. A carefully designed randomized trial seems necessary to give better insight into the issue of optimal IFI in this disease.
- [Show abstract] [Hide abstract] ABSTRACT: To retrospectively investigate the difference between conventionally fractionated (CF) and hyperfractionated (Hfx) radiation therapy (RT), with and without either daily cisplatin (CDDP) or carboplatin (CBDCA), in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) enrolled onto two consecutive prospective randomized studies. Treatment consisted of CF RT (70 Gy, group 1), CF RT and either daily CDDP (6 mg/m2) or daily CBDCA (25 mg/m2; group 2), Hfx RT (77 Gy, 1.1 Gy bid; group 3), or Hfx RT and daily CDDP (group 4). Hfx RT plus CDDP achieved better overall survival (OS) and local recurrence-free survival (LRFS) than any other group. There was an insignificant difference favoring Hfx RT over CF RT, either alone or in combination with CDDP or CBDCA, regarding both OS (P =.058 and P =.051, respectively) and LRFS (P =.088 and P =.091, respectively). No difference was seen between CF RT plus chemotherapy (CHT) and Hfx RT alone regarding either OS (P =.32) or LRFS (P =.48). Regional recurrence-free survival was similar in the four treatment groups. CF RT plus CHT and Hfx RT plus CDDP achieved better distant metastasis-free survival than CF RT and Hfx RT. High-grade toxicity was significantly more frequent in Hfx RT plus CDDP than in any other group, except in the Hfx RT group. Hfx RT led to significantly more acute toxicity and xerostomia than CF RT plus CHT. Hfx RT was more toxic than CF RT, either alone or with concurrent CHT. Results of this study show that there may be a therapeutic benefit for CF RT plus CHT over Hfx RT plus CDDP in patients with SCCHN, but this cannot be firmly established without a larger and well-planned controlled trial.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with high-dose hyperfractionated radiation therapy (Hfx RT) and concurrent chemotherapy (CHT) consisting of carboplatin (C) and etoposide (E). During three prospective randomized phase III and one prospective phase II study enrolling a total of 536 patients, 301 patients were treated with high-dose Hfx RT (69.6 Gy) and either low-dose daily CE (50 mg each) (n = 163) or daily CE (30 mg each) accompanied by "weekend" CE (100 mg of each on Saturdays and Sundays) (n = 138). The median survival time for all 301 patients is 22 months and 5-year survival is 24%. Median local recurrence-free survival (LRFS) time is 21 months and 5-year local recurrence-free survival is 32%. The median time to distant metastasis is 25 months, and 5-year distant metastasis-free survival (DMFS) is 35%. Only the type/schedule of CHT administration did not influence overall survival, LRFS, and DMFS. On multivariate analyses using these three endpoints, age stage, interfraction interval, and type/schedule of CHT administration did not predict survival, LRFS, and DMFS, while gender, KPS, and weight loss did. Only high grade hematologic toxicity was more frequent in weekend CHT group. High dose Hfx RT and concurrent low-dose daily CE with or without weekend CE is an active treatment approach in stage III NSCLC that led to high overall survival, LRFS, and DMFS rates.
- [Show abstract] [Hide abstract] ABSTRACT: To provide updated outcome data (10 years) of a Phase II study of combined surgery, postoperative radiotherapy, and adjuvant chemotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma. In 23 adult patients, surgery, postoperative radiotherapy (60 Gy in 30 daily fractions within 6 weeks), and adjuvant modified chemotherapy (procarbazine 60 mg/m(2) on Days 1-14, lomustine 100 mg/m(2) on Day 1, and vincristine 1.4 mg/m(2) [maximum 2 mg] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred. The median follow-up was 116 months for all patients. The median survival time was 118 months, and the 5-year and 10-year survival rate was 57% and 47%, respectively. The median time to tumor progression was 78 months, with a 5-year and 10-year progression-free survival rate of 52% and 39%, respectively. Gender, age, Karnofsky performance status, location, and histologic type did not influence survival. Patients with tumors <or=4 cm did better than those with tumors >4 cm (p = 0.0470), as did those with total tumor resection compared with those with subtotal tumor resection or biopsy only (p = 0.0024). Gender, Karnofsky performance status, location, and histologic type did not influence progression-free survival, but younger age (p = 0.0389), smaller tumor size (p = 0.0357), and more radical surgery (p = 0.0033) correlated positively with it. Acute high-grade (Grade 3 or worse) chemotherapy-related toxicity was mainly hematologic, with 3 patients (13%) experiencing acute Grade 4 toxicity. The results of this 10-year update confirmed that the trimodality approach is effective in patients with anaplastic oligodendroglioma and oligoastrocytoma.
- [Show abstract] [Hide abstract] ABSTRACT: The impact of various clinical pretreatment prognostic factors in patients with malignant glioma treated with a combined modality approach was investigated in 229 patients treated on four consecutive prospective phase II studies. The median survival time for all 229 patients is 14 months, and 2- and 5-year survival rates are 34%, and 9%, respectively. The median time to tumor progression is 14 months, and 2- and 5-year progression-free survival rates are 32%, and 9%, respectively. Females did better than males, while patients 55 years or less did better than those more than 55 years. Patients with Karnofsky performance status (KPS) 80 to 100 did better than those with KPS 50 to 70 as well as did patients having preoperative tumor sizes 4 cm or less when compared to those with larger tumors. Frontal tumor location as well as more extensive surgery favorably influenced survival. Patients harboring anaplastic astrocytoma fared significantly better than those with glioblastoma multiforme. Both univariate and multivariate Cox analyses confirmed independent influence of these prognosticators. When progression-free survival was used as an endpoint, all seven variables remained independent prognosticators. This study showed that sex, age, KPS, tumor size, tumor location, histology, and extent of surgery are independent prognosticators in patients with malignant glioma treated with combined modality approach.
- [Show abstract] [Hide abstract] ABSTRACT: To provide a 10-year update of hyperfractionated radiation therapy (Hfx RT) in adults with incompletely resected supratentorial low-grade glioma. A total of 37 patients were treated with 55 Gy in 50 fractions in 25 treatment days in 5 weeks to tumor plus 2 cm, and additional 17.6 Gy given in 16 fractions in 8 treatment days in 1.5 weeks to tumor plus 1 cm, (1.1 Gy twice daily). Total dose was 72.6 Gy in 66 fractions in 33 treatment days in 6.5 weeks. After a median follow-up time of 121 months for all patients, the median survival time (MST) for all 37 patients was 145 months, whereas 10-year survival rate was 67%. Median time to tumor progression (MTP) has not yet been attained, but 10-year progression-free survival (PFS) rate was 62%. There was no difference in survival or PFS regarding gender, age, location, site, size, CT enhancement, and histology; whereas lower KPS, higher neurologic status, and lesser extent of surgery had an adverse influence. Infield progression occurred in 15 (88%), whereas in only 2 (12%) patients, tumor progression was described as marginal. Brain necrosis has not been observed so far. Autopsy findings confirmed recurrent glioma and excluded post-RT necrosis in 14 (38%) patients. Of those, 7 (50%) patients had either Grade 3 (n = 4) or Grade 4 (n = 3) glioma. High-dose HFX RT is effective with mild to moderate toxicity. Further studies are warranted with more patients before testing it against standard fractionation RT in this patient population.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the influence of various clinical prognostic factors in patients with glioblastoma multiforme (GBM) treated with a combined modality approach. A total of 175 patients with GBM was treated in four consecutive prospective phase II studies using surgery, hyperfractionated or accelerated hyperfractionated radiotherapy (RT) and either adjuvant or concurrent or pre-irradiation chemotherapy (CHT) between January 1988 and December 1993. The median survival time for all 175 patients was 14 months and 1-3-year survival (OS) rates were 57%, 34% and 24%, respectively. The median time to tumour progression was 12 months, and 1-3-year progression-free survival (PFS) rates were 43%, 11% and 7%, respectively. Survival analysis showed that of all investigated prognostic factors, only gender did not influence survival. Patients </=55 years did better than those >55 years; patients with KPS 80-100 did better than those with KPS 50-70; patients with frontal tumours did better than those with tumours in other locations; patients with tumours up to 4 cm did better than those with larger tumours, as did patients with either subtotal or gross total tumour resection when compared to those undergoing biopsy only. Multivariate analysis showed that gender and tumour location did not independently influence survival. When PFS was used as the endpoint, only gender did not influence PFS, as confirmed by multivariate analysis.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the effect of treatment interruptions due to high-grade (> or =3) toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy (Hfx RT). Of 116 patients treated with total tumour doses of 69.6 Gy, 1.2 Gy b.i.d. fractionation, 44 patients refused surgery while 72 patients were medically inoperable due to existing co-morbid states. Patients who were medically inoperable had worse KPS (P=0.0059) and more pronounced weight loss (P=0.0005). Among them, 12 patients experienced high-grade toxicity and 11 of them with either acute (n=6) or "consequential" late (n=5) high-grade toxicity requested interruption in the Hfx RT course (range, 12-25 days; median, 17 days). Superior survival (OS) was observed in patients who refused surgery when compared to those who were medically inoperable (P=0.0041), as well as superior local recurrence-free survival (LRFS) (P=0.011), but not different distant metastasis-free survival (P=0.14). Cause-specific survival (CSS) also favoured patients who refused surgery (P=0.004). Multivariate analysis showed independent influence of the reason for not undergoing surgery on OS (P=0.035), but not on LRFS (P=0.084) or CSS (P=0.068). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 11 of 72 patients with medical inoperability and co-morbid states experienced high-grade toxicity and had treatment interruptions to manage toxicity (P=0.0064). Patients without treatment interruptions had significantly better OS (P=0.00000), LRFS (P=0.00000) and CSS (P=0.00000) than those with treatment interruptions. When corrected for treatment interruptions, the reason for not undergoing surgery independently influenced OS (P=0.040), but not LRFS (P=0.092) or CSS (P=0.068). In contrast to this, treatment interruption was independent prognosticator of all three endpoints used (P=0.00031, P=0.0075 and P=0.00033, respectively). When 11 patients with treatment interruptions were excluded, the reason for not undergoing surgery still affected OS (P=0.037) and CSS (P=0.039) but not LRFS (P=0.11). Multivariate analyses using OS, CSS and LRFS showed that the reason for not undergoing surgery affected OS (P=0.0436), but neither CSS (P=0.083) nor LRFS (P=0.080).
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the influence of potential pre-treatment clinical prognostic factors in stage IV non-small cell lung cancer (NSCLC). A total of 285 patients were enrolled in two consecutive prospective randomised studies which compared (study 1) carboplatin and prolonged oral etoposide (group 1; n=58) with the same etoposide alone (group 2; n=59), and (study 2) carboplatin and prolonged oral etoposide (group 1; n=84) with the same carboplatin and high-dose intravenous etoposide (group 2; n=84). The median survival time for all 285 patients was 7 months, while 1- and 2-year survival rates were 29% and 8%, respectively. Age did not impact on outcome ( P=0.21), while female patients did significantly better than male patients ( P<0.0001). Patients with KPS 80-100 did significantly better than those with KPS 50-70 ( P<0.0001), as did patients with less pronounced weight loss ( P<0.0001) and those with only one metastatic site when compared to those having at least two metastatic sites ( P<0.0001). When evaluated regarding the metastatic site, only subcutaneous metastatic site did not influence survival. This was confirmed within univariate analyses, but when multivariate analyses were done gender, KPS, weight loss, number of metastatic sites, presence of liver metastases and presence of brain metastases independently influenced survival, while age and other metastatic locations did not. In this analysis, gender, KPS, weight loss, number of metastatic sites, presence of liver metastases and presence of brain metastases independently influenced survival in patients with stage IV NSCLC treated with CHT.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated a risk of developing radiation myelitis during four prospective studies using hyperfractionated radiation therapy (HFX RT) with and without concurrent chemotherapy (CHT) during which a portion of thoracic spinal cord received a dose > or = 50.4 Gy given via 1.2 Gy b.i.d. fractionation. Of 536 patients with Stage III non-small cell lung cancer (NSCLC) which were treated on three prospective randomised Phase III studies and one Phase II study, 336 patients received irradiation dose > or = 50.4 Gy to a portion of their spinal cord and survived >1 year after the beginning of therapy. None of these 336 patients developed thoracic radiation myelitis. Therefore, the influence of potentially contributing factors on the occurrence of radiation myelitis, such as cord length, interfraction interval, or administration of concurrent CHT was not possible to investigate. These results give new insight about the influence of total dose/dose per fraction/interfraction interval with or without concurrent CHT on the thoracic spinal cord toxicity.
- [Show abstract] [Hide abstract] ABSTRACT: To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy (Hfx RT) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide. A total of 195 patients (Group I, 98; Group II, 97) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d. fractionation and daily 50 mg each of carboplatin and etoposide during the RT course (Group I) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend (Saturdays and Sundays) 100 mg each of carboplatin and etoposide during the RT course (Group II). No difference was found regarding median survival time and 5-year survival rates (20 vs. 22 months and 20% vs. 23%; p = 0.57). Median time to local progression was 20 and 19 months, respectively, while 5-year local progression-free survival rates were 28% and 27%, respectively (p = 0.66). Also, there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival (21 vs. 25 months and 29% vs. 34%, p = 0.29). There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly more high-grade (> or = 3) hematologic toxicity (p = 0.0046). Late high-grade toxicity was not different between the two treatment groups. The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose, daily carboplatin/etoposide, but it led to a higher incidence of acute high-grade hematologic toxicity.
- [Show abstract] [Hide abstract] ABSTRACT: To investigate the incidence of second cancers occurring in patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with radiation therapy (RT) alone. Seventy-eight patients had been treated with conventionally fractionated (CF) RT (1982 to 1987), and 116 patients had been treated with hyperfractionated (Hfx) RT (1988 to 1993). Tumor doses were 60 Gy for CF and 69.6 Gy (1.2 Gy bid) for Hfx. A total of 26 patients developed second cancers. The cumulative incidence of second cancer was 21.8% (SE, 4.7%) at 5 years and 34.8% (SE, 6.7%) at 10 years. For second lung cancers, it was 6.0% (SE, 2.8%) at 5 years and 14.2% (SE, 5.2%) at 10 years, and for second nonlung cancers, it was 16.3% (SE, 4.2%) at 5 years and 22.2% (SE, 5.7%) at 10 years. The rate of developing second cancer per patient per year was 4.3% (95% confidence intervals [CI], 2.7% to 5.9%), with the rates being 1.4% (CI, 0.5% to 2.3%) for the second lung cancers and 2.8% (CI, 1.5% to 4.1%) for second nonlung cancers. The rate of developing second cancers during the first and second 5-year period after RT (0 to 5 and 5 to 10 years) was 4.3% (CI, 2.4% to 6.2%) and 4.2% (CI, 0.6% to 7.8%), respectively, for all cancers. These rates were 1.0% (CI, 0.1% to 1.9%) and 2.2% (CI, 0% to 4.6%), respectively, for second lung cancers, and 3.2% (CI, 1.6% to 4.8%) and 1.5% (CI, 0% to 3.6%), respectively, for second nonlung cancers. Long-term survivors after RT alone for early stage NSCLC carry the same risk of developing second cancer, either lung or nonlung, as their counterparts treated surgically when the results of this study are compared with those of the published literature.
- [Show abstract] [Hide abstract] ABSTRACT: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60 Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200 mg/m2, and VP 16, 200 mg/m2, both given once weekly during the RT course. The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.
- [Show abstract] [Hide abstract] ABSTRACT: The current study was conducted to investigate retrospectively whether elective ipsilateral neck irradiation (EINI) is effective in controlling subclinical neck disease in patients with locally advanced (T3 and T4) nonmetastatic (N0, M0) squamous cell carcinoma (SCC) of the maxilla. Between 1987 and 1993 a total of 44 patients were treated with EINI. The primary tumor bed was treated with 60 grays (Gy) in patients undergoing radical maxillectomy or with 66 Gy in patients undergoing partial maxillectomy. The ipsilateral upper and lower neck (down to the clavicle) was treated with either opposing anteroposterior-posteroanterior fields or appositional electron fields. The dose of elective neck radiotherapy was 50 Gy in 25 daily fractions. The 5-year and 10-year survival rates (with standard error [SE]) were 66% (SE 7%) and 60% (SE 8%), respectively, whereas the 5-year and 10-year recurrence free survival rates both were 64% (SE 7%). The 10-year local recurrence free survival rate was 69% (SE 7%), whereas the 10-year regional recurrence free survival rate was 94% (SE 4%). Of the 2 patients who developed a recurrence in the neck, 1 was salvaged successfully by surgery, producing an ultimate 10-year regional recurrence free survival rate of 97%. The 10-year distant metastasis free survival rate was 91% (SE 4%). The findings of the current study appear to suggest the potential efficacy of EINI in patients with locally advanced, nonmetastatic SCC of the maxilla and that the high rate of control of cervical lymph nodes may lead to better overall survival than that reported in the majority of the recent series.
- [Show abstract] [Hide abstract] ABSTRACT: To investigate whether the addition of cisplatin (CDDP) to hyperfractionation (Hfx) radiation therapy (RT) offers an advantage over the same Hfx RT given alone in locally advanced (stages III and IV) squamous cell carcinoma of the head and neck. One hundred thirty patients were randomized to receive either Hfx RT alone to a tumor dose of 77 Gy in 70 fractions in 35 treatment days over 7 weeks (group I, n = 65) or the same Hfx RT and concurrent low-dose (6 mg/m(2)) daily CDDP (group II, n = 65). Hfx RT/chemotherapy offered significantly higher survival rates than Hfx RT alone (68% v 49% at 2 years and 46% v 25% at 5 years; P =.0075). It also offered higher progression-free survival (46% v 25% at 5 years; P =.0068), higher locoregional progression-free survival (LRPFS) (50% v 36% at 5 years; P =.041), and higher distant metastasis-free survival (DMFS) (86% v 57% at 5 years; P =.0013). However, there was no difference between the two treatment groups in the incidence of either acute or late high-grade RT-induced toxicity. Hematologic high-grade toxicity was more frequent in group II patients. As compared with Hfx RT alone, Hfx RT and concurrent low-dose daily CDDP offered a survival advantage, as well as improved LRPFS and DMFS.
University of BelgradeBeograd, Central Serbia, Serbia