Influence of overall treatment time and radiobiological parameters on biologically effective doses in cervical cancer patients treated with radiation therapy alone

The aim of the study was to examine the influence of overall treatment time (OTT) on the value of calculated biological effective doses (BEDs) for different biological variables. These variables were: tumour proliferation rate, different cell radiosensitivity (alpha=0.2, 0.3, and 0.4 /Gy), and different start time for repopulation (Tk=21, 28, and 35 days). Also the influence of age (), Hb level (), tumor proliferation rate (bromodeoxyuridine labelling index; BrdUrdLI), and DNA ploidy on survival after shorter (60 days) OTT was investigated. The study included 229 patients with cervix carcinoma treated entirely by standard radiotherapy (RT) (external beam RT plus low-medium dose-rate (LDR/MDR) brachytherapy (BT) at the Center of Oncology in Krakow. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill. BEDs 10 (for tumours) were calculated with consideration of OTT for each patient and tumour proliferation rate (standardized potential doubling time; standardized Tpot) based on BrdUrdLI assessed on biopsy material before RT. Median OTT was 90 days (range 30-210). The mean calculated total BED for point A for tumour and 'early reactions' was equal to 103.0 Gy10. The longest median survival time--52 months--was seen for patients treated with OTT 8.8%) BED loss was 1.4 Gy/day and for slowly proliferating tumours (BrdUrdLI 50 years (p=0.003) and high Hb level (>116 g/l) (p=0.041). For longer treatments (OTT >60 days) the unfavourable parameters were: age 相似文献   

Tumour cell kinetics as a prognostic factor in squamous cell carcinoma of the cervix treated with radiotherapy.

PURPOSE: Proliferative rate and DNA ploidy status were evaluated by flow cytometry in cervical cancer patients, prior to radiotherapy, to assess their importance as prognostic factors to predict survival rates. MATERIAL AND METHODS: Between 1987 and 1995, a total of 260 patients with squamous cell carcinoma (SCC) of the cervix, FIGO stages IB-IIIB were analysed. Tumour samples were incubated with bromodeoxyuridine (BrdUrd) in vitro to measure their total labelling index (totLI) and LI (totLI for diploid and anLI for aneuploid tumours). Proliferation was also assessed by S-phase fraction (SPF) analysis of the DNA profile. Patients had intracavitary therapy (three applications, each of 16 Gy to point A) and XRT of 40-50 Gy given over 4-5 weeks. RESULTS: The cervical tumours were characterized by a high proliferation rate which varied within each clinical stage of disease. The totLI ranged from 1.1 to 33.1% with median value of 9.6% whilst the LI ranged from 1.1 to 37.1% with a median value of 10.9%. Univariate analysis identified patient's age (cut-offpoint < or = 50&greater; years) and to a lesser extent proliferation (cut-off point, median totLI=9.6%) as significant prognostic factors for 5-year survival. The median survival time for younger patients ( < or = 50 years) with tumours of low proliferation (totLI < or = 9.6%) tumours was 17.5 months compared with 56 months in the faster proliferating tumours (P=0.0354). In the older patient sub-group, proliferation rate had no influence on survival. The median LI value was not a useful parameter in survival. Cox multivariate analysis showed that patient age ( < or = 50 years) and low proliferation of the tumour cells (totLI < or = 9.6) were unfavourable prognostic factors for cervical cancers treated with radiotherapy. DNA ploidy was not significant in this series. CONCLUSIONS: These data suggest that further improvements in therapy might be gained by selection of alternative treatments strategies such as neoadjuvant chemotherapy or radiation sensitizers in younger patients with more slowly proliferating tumours.     

Proliferation kinetics and prognosis in gastric cancer after resection

The influence of proliferation and proliferation kinetics on prognosis in gastric cancer after complete resection are controversial. In a prospective study we investigated the tumour specimens of 111 patients after resection of gastric cancer, who received 200 mg intravenous (i.v.) bromodeoxyuridine (BrdU) pre-operatively. The following biological parameters were analysed in the tumour tissue using flow-cytometry: DNA ploidy, proportion of S-phase cells, BrdU labelling index (LI), DNA synthesis time (T(s)), potential tumour doubling time (T(pot)), proliferating cell nuclear antigen (PCNA) and Ki-67 LI. The median follow-up time was 40 months (range 19-62 months). Besides the established pathohistological prognostic factors, univariate analysis revealed a prognostic influence on survival for BrdU LI, T(pot) and the proportion of S-phase cells. By multivariate Cox analysis of the completely resected cases, only tumour stage and T(pot) had a significant, independent influence on survival. By classification and regression trees (CART) analysis, resection status, tumour stage and T(pot) defined risk groups with significantly different outcomes. A short T(pot) was a predictor of better survival in stage I, II and IIIA tumours. Ploidy and the other investigated proliferation-related parameters failed to demonstrate any influence on prognosis after resection of gastric cancer.     

Tumour diploidy and survival in breast cancer patients with BRCA2 mutations

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24–2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91–4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41–1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.     

No significant predictive value of c- erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer

To document whether c-erbB-2 over-expression or p53 accumulation in tumour cells was predictive of response to chemo- or radiotherapy, we analyzed a population of patients with breast cancer assigned to neo-adjuvant therapy (median follow-up: 54 months). T2/T3-N0N1b-M0 tumours (329 cases) were treated either by FAC chemotherapy or by radiotherapy before surgery, and the clinical response was classified as complete or incomplete. Expression of c-erbB-2 and p53 was retrospectively evaluated by immunohistochemistry. Proliferation rate was assessed by means of MIB-1 antibody and by S-phase fraction. A complete response to chemotherapy was observed in 38/167 patients (23%). Complete response rate was 20% in c-erbB-2-negative tumours, and rose to 31% in tumours with c-erbB-2 over-expression, but this trend was not statistically significant. There was no correlation between p53 staining and response to treatment, whereas chemosensitivity was found correlated with histological grade and S-phase. A complete response to radiotherapy was observed in 64 of the 156 evaluable patients (41%). Complete response rate was 41% in c-erbB-2- or p53-negative tumours, 54% in tumours with c-erb-B-2 over-expression, and 44% in tumours with p53 accumulation. There was no correlation between response to radiotherapy and histological grade or proliferative rate. No prognostic value was found for c-erbB-2 or p53 expression, whereas the 5-year survival rate was 85% for patients presenting a tumour with a low proliferating index (MIB-1 < 10%), and 68% for patients presenting a tumour with a high proliferative index. In multivariate analysis, node status (RR = 2), MIB-1 immunostaining (RR = 2), and tumour size (RR = 1.8) were found to be associated with survival. These results indicate that c-erbB-2 or p53 expression is not significantly associated with tumour response to neo-adjuvant chemo/radiotherapy in our series of breast cancers. Int. J. Cancer (Pred. Oncol.) 79:27–33, 1998. © 1998 Wiley-Liss, Inc.     

The prognostic significance of tumour cell proliferation in squamous cell carcinomas of the oesophagus.

Tumour samples from 150 patients with squamous cell carcinoma of the oesophagus were investigated immunohistochemically with the monoclonal antibody MIB-1, which recognises proliferating cells. Using light microscopy, the number of MIB-1-positive tumour cells was counted in the areas with the highest proliferative activity. The MIB-1 index was determined as the proportion of MIB-1-positive and MIB-1-negative tumour cells. A considerable variation of the MIB-1 indices was found between the different tumours with a minimum of 6% and a maximum of 95% (median, 33%). The MIB-1 index correlated significantly with the mitotic activity in the tumour tissue (r = 0.33; P = 0.0001) and with the proportion of apoptotic tumour cells (r = 0.25; P = 0.0017). No significant correlation was found between the MIB-1 index and various other prognostic parameters including pT classification, pN classification, tumour grade, blood vessel invasion and lymphatic vessel invasion. In the univariate survival analysis no significant difference was found between tumours with low (< or = 33%) and high MIB-1 index (> 33%) 5-year survival rate: low MIB-1 index, 19.2%; high MIB-1 index, 22.2%). In a Cox proportional hazard regression analysis only the parameters lymphatic vessel invasion (P = 0.0001), pT classification (P = 0.0034) and pN classification (P = 0.0256), but not the MIB-1 index, could be verified as independent prognostic variables. In conclusion, evaluation of the MIB-1 index does not provide prognostic information for oesophageal cancer patients.     

The safety and efficacy of Cyberknife® for thymic malignancy

PurposeTo evaluate the safety and efficacy of Cyberknife® (CK) for the treatment of primary or recurring thymic tumours.Materials and methodsWe retrospectively reviewed 12 patients (16 tumour lesions) with primary or recurring thymic tumours who were treated with CK between March 2008 and October 2017. Their data was stored in prospectively collected database. Kaplan–Meier method was used to calculate survival curves.ResultsFive patients (41.7%), who had inoperable disease or refused surgery, were treated with CK initially, and 7 patients (58.3%) were treated with CK when they had recurrence diseases. The disease sites treated with CK were primary tumour site (5), regional lymph nodes (4), tumour bed (3), chest wall (2), pleura (1), and bone (1). The median target volume was 43.8 cm³ (range, 13.1–302.5 cm³) for the 16 tumour lesions. The median follow-up time was 69.3 months (range, 9.7–124.8 months). The median survival time was 48.2 months, and the 5-year and 10-year OS rates were 68.2% and 45.5%, respectively. A high response rate for the tumour lesions irradiated with CK was obtained. Only one patient (8%) experienced in-field recurrence, and the 5-year local recurrence free survival was 90.9%. A case indicated that CK may induce the abscopal effect, which provides the potential to combine CK and immunotherapy. No severe radiation related toxicities were observed, and no treatment related death occurred.ConclusionCK treatment resulted in good outcomes, particularly local control, with minimal side effects, in highly selected patients with primary and recurring thymic tumours. More studies with larger sample are needed.     

Percutaneous CT-guided thermal ablation as salvage therapy for recurrent non-small cell lung cancer after external beam radiotherapy: A retrospective study

Purpose: The aim of this study was to evaluate radiofrequency ablation (RFA) and microwave ablation (MWA) as a viable salvage option for patients with locally recurrent non-small cell lung cancer (NSCLC) after radiotherapy. Materials and methods: This retrospective study was conducted on patients who had received thermal ablation for recurrent NSCLC post-curative radiotherapy. Medical records and follow-up imaging with computed tomography (CT) and PET-CT were analysed to determine time to local progression (TTLP) and overall survival (OS). TTLP was determined according to the modified RECIST criteria. Results: Twelve patients, mean age 71?±?7 years, received 17 thermal ablation sessions, with RFA performed for four lesions and MWA for 13. Nine tumours were squamous cell cancers (SCC) and eight were adenocarcinomas. Eleven tumours had recurred post-external beam radiation and one post-stereotactic body radiation therapy. Mean tumour size was 34.2?±?12.8?mm, tumour stages prior to radiotherapy were Ia (2), Ib (3), IIa (4), IIb (1) and III (2). Follow-up period was 19?±?11 months. Overall median TTLP was 14 months (95% CI: 8, 19), and median OS was 35 months (95% CI: 12, 58). Mean TTLP for tumours <30?mm was 23 months and for tumours >30?mm 14 months (p?=?0.20). Recurrence rates reduced from 50% after initial ablation to 20% with a second ablation. Complication rate for pneumothorax requiring intervention was 17%. Conclusion: Both RFA and MWA ablation prolonged local tumour control with minimal morbidity in this study group of recurrent NSCLC after radiotherapy.     

Changes in biological markers after primary chemotherapy for breast cancers

The profiles of functional (proliferative rate and cell distribution in the cell cycle) and phenotypic (nuclear DNA content and hormone receptor status) biological markers and the expression of P53 and Bcl-2 proteins were prospectively evaluated in breast cancers before and after different regimens of primary chemotherapy. Overall, changes induced on the 2 proliferation indices (³H-thymidine labelling index, ³H-dT LI, and flow-cytometric S-phase fraction, FCM-S) mainly consisted of a decrease for rapidly proliferating tumours and an increase or no change for slowly proliferating tumours. However, when considered as a function of treatment type, changes of ³H-dT LI and FCM-S were superimposable in rapidly proliferating tumours, regardless of the type of treatment, and in slowly proliferating tumours only after anthracycline-including regimens. Conversely, following CMF, FCM-S was increased in 90% of the cases and ³H-dT LI in only 50%. Our data imply that the 2 proliferation indices could reflect different phenomena: an actual variation of proliferative activity by ³H-dT LI and an accumulation of cells in the S-phase by FCM-S. In addition, a higher accumulation of cells in G₂-M phases could be detected by FCM after anthracycline-including regimens than after CMF. The fraction of P53-positive cells was reduced by primary chemotherapy in about 50% of P53-positive tumours, whereas Bcl-2 expression was only marginally affected. DNA ploidy and hormone receptor status did not change in about 75% of cases, regardless of the chemotherapeutic regimen. © 1995 Wiley-Liss, Inc.     

Prospective evaluation of cell kinetics in head and neck squamous carcinoma: the relationship to tumour factors and survival.

Tumour growth rates were measured in 105 patients using in vivo incorporation of bromodeoxyuridine (BrdU) and investigated for any relationship to tumour factors or survival. The median labelling index (LI) was 8.7%, the duration of S-phase (Ts) was 14 h and the potential doubling time (Tpot) was 5.9 days. The labelling index in aneuploid tumours was significantly higher than that in diploid tumours. However the total labelling index (TLI) did not differ significantly between aneuploid and diploid tumours, and so it would seem likely that the difference in LI is due to the dilutional effect of benign tissue upon the calculation of LI in diploid tumours. The total labelling index, duration of S-phase and potential doubling time were not related to the tumour factors examined (site, T stage, N stage, stage grouping). Interim survival analysis was carried out and there was no difference in survival between those patients with high values for TLI, Ts, and Tpot and those with low values.     

Identification of brain tumour initiating cells using the stem cell marker aldehyde dehydrogenase

Aldehyde dehydrogenase (ALDH) has been identified in stem cells from both normal and cancerous tissues. This study aimed to evaluate the potential of ALDH as a universal brain tumour initiating cell (BTIC) marker applicable to primary brain tumours and their biological role in maintaining stem cell status.Cells from various primary brain tumours (24 paediatric and 6 adult brain tumours) were stained with Aldefluor and sorted by flow cytometry. We investigated the impact of ALDH expression on BTIC characteristics in vitro and on tumourigenic potential in vivo.Primary brain tumours showed universal expression of ALDH, with 0.3–28.9% of the cells in various tumours identified as ALDH⁺. The proportion of CD133⁺ cells within ALDH⁺ is higher than ALDH cells. ALDH⁺ cells generate neurospheres with high proliferative potential, express neural stem cell markers and differentiate into multiple nervous system lineages. ALDH⁺ cells tend to show high expression of induced pluripotent stem cell-related genes. Notably, targeted knockdown of ALDH1 by shRNA interference in BTICs potently disturbed their self-renewing ability. After 3 months, ALDH⁺ cells gave rise to tumours in 93% of mice whereas ALDH cells did not. The characteristic pathology of mice brain tumours from ALDH⁺ cells was similar to that of human brain tumours, and these cells are highly proliferative in vivo.Our data suggest that primary brain tumours contain distinct subpopulations of cells that have high expression levels of ALDH and BTIC characteristics. ALDH might be a potential therapeutic target applicable to primary brain tumours.     

p53 overexpression as a prognostic factor for advanced stage bladder cancer

Overexpression of the TP53 gene protein detected by immunohistochemistry appears to identify those patients with superficial bladder cancer at risk of the development of muscle invasive or metastatic disease. However, the role of p53 overexpression in patients with advanced or metastatic bladder cancer is not yet well established. In the present study, 44 specimens from 44 patients with advanced stage bladder tumours (T₂–T₄) undergoing radical cystectomy were investigated for different biological and clinical characteristics as possible prognostic factors: sex, age, depth of tumour infiltration, T-stage, histological grade, lymph node status, application of adjuvant systemic chemotherapy (MVAC), proliferative activity (staining for proliferating cell nuclear antigen (PCNA) by monoclonal antibody (PC10) as well as overexpression of the p53 oncoprotein (monoclonal antibody pAb 1801)). After a median follow-up of 22 months, 16 of the 23 patients (70%) with more than 40% of tumour cells stained positively for p53 (Group B) died from tumour progression compared with 7 of the 21 patients (33%) with less than 40% of tumour cells positive for p53. During univariate analysis, p53 overexpression (P = 0.008), staining for PCNA (80% of cells positive) (P = 0.01) and tumour stage (P = 0.01) were significant prognostic factors for survival, among which p53 overexpression (P = 0.023) as well as T-stage (P = 0.012) remained independent significant predictors during multivariate analysis. Prospective studies are needed to confirm the independent prognostic potential of p53 overexpression in patients with advanced bladder cancer. The availability of more refined prognostic factors should assist decision making regarding the value of more aggressive treatment options, such as adjuvant or neoadjuvant chemotherapy, for prognostically defined subgroups of patients.     

Preoperative weekly cisplatin,epirubicin, and paclitaxel (PET) improves prognosis in locally advanced breast cancer patients: an update of the Southern Italy Cooperative Oncology Group (SICOG) randomised trial 9908

BackgroundThe present article reports the updated survival outcome of the 200 patients enrolled in the Southern Italy Cooperative Oncology Group 9908 trial, which compared 12 weekly cycles of cisplatin–epirubicin–paclitaxel (PET) with 4 triweekly (once every 3 weeks) cycles of epirubicin–paclitaxel (ET) in patients with locally advanced breast cancer (LABC).MethodsThe effects of treatment, pathologically documented response (pathological response), pre- and post-treatment biomarkers on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) are analysed.ResultsAt a median follow-up of 74 (range 48–105 months) months, the 5-year RFS, DMFS, and OS were 64 % versus 53% (P = 0.11), 73% versus 55% (P = 0.04), and 82% versus 69% (P = 0.07) in PET and ET, respectively. At multivariate analysis, after adjusting treatment effect for pretreatment biomarkers, PET independently predicted better DMFS (P = 0.018) and OS (P = 0.03), whereas the impact on RFS was of borderline significance (0.057). PET treatment was significantly better than ET treatment only in high-grade or highly proliferating tumours. The better outcome in PET arm was the results of both the higher rate of patients with optimal pathological response and the lower rate of patients with biologically aggressive residual tumour.ConclusionsThe PET weekly regimen significantly improves both DMFS and OS in LABC patients, compared with the triweekly ET combination. The therapeutic advantage is limited to patients with highly aggressive tumours.     

Proliferative behaviour of an oestrogen sensitive rat mammary tumour: evidence for a paracrine interaction between tumour and stroma.

An oestrogen-sensitive rat mammary tumour (OES HR1) has been grown in normal female rats and in female and male rats supplemented with oestrone. In some rats, after the tumour was established, both exogenous and endogenous sources of oestrogen were removed--a treatment which inhibited further growth of the tumour. The proliferative characteristics of the tumours were measured by injecting the rats with deoxybromouridine (BrdU) 4 h before removing the tumour. Extracted nuclei were reacted with anti-BrdU and the labelling index and DNA content measured by flow cytometry. A correlation between the number of (diploid) host cells present and the number of (aneuploid) tumour cells in S-phase of the cell cycle was observed. This result suggests that there are paracrine interactions between tumour and host cells. We also observed that, on oestrogen ablation, the labelling index was significantly reduced while the percentage of cells in S-phase changed far less. The demonstration that there are cells in S-phase which are not proliferating highlights a possible problem with the measurement of proliferation in human tumours from a DNA histogram.     

The selective inhibitory effect of hyperthermia on the metabolism and growth of malignant cells

Hyperthermia (42° C.) exerted an inhibitory effect on the O₂ uptake of rabbit VX2 carcinoma cells in vitro, and led to a decrease in viability and growth potential of the cells, as measured by their ability to produce tumours in rabbits. Anaerobic glycolysis of the tumour cells was unaltered by hyperthermia. Respiration and anaerobic glycolysis of normal rabbit liver, kidney and red blood cells were unaffected by the elevated temperature. Local heat was applied to established VX2 tumours in vivo, with a subsequent reduction in tumour size in all cases, the most effective therapy regime being 3 one-hour applications of heat within the mean cell generation time of the tumour. Following heating there was rapid and widespread tumour cell necrosis and lysis, with subsequent replacement of the tumour architecture by connective tissue. There was a prolongation of survival time in 50% of the treated animals, which are still alive 18 months after therapy; all the control animals died within 10 weeks. The selective inhibitory effects of hyperthermia on cancer cells, and its application to human neoplasms, are discussed.     

Tumour cell repopulation during fractionated radiotherapy: Correlation between flow cytometric and radiobiological data in three murine tumours

This study tested whether the potential doubling time of tumour cells measured before or during treatment could predict the repopulation rate of surviving clonogens during fractionated radiotherapy. Tumours used for the study were a fibrosarcoma (SSK 2), an adenocarcinoma (AT 7) and a squamous cell carcinoma (AT 478), all grown subcutaneously in the C3H mouse. Potential doubling times (T_pot) were measured using the thymidine nanalogue iododeoxyuridine (IUdR) and flow cytometry. Results were compared with previous radiobiological studies on these tumours in which repopulation rates during radiotherapy were estimated using the tumour growth delay and tumour cure assays. Fractionated treatments consisted of daily doses of 4 or 8 Gy to clamped (hypoxic) tumours, 6 days per week for 1–3 weeks. T_pot values increased markedly during therapy for two of the tumours (SSK 2 and AT 478), by a factor of more than 10 for AT 478 in the third treatment week. T_pot remained approximately constant for the third tumour (AT 7). In no case was there evidence from the labelling studies of a shortening of T_pot which would suggest accelerated repopulation. From the radiobiological data, effective clonogen doubling times during radiotherapy were calculated from the doses required to produce a given effect in short and long treatment schedules. In the second week of treatment, effective clonogen doubling times in two tumours were approximately equal to the pretreatment T_pot, and shorter than the pretreatment T_pot in the third tumour. At some time during treatment, the surviving clonogens in these tumours therefore proliferated at the same rate or faster than before treatment. The difference between the labelling and radiobiological measurements was ascribed to the fact that, shortly after the start of a fractionated treatment, the IUdR labelling technique measures primarily doomed cells. These results show that kinetic measurements using DNA labelling techniques made during fractionated radiotherapy in most cases do not reflect the proliferation status of the surviving cells which are responsible for treatment outcome. Pretreatment T_pot measurements give a much better indication of the proliferation rate of surviving cells but in some cases may underestimate repopulation during radiotherapy.     

Correlation of in vitro drug sensitivity testing of long-term small cell lung cancer cell lines with response and survival

In vitro drug sensitivity testing (DST) of long-term cultures from small cell lung cancer (SCLC) tumours was correlated with response and survival after four cycles of etoposide and cisplatin. 27 cell lines from 25 patients were tested by the semi-automated MTT assay after a median culture of 29 months. The logs of the IC₅₀ concentrations for etoposide and cisplatin were correlated with each other. For both drugs, median IC₅₀ values of patients with partial or complete responses (“responders”) were significantly lower (7–8 fold) than those of non-responders. When survival was plotted according to whether drug IC₅₀ values were in the upper or lower halves, curves for etoposide were significantly different, but those of cisplatin were not. DST of the long-term cell lines by MTT assay was significantly correlated with the Weisenthal dye exclusion assay of earlier passages of the same cell lines. DST of long-term SCLC cultures can predict clinical response and, for etoposide, survival. Disease-oriented panels of carefully selected, continuous, human tumour cell lines can be used to screen new drugs.     

Multifocal breast cancer and survival: Each focus does matter particularly for larger tumours

PurposeThe objective of this study is to determine whether the aggregate tumour size of every focus in multifocal breast cancer more accurately predicts 10-year survival than current staging systems which use the largest or dominant tumour size.Patients and methodsThis study examined the original histological reports of 848 consecutive patients with invasive breast cancer treated in New South Wales (NSW), Australia between 1 April 1995 and 30 September 1995. Multifocal tumours were assessed using two estimates of pathologic tumour size: largest tumour focus diameter and the aggregate diameter of every tumour focus. The 10-year survival of patients with multifocal tumours measured in both ways was compared to that with unifocal tumours.ResultsAt a median follow-up of 10.4 years, 27 of 94 patients (28.7%) with multifocal breast cancer have died of breast cancer compared to 141 of 754 (18.7%) with unifocal breast cancer (P = .022). Ten-year survival was not affected by size for tumours measuring 20 mm or less, whether or not dominant tumour size (87.9%) or aggregate tumour size (87.0%) was used for multifocal tumours, compared to unifocal tumours (88.1%). For tumours larger than 20 mm, 10-year survival was 72.1% for unifocal tumours compared to 54.7% (P = .008) for multifocal tumours using dominant tumour size, but this was 69.5% and not significant when multifocal tumours were classified using aggregate tumour size (P = .49). Multivariate analysis also confirmed the above-mentioned results after adjustment for important prognostic factors.ConclusionAggregate size of every focus should be considered along with other prognostic factors for metastasis when treatment is planned. The current convention of using the largest (dominant) lesion as a measure of stage and associated breast cancer survival needs further validation.     

DNA ploidy and S-phase in primary malignant melanoma as prognostic factors for stage III disease.

In 82 patients with stage III malignant melanoma, the primary tumours were investigated by DNA flow cytometry. The tumours were classified as DNA diploid (n = 36), tetraploid (n = 11) and aneuploid (n = 35). By univariate analysis a significant correlation with post-recurrence survival was found for time to first metastasis, DNA-ploidy and S-phase fraction. By multivariate analysis, significant prognostic variables were found to be the time to first metastasis (P = 0.006), and ploidy (P = 0.011). Patients with diploid melanomas and a long recurrence-free interval had a median post-recurrence survival time of 45 months compared to 18 months in patients with DNA aneuploid tumours and an early recurrence. The S-phase could be estimated in 47 primary melanomas and was found to be a significant prognostic variable (P = 0.017). The median survival was 45 months for patients with melanomas with a S-phase fraction below 5%, and 19 months for melanomas with S-phase above 10%. The prognostic value of the S-phase remained significant even after adjustment for recurrence-free interval and DNA ploidy.     

Clinical Outcome of Sacral Chordoma Patients Treated with Pencil Beam Scanning Proton Therapy

AimsSacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy.Methods and materialsSixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan–Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.ResultsThe median follow-up was 48 months (range 4–186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3–7 years after proton therapy.ConclusionsOur data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume <130 ml and tumour restricted to the bone are favourable prognostic factors for local tumour control.