Concurrent chemoradiation therapy with docetaxel/cisplatin followed by docetaxel consolidation therapy in inoperable stage IIIA/B non-small-cell lung cancer: results of a phase I study.

INTRODUCTION: Docetaxel consolidation therapy (DCT) after concurrent cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in non-small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed to determine the maximally tolerated dose (MTD) for DCT. PATIENTS AND METHODS: Patients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 22, 29, and 36, with concurrent radiation therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable disease, partial response, or complete response were given DCT on days 71, 92, and 113. DCT was started with 75 mg/m2 and titrated depending on tolerability. The MTD of docetaxel was defined as the dose preceding that at which 3 or more patients experienced dose-limiting toxicity (DLT). RESULTS: Of 23 patients enrolled (median age, 58.8 years +/- 7.3 years), 19 received complete CRT (4 withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient died and 1 became operable, leaving 17 patients eligible for DCT starting at 75 mg/m2. After the third patient with DLT, dose was reduced to 60 mg/m2. Median survival was 27.6 months +/- 23.1 months. Median TTP was 12.4 months +/- 10.7 months. CONCLUSION: The MTD of DCT after concurrent cisplatin/docetaxel CRT was determined to be 60 mg/m2, but toxicity was considerable. The benefit-risk ratio of DCT has, however, been questioned by a placebo-controlled phase III trial. Further phase III trials need to consider further stratification factors (pretreatment forced expiratory volume [FEV]1, hemoglobin, performance, and stage) to define a role for DCT in patients with NSCLC.

Effect of total mesorectal excision on the outcome of rectal cancer after standardized postoperative radiochemotherapy: do randomized studies translate into clinical routine?

PURPOSE: To compare local control, disease-free survival and overall survival after postoperative radiochemotherapy with or without total mesorectal excision (TME) in a retrospective analysis. PATIENTS AND METHODS: Between 1993 and 2002, 103 patients with UICC stage II and III rectal cancer were treated by surgery and postoperative chemoradiation. Group B (n = 50; 1993-1998) were operated before TME era without using TME and group A (n = 53; 1998-2002) with TME; both groups received identical radiochemotherapy to a total dose of 50.4 Gy (median) and two courses of continuous 5-fluorouracil infusion. RESULTS: Patients in group A (TME) showed a significant improvement in 5-year disease-free survival (71.1%; 46.8%) and freedom from distant metastases (76.3%; 46.9%) and a marked improvement of local control (85.2%; 62.5%). Acute and late toxicity were significantly less frequent in group A. CONCLUSION: Radiochemotherapy cannot compensate an insufficient surgical procedure. These data confirm that TME is the standard. High outcome quality can be achieved in daily practice compared to results of randomized studies without patient selection.

Patterns of care in the radiotherapy of prostate cancer in Northern Bavaria 1998-2000.

PURPOSE: A patterns-of-care study of radiotherapy (RT) in prostate cancer was performed in Northern Bavaria, Germany, to characterize patient selection, treatment strategies and outcome for the time period 1998-2000. MATERIAL AND METHODS: Patients who received curative-intent radical or postoperative RT were identified from the databases of six centers (one university, five teaching/regional hospitals). Two centers treated < 20 patients and were excluded from further analysis. At the remaining four centers, 148 patients receiving radical RT and 134 undergoing postoperative RT were analyzed for pretreatment and RT characteristics and actuarial biochemical control (BC; ASTRO definition). RESULTS: All patients were treated with three-dimensional conformal external-beam techniques. In radical RT patients, cT- and cN-stages as well as the frequency of (neo)adjuvant hormonal therapy (53-91%) and RT to pelvic nodes (2-97%) and the mean total RT dose (64.8-71.0 Gy) varied significantly between centers. In postoperative RT, centers differed significantly in R-status, initial prostate-specific antigen (PSA) and nodal RT frequency (2-89%), whereas total RT doses were similar (62.3-64.8 Gy). After radical RT, 5-year BC was 68.6% and differed significantly between centers on univariate analysis. In a multivariate model, only total RT dose showed a trend toward an effect on BC. In postoperative RT patients, overall 5-year BC was 82.1%, and age and initial PSA were associated with BC on multivariate analysis. CONCLUSION: From 1998 to 2000, radical RT for prostate cancer at the Northern Bavarian centers now studied was performed with three-dimensional conformal technique to conservative total doses and selection criteria for postoperative RT were highly variable.

Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group.

PURPOSE: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. PATIENTS AND METHODS: Patients with non-small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m2 and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m2 weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. RESULTS: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). CONCLUSION: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.

Glucose requirement for hypoxic accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha).

Hypoxia-inducible factor-1alpha (HIF-1alpha) is both a potential endogenous marker of tumor hypoxia and therapeutic target, and elevated HIF-1alpha protein levels have been shown to be associated with increased hypoxic radiation resistance in FaDu human pharyngeal carcinoma cells in vitro. Here, we found that in FaDu xenografts, no significant HIF-1alpha protein accumulation was detectable by either flow cytometry or Western blot, despite the presence of hypoxic (pimonidazole-positive, radiation resistant) cells. To investigate the effect of different tumor microenvironment conditions on hypoxic HIF-1alpha accumulation, we performed in vitro hypoxia experiments (0.1% O2, 24 h) with manipulation of pH (7.4 vs. 6.7), glucose (0-5.5 mM) and serum (0 or 10%) availability in FaDu and HT 1080 human fibrosarcoma cells. Hypoxic induction of HIF-1alpha protein was strongly dependent on glucose availability and largely abolished at 0.55 mM glucose or less in both cell lines. This glucose effect was confirmed in a hypoxia-responsive-element (HRE)/enhanced-green-fluorescent-protein (EGFP) reporter assay in transfected HT 1080 cells and possibly explains a lack of HIF-1alpha protein in hypoxic tumor cells.

Is survival following post-operative radiotherapy in pN1-non-small cell lung cancer reduced? Results of a multivariate analysis.

Prognostic factors and the role of post-operative radiotherapy (PORT) in patients with pN1 nodal stage following surgery for NSCLC were identified. The clinical course of 211 patients with pN1 nodal involvement following thoracic surgery were reviewed, 97 of them received PORT. Multi-variate survival analysis with respect to prognostic factors (including treatment) was performed. The most frequent site of recurrence was the ipsilateral bronchus-stump or hilus (63% of recurrences). The 5-year rate of intercurrent deaths for PORT was 1% vs 6% in the group without PORT. The 5-year rate of locoregional recurrence was similar (24% vs 19%) for PORT vs no PORT (p=0.97). PORT patients had a higher rate of distant metastases (p=0.04). The 5-year rate of overall survival was 45% without PORT and 25% with PORT (p=0.003). Multivariate survival analysis identified 4 prognostic factors associated with decreased survival rate: age, extended pneumectomy, number of involved nodes and PORT dose. A PORT dose of 50 Gy corresponds to an increase in relative risk of death in the range of 1.5. Patients with PORT do not have an increased rate of intercurrent deaths. However in this cohort, PORT in pN1 patients was associated with a decreased survival rate due to distant metastases. Even after correction with respect to accepted prognostic factors in multivariate survival analysis, PORT was not able to improve or equalize prognosis of these negatively selected patients. The main site of recurrence is the bronchial stump and hilus. If PORT is applied in pN1 patients, a reduction of the target volume should be discussed since local control in high-risk patients may be of relevance.

Recurrent rectal cancer within the pelvis. A multicenter analysis of 123 patients and recommendations for adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Recommendations for radiation ports in adjuvant radiation therapy for rectal cancer are mainly based on analysis of recurrence patterns. To evaluate whether changes in surgical technique have influenced this pattern of recurrence, a multicenter retrospective analysis was carried out on a patient population treated recently. PATIENTS AND METHODS: 123 patients were evaluated with the help of a CT-based self-developed 3-D data file system and an extensive questionnaire. Major inclusion criteria (one sufficient) for eligibility were: histological confirmation, clear bone destruction, and a positive PET scan, or at least three minor criteria: progressive soft tissue mass, invasion of adjacent organs on follow-up CT or MRI, rising tumor markers, and typical appearance in cross-sectional imaging. Clinical or serologic signs of inflammation were exclusion criteria. RESULTS: Initially, 54% of the evaluated patients were N0; in the remainder, N1 and N2 were distributed evenly. Initial T-category was T1 in 2%, T2 in 24%, T3 in 60%, and T4 in 13%, the male-to-female ratio was 2:1. Recurrent tumors were mainly situated in the posterior part of the bony pelvis as displayed in the figures. When abdominoperineal resection was compared to low anterior resection as primary operation, there was a significant difference in extension of recurrent tumors in the inferior parts of the pelvis (p<0.025 in all statistical tests applied), whereas no significant difference was found in the superior parts of the pelvis. CONCLUSION: Based on these results, a modest field size reduction in adjuvant radiotherapy for rectal cancer seems feasible, offering the perspective of a reduction in acute and late side effects.

Induction chemotherapy with paclitaxel and cisplatin and CT-based 3D radiotherapy in patients with advanced laryngeal and hypopharyngeal carcinomas--a possibility for organ preservation.

BACKGROUND: To evaluate the effect of paclitaxel/cisplatin induction chemotherapy (ICHT) and CT-based radiotherapy (RT) on larynx preservation, tumor control, and survival in patients with larynx/hypopharynx carcinoma eligible for total laryngectomy (TL) or TL plus partial pharyngectomy (TLPP). PATIENTS AND METHODS: Fifty patients eligible for TL or TLPP were enrolled onto a prospective study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22). In patients with complete or partial tumor response RT (69.9 Gy in 5.5 weeks at the gross tumor, 50.4 Gy in the lymphatic drainage; single dose: 1.8 Gy, concomitant boost: 1.5 Gy) was applied. Non-responders had TL/TLPP and RT with total doses adapted to the radicality of tumor resection (56-70 Gy). RESULTS: The response rate to ICHT was 88% (10% complete, 78% partial response). At a median follow-up period of 25 months the larynx preservation rate was 84%. The 2-year local-regional control rate was 91% and the 2-year overall survival rate was 72.3%. The 3-year estimate to survive with functional larynx is 60%. CONCLUSION: In a large portion of patients eligible for TL or TLPP the larynx was preserved by paclitaxel/cisplatin ICHT and 3D RT.

A little to a lot or a lot to a little? An analysis of pneumonitis risk from dose-volume histogram parameters of the lung in patients with lung cancer treated with 3-D conformal radiotherapy.

PURPOSE: To determine whether a little dose to a large normal lung volume or a high dose to a small lung volume is more critical for induction of clinical pneumonitis. The second question is if dose-volume histogram (DVH) parameters are more reliable, if the lungs are analyzed as separate organs or as a whole organ. PATIENTS AND METHODS: We analyzed the clinical and DVH data from 49 patients treated for a thoracic malignancy using 3-D conformal treatment plans. 18 patients had developed a clinical pneumonitis (CTC II or III). The majority of patients (n = 48) received radiochemotherapy for non-small-cell lung cancer (NSCLC) with a combination of paclitaxel and carboplatin. Patients were generally treated 5 fx/week, single dose 2 Gy, using a two-series approach (shrinking field) up to a total dose of 60-70 Gy. For every individual patient, the overall dose distribution was recalculated in the Helax-TMS by means of adding dose plans according to the total dose applied in each series. The lungs were defined both as separate organs and as a whole organ. Low-dose volume (< or = 10 Gy, Vlow), moderate-dose volume (> 10-40 Gy, Vmod) and high-dose volume (> 40 Gy, Vhigh), as well as V10-V40 and mean lung dose (MLD) were defined from the cumulative DVH. Dose-effect relationships were fitted with a logistic regression model. RESULTS: Manifestation of clinical pneumonitis was within 3 months from termination of irradiation in all cases. For the ipsilateral lung, the incidence of pneumonitis was closely correlated to Vhigh. The pneumonitis rate increased from 13% up to 60%. By contrast, with increasing Vlow the pneumonitis rate dropped to < 10%. A similar but less pronounced effect was seen for the total lung. The lung volumes Vlow, Vmod and Vhigh of the ipsilateral, contralateral and whole lung were significantly correlated to the corresponding MLD. The incidence of pneumonitis increased with increasing MLD for the ipsilateral lung with a D50 of 32 Gy and a gamma 50 of 0.98. For the whole lung, the observed increase was less steep. MLD showed a close correlation to NTCP calculated by the Kutcher model. However, NTCP calculation overestimated the pneumonitis risk for the ipsilateral lung and underestimated the risk for the whole lung due to the steeper gradient. The logistic regression curve for the DVH parameters V10-V40 showed an increase of steepness toward higher doses. From the logistic regression curves, a DVH template indicating critical borders of V10-V40 was generated for the ipsilateral as well as for the total lung. CONCLUSION: Our data indicate that it is reasonable to disperse the dose outside the target volume over large areas in order to reduce the volumes of lung receiving > 40 Gy. Reducing the high-dose volume reduces the pneumonitis rate more than a corresponding reduction in the low-dose regions of the DVH. Landmarks for DVH optimization as defined in this analysis may serve as a basis for DVH contrains in IMRT planning. Separate organ analysis produced more reliable results and should be preferred to whole-organ analysis, if techniques mainly involving one side of the lung are applied. Further validation of these constraints is necessary prior to general recommendation.

Secretory activity and cell cycle alteration of alveolar type II cells in the early and late phase after irradiation.

PURPOSE: Type II cells and the surfactant system have been proposed to play a central role in pathogenesis of radiation pneumonitis. We analyzed the secretory function and proliferation parameters of alveolar type II cells in the early (until 24 h) and late phase (1-5 weeks) after irradiation (RT) in vitro and in vivo. METHODS AND MATERIALS: Type II cells were isolated from rats according to the method of Dobbs. Stimulation of secretion was induced with terbutaline, adenosine triphosphate (ATP), and 12-O-tetradecanoylphorbol-13-acetate (TPA) for a 2-h period. Determination of secretion was performed using (3)H-labeled phosphatidylcholine. For the early-phase analysis, freshly isolated and adherent type II cells were irradiated in vitro with 9-21 Gy (stepwise increase of 3 Gy). Secretion stimulation was initiated 1, 6, 24, and 48 h after RT. For late-phase analysis, type II cells were isolated 1-5 weeks after 18 Gy whole lung or sham RT. Each experiment was repeated at least fivefold. Flow cytometry was used to determine cell cycle distribution and proliferating cell nuclear antigen index. RESULTS: During the early-phase (in vitro) analysis, we found a normal stimulation of surfactant secretion in irradiated, as well as unirradiated, cells. No change in basal secretion and no dose effect were seen. During the late phase, 1-5 weeks after whole lung RT, we observed enhanced secretory activity for all secretagogues and a small increase in basal secretion in Weeks 3 and 4 (pneumonitis phase) compared with controls. The total number of isolated type II cells, as well as the rate of viable cells, decreased after the second post-RT week. Cell cycle alterations suggesting an irreversible G(2)/M block occurred in the second post-RT week and did not resolve during the observation period. The proliferating cell nuclear antigen index of type II cells from irradiated rats did not differ from that of controls. CONCLUSION: In contrast to literature data, we observed no direct effect of radiation on secretory activity in the early phase after RT. In our study of isolated type II cells, as well as in intact animals, RT did not result in an impaired surfactant secretion up to 5 weeks after RT. Our in vivo experiments even showed an increased response of phosphatidylcholine secretion to all known secretagogues at Weeks 3 and 4 after whole lung RT, possibly due to inflammatory cytokines. Cell cycle alterations with G(2)/M block and cell loss in the late post-RT period may contribute more to the manifestation of radiation-induced lung damage than functional impairment in type II cells.

Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer.

BACKGROUND: To evaluate the influence of total dose and tumor volume on local control and survival in primary radiotherapy of non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively analyzed the clinical course and CT-derived pre- and post-therapeutic tumor volume data of 135 patients with NSCLC undergoing primary radiotherapy at our department between 1989 and 1996. Among these, a total of 192 spatially separated tumor volumes (135 primary tumors, 1 additional intrapulmonary tumor, and 56 involved lymph nodes) were available for analysis. In all patients, treatment was planned using CT-based three-dimensional treatment planning. The dose to each tumor volume was derived from the individual dose plans. Mean total dose was 59.9 Gy (range: 30-80 Gy). All but 3 patients were followed until death. For local control analysis, each tumor was analyzed separately, and its remission status was determined in serial follow-up CT scans. A total of 784 CT scans were analyzed. Actuarial local control analysis was performed for the 192 separated tumor volumes, and survival analysis was performed for the 135 patients. Tumor control probability was calculated using a Poisson statistical model. RESULTS: Overall 1- and 2-year local control rate was 50% and 37%, respectively. The 2-year local control rate for tumors <50 ccm, 50-200 ccm, and >200 ccm was 51%, 22%, and 10%, respectively (p = 0.02). The 2-year local control rate for dose levels < or = 60 Gy and >60 Gy was 28% and 43% (p < 0.001). For the subgroup of 147 tumors smaller than 100 ccm, the local control rate increased up to 70% (1 year) and 51% (2 years) with doses of more than 60 Gy. For tumors larger than 100 ccm, no dose effect was seen. Only 2 of 45 tumors >100 ccm were controlled more than 2 years. Multivariate analysis revealed tumor volume, total dose, histopathologic type, and grading as significant and independent prognostic factors for local control. The number of delay days by split course (if used) and application of chemotherapy was not found to influence local control. Overall 1- and 2-year survival rate was 42% and 13%. Total radiation dose, chemotherapy, and T and N stage---but not tumor volume---were found to be independent and significant prognostic factors for survival in multivariate analysis. CONCLUSION: Tumor volume is an important predictor of local control in NSCLC. We found a clear dose effect for local control and survival in NSCLC. Long-term local control for a significant proportion of patients seems possible for small tumors only (<100 ccm, i.e., maximum diameter 6 cm) with doses of 70 Gy and more. Tumors of > or = 100 ccm are unlikely to be controlled long term by conventional doses up to 70 Gy. These results support dose escalation in patients with NSCLC.