Parallel-opposed fields versus four fields, and two- versus three-dimensional radiotherapy planning in thin patients with gynecological malignancies.

Conformal radiotherapy constitutes the standard management of pelvic malignancies, yet its role in thin patients remains debatable. This study compares dose distribution for 2D and 3D treatment techniques for cobalt (60Co) and high energy photons from linear accelerator (LA) in cervical and endometrial cancer patients with antero-posterior diameter of less than 20 cm. CT-based 3D treatment planning and 2D simulation were performed in 10 patients. Particular techniques were compared in terms of treatment portal areas, coverage of planning target volume (PTV) and sparing of critical organs. For 60Co beams, PTV was not covered adequately with 2D fields in nine patients and with conformal fields in seven. For LA, PTV was not adequately covered with 2D two-field and 2D four-field ("box") technique in three and one patients, respectively. Mean bladder dose was comparable for all plans. Both 2D "box" and 3D "box" technique spared additional portion of the rectum volume included in 95% isodose, compared to two-field plan. 3D treatment planning better protected the small intestine. Use of multiple field techniques and 3D planning allows for some improvement of PTV coverage and normal tissue sparing, although the magnitude of this benefit must be weighted against savings of time and labour related to use of simpler treatment techniques.

Prognostic relevance of proliferating cell nuclear antigen and p53 expression in non-small cell lung cancer.

Prognostic value of p53 and PCNA expression in non-small cell lung cancer (NSCLC) remains controversial. In this study we determined the relevance of these abnormalities in terms of overall survival and disease-free survival in 95 NSCLC patients who underwent curative pulmonary resection. Expression of p53 was found in 44 samples (45%), expression of PCNA-in 79 samples (83%), and expression of both markers-in 35 samples (36%). There was no relationship between expression of either protein and major clinicopathological characteristics. Median survival for patients with and without p53 expression was 36 and 33 months, respectively and 5-year survival probability-29 and 37%, respectively (P=0.73). Median survival for patients with and without PCNA expression was 36 and 27 months, respectively and 5-year survival probability-35 and 25%, respectively (P=0.60). There was no significant difference in overall survival between particular groups of patients with tumors carrying four possible p53/PCNA phenotypes. In multivariate analysis including patient age, sex, tumor stage, tumor type and differentiation, p53 and PCNA expression, the only variable important for survival was stage of disease. These results suggest the lack of prognostic relevance of p53 and PCNA expression in surgically treated NSCLC patients.

Rectal doses in intracavitary brachytherapy of gynecological malignancies: comparison of two dosimetric methods.

PURPOSE: To compare calculated rectal doses obtained by two dosimetric methods in intracavitary brachytherapy of gynecological malignancies. MATERIALS AND METHODS: This analysis included 124 intracavitary applications performed in 102 patients with cervical or endometrial cancer. The pelvic dose distribution based on orthogonal intracavitary placement films was calculated with the computer planning system. In each application the rectal dose was defined in the specific rectal point determined by both the use of a wire marker inserted into the rectum (R1) and by packing the vagina with radio-opaque gauze - the method recommended by the ICRU Report 38 (R2). The comparison included R1 and R2 doses as well as the respective radiobiological equivalent doses determined by the linear-quadratic model (r1 and r2). RESULTS: In 83% of applications the absolute value of R1 was lower than R2. The mean difference between R1 and R2 was 3.7 Gy (95% CI 3.03-4.41 Gy) and between r1 and r2 7.2 Gy (95% CI 5.77-8.56 Gy). These differences were significant (P<0.001 for both comparisons). The difference between the doses was not influenced by the type of applicator and remained significant even when a systemic+/-10% error of method was assumed. CONCLUSION: The rectal point dose determined with the use of rectal wire marker may be underestimated, therefore this method should be discouraged in gynecological brachytherapy.

Recurrent endometrial cancer after surgery alone: results of salvage radiotherapy.

PURPOSE: Postoperative irradiation of endometrial cancer patients decreases the risk of local recurrence but is associated with a number of long-term sequelae. In a proportion of patients, no immediate postoperative radiotherapy is applied and this treatment is introduced only at relapse. The aim of our study was to assess the long-term results of salvage radiotherapy in previously nonirradiated endometrial cancer patients who developed local recurrence, and to evaluate the impact of patient- and treatment-related factors on treatment efficacy. METHODS AND MATERIALS: We performed a detailed retrospective analysis of 73 endometrial cancer patients given radiotherapy for local recurrence after the initial surgery only. The mean age at diagnosis of the recurrence was 63 years (range, 39-78 years). Median time to recurrence was 11 months (range, 1-19 months). All recurrences were staged with the use of Perez modification of the International Federation of Gynecology and Obstetrics (FIGO) staging system for primary vaginal carcinoma. There were five (7%) Stage I patients, 43 (59%) Stage II patients, and 25 (34%) Stage III patients. Forty-four patients (60%) received both external beam irradiation (EBRT) and endovaginal brachytherapy (BRT), 17 (23%) received only BRT, and 12 (17%) received only EBRT. The mean total physical radiation dose was 75.9 Gy (range, 8-130 Gy), and the mean normalized total dose (NTD) calculated on the base of the linear-quadratic model was 86.6 Gy (range, 8.5-171.9 Gy). Median follow-up for alive patients was 8.8 years (range, 3-21 years). The impact of patient-, tumor-, and therapy-related factors on the treatment outcome was evaluated with the use of uni- and multivariate analyses. RESULTS: Three- and 5-year overall survival rates were 33% and 25%, respectively. In the univariate analysis, lower stage of recurrent disease (p < 0.0005), combined EBRT and BRT (p = 0.027), higher total radiation dose (p = 0.031), and higher NTD (p = 0.006) were significantly correlated with better survival. In the multivariate analysis, only stage of recurrent disease (p < 0.005) and high total dose (p = 0.047) were independently correlated with better survival. Lower FIGO stage of recurrence (p = 0.023) and higher total dose (p = 0.005) were also independently correlated with longer time to progression, whereas higher radiotherapy dose was the only factor correlated with better local control (p = 0.029). CONCLUSIONS: The efficacy of salvage radiotherapy in endometrial cancer patients with local failure after previous surgery is limited. Factors determining treatment outcome include advancement of the tumor at relapse and radiotherapy dose.

[Prognostic value of P53 protein in cells of non-small cell lung cancer]. / Ocena rokowniczego znaczenia obecnosci bialka P53 w komórkach niedrobnokomórowego raka pluca.

The aim of the study was to evaluate the prognostic relevance of p53 protein in non-small cell lung cancer. The 95 surgically treated patients were included (53 patients with squamous cell carcinoma, 29--with adenocarcinoma, 5--with large cell carcinoma, and 8--with mixed type). The protein was assessed immunohistochemically with the use of monoclonal antibodies DO7, DAKO. Positive staining was present in 44 patients. There was no survival difference between groups with and without protein (median survival--36 and 33 months, respectively; p = 0.86). In the multivariate analysis the only characteristics with prognostic impact in the entire group was stage of the disease. There was no correlation between the expression of p53 protein and disease-free survival. These results indicate that there is no prognostic relevance of p53 protein in non-small cell lung cancer.

Surgery followed by radiotherapy in endometrial cancer: analysis of survival and patterns of failure.

We performed a retrospective evaluation of survival and patterns of failure in 317 consecutive endometrial cancer patients treated between 1974 and 1991 with surgery and adjuvant radiotherapy. Two hundred and forty seven patients (78%) had FIGO stage I disease, 30 (9%) - stage II, 35 (11%) - stage III and 5 (2%) - stage IV. Both low dose rate brachytherapy (BRT) and external beam radiation (EBRT) were applied in 247 patients (78%), only BRT in 49 (15%), and only EBRT in 21 (7%). Median follow-up was 7.3 years. Five-year overall survival was 75%, and five-year disease free survival was 81%. Both overall and disease free survival rates were correlated with stage (P = 0.001 and P = 0.000, respectively). Recurrence occurred in 70 patients (22%): 11 (3.5%) in the pelvis, 51 (16%) outside the pelvis and 6 (2%) both in- and outside the pelvis. Independent risk factors for local recurrence included older age (P = 0.03) and variant histologic subtypes (P = 0.039), whereas independent risk factors for distant spread were stage (P = 0.000) and older age (P = 0.011). Normalized Total Dose (the sum of EBRT and BRT doses, based on linear-quadratic equation), type of radiotherapy regimen, overall radiotherapy time and surgery-to-radiotherapy interval did not correlate with the risk of relapse. Severe early and late radiotherapy complications were observed in 21 (7%) and 35 patients (11%), respectively. In view of the relatively low risk of exclusive pelvic recurrences and the high rate of severe late radiotherapy complications, indications for postoperative radiotherapy and its scheme should be verified. A relatively high rate of extrapelvic recurrences calls for effective systemic adjuvants to surgery. Further definition of high risk patients is warranted in order to tailor postoperative therapy to the prognostic factors and to increase the therapeutic index of management of endometrial cancer.

Clodronate in the management of bone metastases: a clinical study of 91 patients.

The aim of our study was to evaluate the efficacy of oral clodronate supplementing systemic therapy and/or palliative irradiation in 91 patients with painful bone metastases. Clodronate was administered at a daily dose of 1600-3200 mg for a median of 11 months (range 3--36 months). Partial or complete pain relief was achieved in 61 of 88 evaluable patients (69%). Response rate to clodronate in patients who additionally received palliative bone radiation was similar to that in patients who did not receive irradiation (68 and 71%, respectively). Eleven out of 12 bed-ridden patients with metastatic bone pain regained the ability of walking after the treatment with clodronate. Bone pain relief lasted from 1.5 to 36 months (mean 9.3 months). Clodronate was well tolerated in all but three cases (3%) in whom the treatment was discontinued due to intensive adverse gastrointestinal effects. In conclusion, we observed satisfactory symptomatic effect and low rate of adverse reactions in patients with metastatic bone lesions treated with oral clodronate. Further large controlled studies with thorough patient monitoring are warranted to evaluate the real benefit of clodronate, and to define its optimal scheduling.

[Evaluation of the prognostic significance of P53 mutation in patients with non-small cell lung cancer]. / Ocena wartosci rokowniczej mutacji genu P53 u chorych na niedrobnokomórkowego raka pluca.

Prognostic value of p53 gene mutation was determined in 95 radically operated non small cell lung cancer patients (78 males and 17 females, mean age 57.8 years). Study group included 62 cases of squamous cell carcinoma, 30--adenocarcinoma and 3--large cell carcinoma. There were 52 patients in stage I disease, 16--in stage II, 26--in stage IIIa and one--in stage IIIb. Paraffin-embedded samples of resected tumors were assayed for p53 mutations with the use of PCR/SSCP analysis. p53 mutation were present in 22 cases (23%). The median survival in patients with and without p53 mutations were 49 and 75 months (p = 0.46), respectively, and the five-year survival rate 53% and 50%, respectively. In stage I disease the median survival for patients with p53 mutation was 53 months and for those without mutations the median survival could not be determined as more then a half of them were alive. Median survival in stage II patients with and without mutations was 35 months and 44 months (p = 0.62), and in stage IIIA--9.5 months and 17 months, respectively (p = 0.37). The results of this study indicate that p53 gene mutation is not correlated with prognosis in non-small cell lung cancer patients.

Does chemotherapy-induced leukopenia predict a response in small-cell lung cancer?

The correlation between chemotherapy-induced toxicity and treatment outcome in cancer patients has not been studied thoroughly. Our aim was to evaluate whether there is any relationship between chemotherapy-induced leukopenia and response to treatment in small-cell lung cancer (SCLC). Data derived from records of 228 patients treated within two prospective multicentre phase II studies were analysed. In the first study (101 patients) chemotherapy included vincristine, epirubicin and cyclophosphamide and, in the second (127 patients), cyclophosphamide, etoposide and epirubicin; both regimens were given every 3 weeks. In the present analysis, the correlation between treatment outcome (response rate and survival) and highest scores of leukopenia within the first two and up to the fourth chemotherapy cycle, respectively, was evaluated. The objective response rate for the entire group was 66%; 53% in patients whose white blood cells remained normal and 85% in those who developed leukopenia within the first two cycles (P = 0.000). In multifactorial analysis, also including other treatment- and patient-related factors, independent correlation with response to chemotherapy was found for leukopenia (P = 0.001), chemotherapy regimen (P = 0.002) and the combined relative dose intensity (P = 0.018), but not for patient sex, age, performance status, pre-study weight loss, extent of disease and initial white blood cell count. Leukopenia within the first two cycles of chemotherapy was not correlated with survival, whereas such correlation for leukopenia occurring up to the fourth cycle was at the borderline level (P = 0.06). These findings suggest a relationship between chemotherapy-induced leukopenia and tumour response in SCLC.

Late complications after postoperative radiotherapy in endometrial cancer: analysis of 317 consecutive cases with application of linear-quadratic model.

PURPOSE: To evaluate the incidence and risk factors for late complications after postoperative radiotherapy in endometrial cancer patients. METHODS AND MATERIAL: We performed a detailed retrospective analysis of 317 endometrial cancer patients given postoperative radiotherapy. A total of 247 patients (78%) received both intracavitary (BRT) and external beam irradiation (XRT); 49 patients (15%) received only BRT, and 21 (7%) only XRT. BRT included radium (Ra) and cesium (Cs). The mean dose rate for both isotopes at 0.5 cm from the applicator surface was 0.47 +/- 0.06 and 1.42 +/- 0.41 Gy/h, and the mean total dose was 50.5 +/- 10.3 and 48.4 +/- 15.0 Gy, respectively. Mean BRT dose at 0.5 cm was 50.1 +/- 11.7 Gy (range 14.5-71.0). Mean XRT dose in the International Commission on Radiation Units and Measurements (ICRU) reference point was 49.0 +/- 3.7 Gy (range 22.0-66.0) given in fractions of 1.54-2.49 Gy (mean 2.0 +/- 0.17) with a two- or four-field technique. Follow-up ranged from 4 to 21 years (median 7.3). Normalized total dose (NTD) including XRT and BRT doses was calculated based on a linear quadratic equation. RESULTS: Five-year overall survival rate was 75%, and 5-year disease-free survival (censored for noncancer deaths) was 81%. Late radiotherapy complications of any grade occurred in 158 patients (51%), including bowel complications in 41% and urinary bladder complications in 21%. A total of 37 grade 3 or 4 complications were observed in 33 patients (11%), of whom 32 were treated with both XRT and BRT. Severe bowel and/or urinary bladder complications occurred in 24 patients: in 14 of 72 patients (19.4%) who received XRT and Cs BRT, and in 10 of 172 patients (6.0%) applied XRT and Ra BRT. The higher proportion of severe bowel and/or bladder complications in the former group was due to the particularly frequent rate of these events (30.0%) in a subset of 47 patients who received XRT combined with Cs BRT at the dose rate of 1.7 Gy/h and the total BRT dose of 60 Gy. Higher NTD, XRT fraction dose, BRT dose rate, Cs BRT, two-field XRT technique, short overall radiotherapy time, and older age were correlated with increased late-event risk in univariate analysis. Multivariate Cox analysis demonstrated that the independent risk factors for late bowel complications were NTD (p = 0.000) and BRT dose rate (p = 0.036), whereas for bladder complications they were BRT dose rate (p = 0.005) and XRT fraction dose (p = 0.041). Neither clinical factor (age, parity, prior abdominal surgery, FIGO stage, diabetes mellitus, or hypertension) nor the surgery-to-radiotherapy interval, nor overall radiotherapy time was independently associated with the risk of late bladder or bowel complications. CONCLUSIONS: The risk of late complications after postoperative radiotherapy in endometrial cancer depends mainly on treatment-related factors: NTD, BRT dose rate, and XRT fraction dose. The use of combined XRT and BRT increases the risk of late effects. NTD calculations including BRT dose rate and XRT fraction dose enable estimation of radiobiologically equivalent dose and can decrease the risk of mistakes when the radiotherapy regimen is changed.

Influence of brachytherapy applicators geometry on dose distribution in cervical cancer.

AIM: Although the relationship between the dose delivered to adjacent organs (urinary bladder and rectum) and the frequency and severity of treatment complications has been reported in many series, the factors influencing pelvic dose distribution are not well defined. The aim of the study was to assess retrospectively the influence of the size of cervical cancer brachytherapy applicators (ovoids and uterine tandems) on pelvic dose distribution and the impact of various therapy-dependent factors on patient anatomy and on dose distribution in particular applications. PATIENTS AND METHOD: The subject of this study were 356 cervical cancer patients treated with Selectron LDR as a part of their radical radiotherapy. Analysed factors included preceding external beam radiotherapy (EBRT) or brachytherapy applications, use of general anaesthesia for application and the system of pellet loading. RESULTS: Significant correlation was found between the size of applicators and doses to bladder, rectum and points B: larger vaginal applicators produced lower dose in bladder and rectum and higher dose in point B (all p < 0.0001), longer uterine tandems produced lower dose in rectum and higher dose in point B (both p < 0.0001). Significant decrease in the frequency of use of large applicators (ovoids: p < 0.0001, tandems: p = 0.055) and worsening of dose distribution, i.e. higher doses to critical organs (respectively: bladder p = 0.0012, rectum p = 0.02) and lower point B dose (p = 0.0001) were observed at consecutive brachytherapy applications. Similar situation occurred in patients, who received EBRT prior to brachytherapy (ovoids: p < 0.001, tandem: p = 0.04, bladder dose: p = 0.009, rectal dose: p = 0.073, point B dose: p = 0.059). Vaginal applicators were larger (p = 0.026) and the dose distribution was better (bladder: p = 0.023, rectum: p = 0.002, point B: p = 0.0001) in patients who had their insertions performed under general anaesthesia. The comparison of 2 consecutively used systems of pellet loading revealed more favourable dose distribution: lower dose for bladder (p = 0.014) and higher dose for point B (p < 0.0001) for the system, which utilised more sources in ovoids and in the distal part of the uterine tandem, in spite of more frequent use of smaller applicators in this group of patients. In multivariate analysis ovoid size was related to preceding external beam radiotherapy (p = 0.025). Uterine tandem length was dependent on the number of preceding intracavitary applications (p < 0.001) and preceding external beam radiotherapy (p = 0.007). Bladder dose was related to preceding brachytherapy (p = 0.011) and the pattern of pellet loading (p = 0.031). Rectal dose was dependent only on the use of general anaesthesia during application (p = 0.001) and point B dose was dependent on the pattern of pellet loading (p < 0.001) and marginally-on the use of preceding external beam radiotherapy (p = 0.06). CONCLUSIONS: The results of this study allow for identification of treatment-related factors determining pelvic dose distribution in cervical cancer brachytherapy and may potentially enable optimisation of this distribution in particular clinical situation.

Patient-related factors determining geometry of intracavitary applicators and pelvic dose distribution during cervical cancer brachytherapy.

PURPOSE: The aim of this study was to assess retrospectively the influence of the size of cervical cancer brachytherapy applicators (ovoids and uterine tandems) on pelvic dose distribution and to analyze the impact of various patient- and disease-related factors on applicators' geometry and on dose distribution in particular applications. METHODS AND MATERIALS: The subject of this study were 356 cervical cancer patients treated with Selectron LDR as a part of their radical radiotherapy. Analyzed factors included patient age, weight, number of vaginal deliveries, and disease stage. RESULTS: The use of larger vaginal applicators resulted in lower bladder and rectum doses and in higher point B doses (all p < 0.0001); longer uterine tandems produced lower rectum doses and higher point B doses (both p < 0.0001). Increasing patient age and disease stage resulted in a decreased frequency of use of large ovoids (both p < 0.0001) and of long tandems (age: p = 0.0069, stage: p = 0.004). As a result, higher doses to bladder (age: p < 0.0001, stage: p = 0.017) and rectum (age: p = 0.037, stage: p = 0.011) were observed. Increasing age also resulted in lower point B doses (p < 0.0001). Increasing patient weight correlated with less frequent use of long tandems (p = 0.0015) and with higher bladder doses (p = 0.04). Higher number of vaginal deliveries was related to the increase in the use of long tandems (p = 0.002); in patients who had had at least one vaginal delivery, point B doses were significantly higher (p = 0.0059). In multivariate analysis ovoid size and uterine tandem length were dependent on patient age (respectively: p < 0.001 and p = 0.001), disease stage (respectively: p = 0.003 and p = 0.008) and on the number of vaginal deliveries (respectively: p = 0.07 and p = 0.008). Doses to critical organs and to points B were dependent on patient age (respectively: p < 0.001, p = 0.011, and p < 0.001) and on disease stage (respectively: p < 0.001, p = 0.004, and p = 0.048). CONCLUSION: The results of this study allow for identification of some patient- and disease-related factors influencing pelvic dose distribution in cervical cancer brachytherapy. This potentially may enable optimization of the dose distribution in particular clinical situations.

Autopsy findings in small cell lung cancer.

The objective of this study was to assess the pattern of autopsy findings in 174 small cell lung cancer patients treated between 1971 and 1991 at seven Polish medical centres. Eighty nine autopsied patients were previously treated with different chemotherapy regimens including 32 patients who also received chest irradiation, 74 received only supportive care and for 11 patients the data on treatment were not available. The age range at diagnosis was 28-81 years (median 57); there were 39 females (22%) and 135 males (78%). Seventy two patients had limited disease at the time of diagnosis, 86-extensive disease and in 16 the disease extent was not determined. The primary tumor and/or metastases in regional lymph nodes were present in 157 autopsies (90%). There was a significant difference in the rate of locoregional disease found at autopsy in patients given chemotherapy and in those who received only supportive care (85% and 100%, respectively; p = 0.01). Chest radiation therapy given in limited disease as an adjunct to chemotherapy did not decrease the rate of persistent locoregional disease (primary tumor in the chest was found in 92% of irradiated and in 96% of nonirradiated patients). Locoregional tumor deposit only was found in 28 (16%). Distant metastases were distributed in 143 patients (82%) and were found in 25 different locations, most frequently in liver (49%), suprarenal glands (25%), peripheral lymph nodes (21%), kidneys (18%), brain (17%) and pancreas (12%). In 3 patients no tumor foci were found. The number of organs involved varied between 0 and 10 (median 3). The number of involved organs was not dependent on the disease extent at the time of diagnosis and on the type of treatment.