bluuebunny/crossref_metadata_2025 huggingface dataset:
3-D non-coplanar conformal radiotherapy compared to traditional beam arrangements for the adjuvant treatment of gastric cancer
Authors: Soyfer V. , Corn B. , Melamud A. , Alani S. , Tempelhof H. , Agai R. , Shmueli A. , Figer A. , Kovner F.
Published: March 2020

15145

Background: The Current standard of adjuvant treatment for gastric cancer following curative resection is concurrent administration of radiation and 5FU-based chemotherapy (INT0116). Radiation fields are often arranged as AP-PA opposed parallel fields with general recommendations for sparing at least two thirds of one kidney. In the current trial we investigated whether a better radiation distribution is achievable with 3-D conformal approaches as opposed to classical AP-PA fields. Methods: Nineteen patients with adenocarcinoma of stomach were treated by adjuvant chemoradiotherapy using a non-coplanar four field arrangement. In each case parallel planning by AP-PA arrangement and four fields “box was carried out and the generated plans were subsequently compared with dose volume histograms (DVH). Adequate coverage of the CTV was the basis for a comparison between other planning parameters. Separate analysis was performed not for right and left kidney but rather for kidneys exposed to higher and lower doses in each patient (since kidney dose is mostly a function of tumor location inside the stomach and respective nodal drainage). Mean dose of irradiation (MD) and percentage of kidney volume receiving radiation over 20 Gy (V20) were registered. Statistical analysis was performed by 2-tailed T-test. Results: The clinical target volume was adequately covered in all three plannings. In the “higher dose” kidneys group all the differences were statistically significant with the benefit of 3-D plan. In the “lower dose” kidneys group MD differences didn’t reach the level of statistical significance, while V20 data showed statistically significant benefit for 3-D plan. These data indicate that even when the mean doses of radiation are similar, 3-D planning can result in better distribution within the organ - thereby reducing the percentage of organ receiving dose above 20 Gy. DVH of spine was significantly better in 3-D planning. The exposure of liver was minimal in AP-PA technique. Conclusion: Noncoplanar 3-D based conformal planning for postoperative radiation therapy of gastric cancer provides the best results regarding kidney and spinal cord exposure with adequate CTV coverage.

No significant financial relationships to disclose.
Treatment with rAD001 improves the efficacy of siRNA mediated down-regulation of survivin/BIRC5 in pancreatic carcinoma cell lines
Authors: Maute L. , Glienke W. , Milz E. , Bauer N. , Bergmann L.
Published: March 2020

15146

The rapamycin derived mTOR inhibitor RAD001 (everolimus) is cytotoxic to a number of cell lines. Because survivin, an important mediator of apoptosis and cell survival, is one of the targets down-regulated by RAD001, we tested the ability of a combination of RAD001 and siRNA mediated inhibition of survivin to enhance the cytotoxic effects. We have used four pancreatic cancer cell lines, MiaPaCa-2, BxPC-3, AsPC-1 and Panc-1. We found that the cytotoxic effect was enhanced in all cell lines after treatment with RAD001 and survivin siRNA. An efficient way of treatment was the initial down-regulation of survivin with RAD001 and a subsequent incubation with survivin siRNA. We conclude, that the transformation efficiency of siRNA, still a limiting factor in using this method, is more sufficiently combining both ways to down-regulate survivin. Our data indicate that a combination of mTOR inhibitors like RAD001 and survivin-targeted down-regulation with siRNA may improve the efficacy of therapy in pancreatic cancer.

No significant financial relationships to disclose.
Phase II study of induction chemotherapy and concomitant chemoradiotherapy with cisplatin and continuous infusion 5-fluorouracil (PF) for anal carcinoma
Authors: Freire J. G. , Trindade M. C. , Barata A. M. , Venâncio J. , Claro I. , Fernandes A. H.
Published: March 2020

15148

Background: Chemoradiotherapy is the primary treatment for anal squamous cell carcinoma (ASCC). The aim of this trial was to assess activity and toxicity of induction chemotherapy and concomitant chemoradiotherapy with cisplatin (CDDP) and 5-fluorouracil (5- FU). Methods: Inclusion criteria: invasive, non-metastatic ASCC, age < 70 years, WHO performance status 0 - 2, adequate bone marrow and renal function and written informed consent. Treatment: Five courses of chemotherapy with PF: two induction courses (CDDP 100mg/m2 D1, 5-FU 1000mg/m2 D1–5 Q 21d); two concomitant (CDDP 20mg/m2 D1–4 and D28–31, 5-FU 225mg/m2 continuous infusion D1–31) with the first sequence of radiotherapy (45Gy in 25 fractions of 1.8Gy) and, after a five week gap, one concomitant (CDDP 20mg/m2 D1–4, 5-FU 800mg/m2 D1–4) with the radiation boost (15Gy in 6 fractions of 2.5Gy). The primary endpoints were response rate and toxicity. Results: 26 patients (pts) were included from March 2002 to August 2006 [21 women, 5 men; median age 53 years (29–69)]. Tumor location: anal canal 24 pts, anal margin 2 pts. Histology: squamous cell carcinoma 24 pts, basaloid carcinoma 2 pts. Stage: 35% tumors were T3–4 and 58% were N1–3. Nineteen pts (73%) completed the treatment. Failure to complete treatment were disease progression (1 pt), catheter related complications (2 pts), hematological toxicity (1pt), traumatic bone fracture (1pt); two pts died (one metastatic disease; one pulmonary thromboembolism). Twenty three pts were evaluable for response (1 pt too early). Nineteen pts (76%) had a complete remission (CR); four pts (16%) had local disease persistence. Grade 3 toxicities of 30, 22, 19, 16 and 5% were observed for stomatitis, radiation dermatitis, emesis, hematological toxicity and diarrhea. Grade 4 toxicity was 8% (3 pts: hematological, diarrhea, infection). Sixteen pts (62%) had a treatment delay or dose reduction. At a median follow up of 28 months, the overall survival was 73%. Six pts died, 5 of disease progression. Four pts required a colostomy. Conclusions: The results of this small single institution phase II trial, in line with those of RTOG 98–11, suggest that there is no role for CDDP/5-FU chemoradiotherapy for ASCC.

No significant financial relationships to disclose.
Is African-America race (AAR) a risk factor for failure in prostate cancer (PCa)?
Authors: Mann M. J. , Benson M. C. , McKiernan J. M.
Published: March 2020

1515

Background: There is much disagreement as to whether AAR is an independent negative risk factor in biochemical disease-free survival (BCDFS) of PCa. Much of the literature suggests that AAR is a negative risk factor of BCDFS. However, the past decade has seen improvements in treatments that may have affected outcomes in PCa. Thus, we sought to determine if AAR is an independent risk factor for BCDFS in a modern cohort of PCa patients. Methods: A retrospective review of The Columbia Urologic Oncology Database was performed. From ‘91-‘06, 2,747 patients underwent radical prostatectomy and did not receive adjunctive treatment. Of these, 252 (9%) patients were AAR, and 2495 were not of African-American Race (NAAR). Of the NAAR patients, 1,907 (69%) were Caucasian, and 588 (21%) were of other or unknown race. BCDFS was defined as time to first rise in PSA (>0.1ng/mL) or use of secondary therapy after surgery. Patients were stratified based on race (AAR vs NAAR) and year of surgery. BCDFS was evaluated using Kaplan-Meier (KM) analysis with log- rank test. Multivariate Cox regression models were fit and interaction terms were tested with Wall’s test to determine the significance of AAR on BCDFS over 3 time periods (91–95, 96–00, and 01–06). Results: The patients had a median age 61.9 yrs, pathological Gleason sum (GS) 7, and mean PSA 7.7. In KM analysis, AAR was a negative risk factor of BCDFS (p<0.01) over all time periods, had lower mean age at surgery (p<0.01), higher pre-operative PSA (p<0.01), and higher GS (p<0.01). Not surprisingly, once PSA, GS, and stage were controlled across time cohorts, AAR lost significance as a risk factor (p=0.46). When Wall’s test was used to compare the results of a multivariate analysis controlling for the same variables and stratified by time, it was found that outcomes improved over time in patients of AAR and NAAR (p<0.01), but there was no difference between the two groups (p=0.99). Conclusions: Despite previous reports that AAR is an independent negative predictor of outcome, it only appeared to be a negative risk factor in univariate analyses. Despite higher PSA, and GS, AAR was no longer a significant risk factor. Additionally, when stratified by time, patients in more contemporary cohorts had improved outcomes, with no differences between AAR and NAAR patients.

No significant financial relationships to disclose.
Platelet-derived growth factor receptor alpha (PDGFRA) and C-Kit immunohistochemistry (IHC) in gastrointestinal stromal tumours (GISTs)
Authors: Skarlos D. , Kyrodimou E. , Papakonstantinou N. , Klouvas G. , Christodoulou C. , Papadimas G. , Koutselini H.
Published: March 2020

15156

Background: The vast majority of GISTs show activating mutations of the genes coding for c-kit (CD 117) and PDGFRA, two receptor tyrosine kinases (RTKs). The exact role of PDGFRA as this expressed immunohistochemically (IHC), has not been fully elucidated in the diagnosis and treatment of GISTs. The aim of this study was (1) to try to correlate the pathological features of patients (pts) with GISTs, with c-kit and PDGFRA as these expressed by IHC and 2) to correlate the c-kit and PDGFRA with the clinical outcome of the pts. We report here the first part of the study. Materials and Methods: Twenty one (21) pts with GISTs were studied 14 located in the stomach, 3 in small bowel, 3 in colon and 1 in the mesenterium. Criteria for positivity of c-kit were strong membranus, cytoplasmic and paranuclear staining and for PDGFRA dot-like or Golgi pattern of staining. Median age was 61 years while there was a male predominance. Results: C-kit was detected in 95% of cases while PDGFRA in 90.5%. All the GISTs that were positive for PDGFRA were also positive for c-kit. Conclusions: Preliminary results of the first part of the study show that an accurate diagnosis of GISTs can be achieved based on the conventional histological and IHC criteria without the need for mutational analysis.

No significant financial relationships to disclose.
Impact of breast cancer risk assessment in primary care: Modeling clinical outcomes and effectiveness
Authors: Meadows E. , Mershon J. L. , Johnston J. , Iskander R. , DeLong K. , Taylor D. , Kerlikowske K. , Weinstein M.
Published: March 2020

1516

Background: Breast cancer risk assessment (RA) is rarely performed in the primary care setting due to uncertainty regarding the balance of harms and benefits in high risk women subsequently offered chemoprevention. We used a decision model to assess the potential clinical impact of several strategies involving use of routine RA in primary care. Methods: We developed a decision analytic model to compare routine breast cancer RA in primary care to usual care. The RA method was the Gail model, with a 5-year risk of >1.67% being designated as high risk (varied in sensitivity analyses). We assumed that high risk women would be offered 5 years of tamoxifen and that acceptance (70%) and compliance (68%) rates would be incomplete. For women receiving tamoxifen, the relative risk (RR) of incident estrogen-receptor positive invasive breast cancer was 0.31 over the 5 years of treatment, diminishing over the next 5 years after cessation of treatment. RR’s for the other health effects associated with tamoxifen were: vertebral fracture (0.74), endometrial cancer (2.41), stroke (1.6), pulmonary embolism (PE, 3.01), and deep vein thrombosis (DVT, 1.60). The non-breast cancer health effects of tamoxifen were assumed to pertain only to the 5 years of active therapy. All RR’s were applied to age-dependent population-based incidence rates; data sources included published epidemiologic and clinical trial data; model duration was 40 years. Results: In agreement with recommended clinical use of tamoxifen, the results were sensitive to age and the Gail threshold above which chemoprevention was recommended ( Table ). The number of women needed to screen (NNS) to prevent 1 case of breast cancer is 7-fold higher among women aged 50 compared to 65 with a Gail risk of 1.67% (719 vs. 104). Conclusions: The number of women offered treatment, as well as the clinical outcomes and NNS, resulting from routine breast cancer risk assessment varies with the age at RA and treatment threshold selected.

[Table: see text]

No significant financial relationships to disclose.
Second-line chemotherapy in advanced gastric cancer: A retrospective, single-center analysis
Authors: Herrmann C. , Jaeger D. , Herrmann T.
Published: March 2020

15170

Background: The role of second-line chemotherapy in advanced gastric cancer is not yet established. We analyzed patients with advanced gastric cancer treated at our department between 2002 and 2005 comparing the outcome of patients with first-line chemotherapy only and those who received second-line chemotherapy. Patients and Methods: 51 patients with metastatic or recurrent histologically confirmed gastric cancer were analyzed in this retrospective study. The choice of chemotherapy depended on the attending physician. Results: Altogether, 17 patients (33.3 %) were treated with only one chemotherapy regimen, whereas 34 patients (66.6 %) received at least two different chemotherapy regimens. During the last years, the preference for certain chemotherapy regimens changed. At the time of analysis, 9 patients were still alive. Median overall survival was 11 months (range: 1–41). Patients who received only one chemotherapy regimen were older (median age 70, range: 47–81), had a shorter TTP (3.5 months, range: 1–15) and a shorter overall survival (6 months, range: 2–25) than patients receiving sequential chemotherapies (median age 61.5 (range: 33–79) p = 0,009, TTP under first-line therapy 5 months (1–17), p = 0,45, overall survival 14.5 months (2–41), p = 0,001). Response to second-line chemotherapy was assessed in 32 patients: Partial remission was detected in 4 patients (12.5 %), stable disease for = 3 months in 15 patients (46.8 %), whereas disease progression occurred in 12 patients (37.5 %). 10 of 51 patients (19.6 %) received more than two different treatments: 4 patients had third-line chemotherapy, 6 patients had more than 3 different therapies. Overall survival was 13 months (11–22) for patients with third-line chemotherapy and 29 months (16–41) for patients receiving more than three different treatment regimens. Conclusion: Although a number of active antineoplastic drugs are available for the treatment of advanced gastric cancer, the prognosis is still poor. Selected patients may benefit from salvage chemotherapy after failure of first-line chemotherapy.

No significant financial relationships to disclose.
Tailored combined treatment with radiofrequency ablation plus octreotide in advanced hepatocellular carcinoma
Authors: del Prete S. , Addeo R. , Caraglia M. , Faiola V. , Guarrasi R. , Palmeri A. , Capasso E. , Nocera V. , Tarantino L.
Published: March 2020

15173

Background: Local therapies represent a valuable choice in small hepatocellular carcinoma (HCC), however, radiofrequency ablation (RFA) is increasingly used in advanced tumors. Medical treatments generally gave frustrating results in advanced hepatocellular carcinoma. Several biological non chemotherapeutic drugs are currently tested in HCC. Based on the expression of somatostatin receptor subtypes by HCC and the tolerability profile, octreotide was evaluated in single cases and small series of HCC patients and conflicting results are reported. Methods: 35 advanced HCC (26 males, 9 females; age range 55–85 years, median 73 years) were treated with RFA and octreotide with the aim to evaluate safety and determine the effect on disease control and survival. Testing regular and increasing doses of long-acting octreotide (from 20 to 30 mg monthly) were planned in the treatment schedule. Child A and Child B patients were 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included. All patients have multiple liver HCC nodules and one had bone metastases. Treatment with octreotide was maintained until disease progression or unacceptable toxicity. RFA was performed before or during treatment with octreotide according to medical evaluation. Results: In the majority of patients (65,7%) stable disease was obtained. In 3 patients (8,5%) progression of disease was documented. Clinical progression of underlying cirrhosis was identified in four patients and appear to condition the outcome, independently from HCC. Both medical and local treatments were well tolerated. Statistical evaluation was presented at ASCO 2007. Conclusions: The combined treatment with RFA and octreotide can be feasible in advanced HCC patients.

No significant financial relationships to disclose.
The effects of gemcitabine on cell apoptosis and cycle of gastric cancer
Authors: Wang L.
Published: March 2020

15181

Background: To study the effects of gemcitabine on cell apoptosis and cell cycle of gastric cancer Methods: Gastric cancer cells were cultured with different concentrations of gemcitabine (0.001, 0.01 and 0.1μM). MTT test was performed to evaluate the cell proliferation. The cells were divided into three groups: control group (cultured in RPMI-1640) and 5-FU group ( cultured in RPMI-1640 with 5- FU) and gemcitabine group ( cultured in RPMI-1640 with Gemcitabine). Flow cytometry was performed to determine the apoptotic rate and the cell cycle phases. Morphological changes were observed by phasecontrast microscope. Results: The cell proliferation was inhibited in experiment groups treated with gemcitabine and 5-FU, compared with control groups(P<0.01). Gemcitabine can induce cell apoptosis. 0.01μM and 0.1μM gemcitabine were much more effective than 0.001μM. On the third day, S phase cells accounted for 24.5% and G2-M phase cells 0.08% in the control group, while 24.6% and 0.06%, respectively in the gemcitabine group. However, on the seventh day, those came to 20.8% and 0.41% in the control group, and 18.2% and 1. 55% in the gemcitabine group, indicating a significant change in the cell cycle ( P<0.01). Conclusions: Gemcitabine can inhibit the cell proliferation, and it maybe related to cell apoptosis.

No significant financial relationships to disclose.
Phase II study of S-1 as a first-line, S-1 plus cisplatin as a second-line, and weekly paclitaxel as a third-line therapy in patients with advanced gastric carcinoma
Authors: Yamada T. , Rino Y. , Kanari M. , Saeki H. , Yukawa N. , Wada N. , Ooshima T. , Yamada R. , Haruhiko C. , Masuda M. , Imada T.
Published: March 2020

15186

Background: We conducted a pilot phase II study to evaluate the efficacy and safety of S-1 as a First-line, S-1 plus cisplatin as a second-line, and weekly paclitaxel as a third-line therapy for advanced gastric cancer. Patients and Methods: Between 2002 and 2005, 19 patients were enrolled into this study. Chemotherapy consisted of 60 mg/m2 of S-1 for 4 weeks at 6 weeks interval, 60 mg/m2 of S-1 for 3 weeks and 60mg/m2 Cisplatin on day 8 at 5 weeks interval, and paclitaxel 60 mg/m2 day 1, 8, 15 at 4 weeks interval. Results: The response rate was 15.8%, 7.7%, and 0% in the first-, second-, and third-line, respectively. The time to progression was 314 days. The mean survival time was 994 days. The median survival time was not calculated because 12 patients are still alive. With respect to hematological toxicity, the major adverse effect was leukopenia, which reached grades 3–4 in all line. And non-hematological toxicities, the major adverse effect was anorexia, which reached grade 3–4 in the Second line, and no deaths were attributable to the adverse effects of the drugs. Conclusion: This sequential therapy was very effective treatment for advanced gastric cancer with acceptable toxic side-effects.

No significant financial relationships to disclose.
Reduction therapy of ALT levels and prevention of HCC development in patients with HCV-associated cirrhosis
Authors: Rino Y. , Yukawa N. , Yamada T. , Imada T. , Morinaga S. , Ohkawa S. , Miyakawa K. , Ueno M. , Tarao K.
Published: March 2020

1529

Background: Approximately 30 million people worldwide are estimated to have liver cirrhosis (LC) associated with hepatitis C virus (HCV). In addition, patients with HCV-associated liver cirrhosis (HCV-LC) have a high risk of developing hepatocellular carcinoma (HCC). Namely, 60–80% of the patients may develop HCC in 10 years. So, preventing these patients from developing HCC is an urgent problem to be solved. To find a way to prevent the development of hepatocellular carcinoma (HCC) from hepatitis C-virus associated liver cirrhosis (HCV-LC), an analysis of the HCV-LC patients who had reduction therapy of ALT levels was performed. Patients and Methods: Seventy-four consecutive HCV-LC patients of Child Stage A were followed for > 10 years for the development of HCC. They were divided into two groups: In group A, the reduction therapy for ALT levels is aggressively performed and in group B, the reduction therapy was not performed aggressively. Results: Initial ALT was higher in group A than in group B, but there was no significance. After reduction therapy, ALT level was significantly high in group A in the first year. However, there were no significant differences between ALT levels in groups A and B of after the second year. In total, 39 patients out of 74 (52.7%) developed HCC within 13 years from the beginning of the study and 35 patients did not developed HCC in the same observation period. The incidence of HCC development in group B [65.7% (23/35)] was significantly higher than in group A [41.0% (16/39)] (p=0.039). The median HCC developing time in group A (12.8 years) was significantly longer than in group B (3.8 years) (p=0.0013). Multivariate analysis demonstrated that reduction therapy and ALT levels were the significant factors affecting HCC development. The incidence of HCC development in group B was 5.8 times higher than in group A. The high and unclassified ALT groups were 4.6 times and 2.2 times higher than in the low ALT group. Conclusion: The chances of surviving for more than 10 years without developing HCC in the HCV-LC patients of Child Stage A were far more favorable in group A than in group B. These results suggest that aggressive reduction therapy for ALT levels in HCV-LC patients could significantly prevent HCC development.

No significant financial relationships to disclose.
New approaches to cancer prevention—preventive medical examination of patients from the high-risk pre-cancer registry
Authors: Lazarev A. F. , Petrova V. D. , Sinkina T. V. , Terekhova S. A.
Published: March 2020

1546

Background: Such methods of cancer prevention as checkup in rooms for seeing patients’ examination, mass prophylactic examination, screening tests, which are currently in use in Russian Federation, are able to provide detectability of malignancies no more than 0.1%. The research objective was to increase the effectiveness of cancer detection by means of forming of the high-risk pre-cancer registry. Methods: With the help of multivariative analysis the patients with the high risk of malignancies (80–100%) were selected for the high-risk pre-cancer registry. It included patients with obligatory precancerous lesions (531), victims of radiation catastrophes (1024), members of ‘cancer’ families (1833) and patients cured from polyneoplasia (386). All of them were examined, got diagnostic procedures, treatment and rehabilitation according to specially designed schemes. Results: All patients with obligatory precancerous lesions underwent surgery. In 2003–2006 among them there were 23 (4.3%) cases of cancer revealed - 22- in I stage, 1 - in IV stage. In the group of patients from cancer ‘families’ in 2003–2006 69 (3.8%) cases of cancer were revealed - 67 (97.2%) in I and II stages, 2 - in III stage. Among the victims of radiation catastrophes in 2003–2006 there were 28 (2.7%) cases of cancer revealed - 26 (92.8%) in I and II stages, 2 - in III stage. General detectability of cancers among the patients the high-risk pre-cancer registry was 3.2%, the share of early stage (I and II) cancers- 95.9%, cancers in III stage - 4.1%, and there was only 1 case of cancer in IV stage (1.1%) revealed. Besides 65 cases of cancer in situ were detected among the patients of the registry. Conclusions: Preventive medical examination of patients from the high-risk pre-cancer registry makes it possible to increase the effectiveness of detection of precancerous lesions and early cancers.

No significant financial relationships to disclose.
Clinical experience with the new manual and automated large core biopsy systems based on a rotational cutting on a helix
Authors: Janssens J. P. , Rotenberg L. , Sentis M. , Schultz-Wendtland R.
Published: March 2020

1550

Background: Survival from breast cancer has increased significantly in recent years mainly as a result from better imaging techniques, earlier detection and improved tissue sampling. Newer technologies should improve existing biopsies because major drawbacks, including tumor cell displacement, preclude women and physicians to biopsy suspect lesions. A new large core biopsy device with a direct frontal approach, lesser side effects, less sampling needs, lower costs and improved yields has been evaluated in clinical practice. Methods: The results of 70 subsequent transdermal biopsies with rotational cutting on a helix are evaluated with regard to quality of the sample, patient satisfaction and completeness of diagnosis. The patients with a suspect lesion in the breast are selected in an oncological practice. Malignancy was verified by subsequent excision of the lesion. Attention was given to tumor cell displacement. Benign disease was verified by the subsequent clinical course. Results: In 69 patients at least one high quality sample with an average length of 1.8 cm and 0.3 cm diameter could be obtained. One patient refused the procedure. The average number of biopsy cores needed to obtain a reliable diagnosis was 1.5 (mininum 1 - maximum 5). No complication was noted with regard to pain, hemorrhagy, infection or other wound problems. 64 patients quoted the procedure as relative pain free. In 69 patients the diagnosis was complete with regard to the diagnosis of malignancy or benign disease. No destruction, biopsy artefacts or cell displacement was noted on histopathology. In all diagnoses with malignancy the grade of the tumor could be reliably given as well as steroid receptor content and HER2 immunohistochemistry. FISH-HER2 tests were possible in all HER2 positive tumors. Automated biopsies with vacuumassistance had slightly larger samples compared to the manual technique. Conclusions: The new large core biopsy technique with a rotational cutting on a helix performs well in clinical practice. All developmental goals with regard to quality of sample, patient satisfaction and cost price per biopsy have been met. Large core biopsies are now available for a larger population of women at risk for breast cancer with less risk of complication.

No significant financial relationships to disclose.
Impact of PSA decrease at the end of radiotherapy for localized prostate cancer on clinical recurrence and specific cause survival
Authors: de Crevoisier R. , Messai T. , Plantade A. , Slimane K. , Eschwege F. , Koscielny S. , Bridier A. , Wibault P. , Fizazi K.
Published: March 2020

15501

Background: The objective was to identify early predictors of outcome in a large retrospective series of patients treated by external beam radiotherapy only (without androgen deprivation). All the patients had a PSA at the 6th week (PSA6wRT) in the course of RT. Methods: From 1990 to 2004, 409 pts with localized prostate cancer were treated by RT. Median pretreatment PSA (PSApreRT) was 13 ng/mL (0.5–133). Clinical stage was T1 (26%), T2 (60%), and T3 (14%). Gleason score was 4–6 (59%), 7 (31%) and 8–10 (10%). Prognosis was classified as low risk (24%), intermediate (39%) and high risk (37%). The prostate received 65 Gy (2.5 Gy/day) (34%) or 70 Gy (2 or 2.5 Gy/day) (66%). Results: The median follow-up was 57 months (6–190). The median ratio of : PSA6wRT / PSApreRT was 71% (1–374). The 5-year biochemical disease free survival (DFS) rates (RTOG-ASTRO 2006) by PSA6wRT / PSApreRT < 71% or ≥ 71% were: 66% (95% CI: 58–74) and 56% (95% CI: 48–64), respectively (Log rank, p=0.048),. The 5-year clinical (local or metastases) DFS rates by PSA6wRT / PSApreRT < 71% or ≥ 71% were: 96% (95% CI: 93–99) and 85% (95% CI: 79–91), respectively (p=0.03). In multivariate analysis, the prognostic values of PSA6wRT / PSApreRT (as a continuous variable) on biochemical DFS, clinical DFS and cause specific survival are shown in the table . Conclusions: The PSA6wRT / PSApreRT predicts for biochemical DFS, clinical DFS and cause specific survival in localized prostate cancer. This factor could be used to propose adjuvant treatment after radiotherapy, in case of high: PSA6wRT / PSApreRT.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of paclitaxel and vinorelbine (Pac-Vin) in hormone-refractory metastatic prostate cancer (HRPC): A final update
Authors: Sewak S. , Kosmider S. , Ganju V. , Woollett A. , Le B. , Yeo E. , Henry M. , Bell R.
Published: March 2020

15505

Background: Phase 2 trials of Paclitaxel + corticosteroid or Vinorelbine + corticosteroid have shown 20–40% PSA responses. Preclinical models have shown synergy between Paclitaxel and Vinorelbine. A phase I trial showed this to be a tolerable combination. Methods: The aim of this study was to determine the efficacy and safety of Paclitaxel and Vinorelbine. 30 castrate pts with progressive, metastatic prostate cancer were enrolled. Previous radiotherapy, strontium therapy, 1 line of chemotherapy, and concurrent bisphosphonate therapy were allowed. Pts were treated with Paclitaxel 40 mg/m2 (1 hr), and Vinorelbine 20 mg/m2 iv on day-1 & day- 8 of a 21-day cycle. All pts received standard premedication for Paclitaxel including dexamethasone. Results: Baseline pt characteristics were: median ECOG PS of 1 (range 0–2), median age 70.5, mean PSA 413 ng/mL, mean Hb 11.9 g/dL. For 10 pts with measureable disease the partial response rate was 20%, with 70% of pts achieving stable disease (SD). Of 30 assessable pts, 20% had a 50% or greater decline in PSA, and 63% SD, maintained for at least 4 weeks. Median overall survival was 9.7 months. Median progression free survival was 5.1 months. All pts completed quality of life (QOL) questionnaires. Patient’s pain, fatigue, appetite, constipation, and mood improved after 3 cycles of therapy, however, statistical significance was not reached. Grade 3&4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anemia 3%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of neutropenic sepsis. Conclusions: In this poor prognostic cohort of pts (where 17% of pts had received 1 prior chemotherapy regimen) the combination of Paclitaxel and Vinorelbine is a tolerable regimen, which has demonstrated a 20% PSA response. The majority of pts achieved PSA stability. There was similar rate of objective response to this regimen and importantly it stabilized disease in a majority of pts. Furthermore, QOL parameters such as pain were improved. This regimen is one that requires further testing in a poor prognostic cohort of HRPC pts.

No significant financial relationships to disclose.
11C-coline-positron emission tomography/computerized tomography (C-PET/CT) for tumor localization of locally recurrent prostate cancer after radiation therapy
Authors: Sahi D. , Ohlmann C. , Pfister D. , Engelmann U. , Heidenreich A.
Published: March 2020

15519

Background: Radical salvage prostatectomy (sRPE) represents one local secondary treatment option with curative intent in patients failing radiation therapy for localized PCA. C-PET/CT is an innovative imaging technique for the evaluation of PCA. It was the purpose of our study to assess the sensitivity of C-PET/CT to predict local intra- and extraglandular extent of PCA and the presence of lymph node involvement. Methods: 45 patients with biopsy-proven locally recurrent PCA scheduled for sRPE underwent preoperative C-PET/CT. All patients underwent retropubic sRPE with extended pelvic lymphadenectomy. The prostatectomy specimens were processed according to the Stanford protocol and pathohistological results were compared to C-PET/CT findings. Intraglandular location of cancer nodules = 5mm was correlated with PET/CT findings. Results: A total of 45 patients underwent sRPE; mean preop. serum PSA was 7.8 (2–24) ng/ml; mean biopsy Gleason score was 5.6 (4–9). A mean of 19 (10 - 32) lymph nodes were removed. Pathohistology showed stage pT1–2pN0 in 27 (60%), stage pT3a/b and pTxpN1 PCA in 9 (20%) and 9 (20%) of patients, respectively. Positive surgical margins were identified in 5 (11%) patients. C-PET/CT identified 1, 2, 3 or more than 3 intraprostatic cancer nodules in 23 (51.1%), 13 (28.9%) and 9 (20%) patients, respectively. Correlation of prostate biopsy findings with PET/CT findings demonstrated a sensitivity of 90% for PET/CT. There was a low sensitivity for PET/CT detecting lymph node metastases. A positive uptake was identified in 14 (31.1%) patients; pathohistology revealed positive lymph nodes in 9 patients with only 4 patients exhibiting positive 11C-choline uptake and 5 patients having demonstrated a negative preoperative PET/CT scan. Conclusions: C-PET/CT is a valuable imaging modality for the detection of locally recurrent prostate cancer after radiation therapy. Due to its high sensitivity it might replace prostate biopsy prior to sRPE and it might be of additional value in patients with a negative biopsy but a high suspicion of local recurrence. The value of PET/CT for the identification pN1 disease is of modest value and not reliable.

No significant financial relationships to disclose.
Prognostic and biologic impact of molecular markers in papillary renal cell carcinoma
Authors: Riggs S. B. , Klatte T. , Seligson D. B. , Pantuck A. J. , Leppert J. T. , Lam J. S. , Zomorodian N. , Kabbinavar F. F. , Belldegrun A. S.
Published: March 2020

15525

Background: Papillary renal cell carcinoma (PRCC) is the second most common histological subtype among patients undergoing surgery for kidney cancer, but the molecular profile of this entity is not well characterized. The goals of this study were (1) to evaluate differences in expression between type 1 and 2 PRCC, and (2) to analyze the prognostic impact of molecular markers. Methods: We examined clinicopathological and molecular parameters of 42 patients treated with nephrectomy with the final pathology being PRCC. A tissue microarray consisting of the tumor specimens was constructed. Immunohistochemical staining was performed with antibodies directed against CAIX, CAXII, CXCR3, Gelsolin, HIF-1a, Ki-67, Vimentin, EpCAM, p21, p27, p53, pS6, pAkt, PTEN, VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2, and VEGF-R3. Staining was analyzed by one anatomical pathologist (DS) who was blinded to outcome. Mann- Whitney’s U-test was used to compare marker expressions between type 1 and 2. Endpoint was disease-specific survival (DSS). Expression cut-offs were detected by using recursive partitioning. The Kaplan-Meier curves were compared using the log-rank test. Results: At last follow-up, 21 patients (50%) had died including 12 (29%) of RCC. The median follow-up for the patients alive was 8 years. Type 1 PRCC had significantly higher expression of nuclear p27, nuclear pAkt, and p53 compared with type 2. Since none of these 3 markers provided prognostic information, survival analyses were performed together for both types. Using the cut-offs identified with recursive partitioning, higher expression of Ki-67 (p=0.02), lower gelsolin (p<0.001), lower p21 (p=0.01), higher cytoplasmic p27 (p=0.01), higher endothelial VEGF-A (p=0.01), lower epithelial VEGF-D (p=0.04), and lower endothelial VEGFR-3 (p=0.01) were adverse prognostic factors. Conclusions: Out of 19 molecular markers, a specific molecular profile for PRCC was identified. pAkt, p27, and p53 can assist in subdividing type 1 and type 2 PRCC. Ki-67, gelsolin, p21, p27 and proteins of the VEGF family were found to be important prognostic factors among these patients. Although prognostic relevant, the VEGF proteins cannot be used to differentiate type 1 and 2 PRCC.

No significant financial relationships to disclose.
A phase I study of bevacizumab in combination with sunitinib in advanced solid tumors
Authors: Cooney M. M. , Garcia J. , Brell J. , Dreicer R. , Beatty K. , Mekhail T. , Bukowski R. , Zwiebel J. , Remick S. C. , Rini B. I.
Published: March 2020

15532

Background: Bevacizumab is a humanized monoclonal antibody that binds to all biologically active isoforms of human vascular endothelial growth factor (VEGF). Sunitinib is a potent tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT, and FLT3. This phase I trial of bevacizumab and sunitinib was undertaken to determine the maximal tolerated dose (MTD), dose-limiting toxicity (DLT), and to evaluate for any tumor response for this novel combination. Methods: Patients (pts) with advanced solid tumors, ECOG performance status 0 or 1, and having adequate organ function were eligible. Patients received bevacizumab IV on days 1, 15, and 29 of a 42 day cycle. Sunitinib was given for 28 days with a 14 day rest. DLT was defined as any grade 4 toxicity, grade 3 cardiac event, hypertension not controlled to < 160/90 mmHg with medication, or proteinuria > 3.5 gm/24 hours. Results: Nine patients, 6 male and 3 female, with tumor types including renal carcinoma (2), bladder (2), pancreatic, testicular, melanoma, gastric, and neuroendocrine were enrolled. The median patient age was 55 years (range 37 to 83). Median number of prior systemic therapies was 2 (range 0 to 3). A total of 15 cycles have been administered (cycles range 1 to 4). Grade 1 or 2 toxicities that occurred with a > 20% incidence included anorexia, bleeding, diarrhea, dyspnea, fatigue, fever, hypomagnesemia, nausea, pain, vomiting, and weight loss. Grade 3 toxicities included hypertension (3 pts), fatigue and hypokalemia (2 pts) and one episode each of hand-foot syndrome, and hypophosphatemia. At the dose level bevacizumab 3 mg/kg and sunitnib 25 mg/day no DLTs were observed. One patient experienced DLTs of grade 4 hypertension and headache at the dose level of bevacizumab 5 mg/kg and sunitinib 37.5 mg/day. This dose level has expanded to six patients and toxicity assessment is continuing. One patient with papillary renal carcinoma has an unconfirmed partial response and three patients have experienced stable disease. Conclusions: Enrollment and toxicity evaluations are ongoing. DLTs of headache and hypertension have occurred. This trial will determine the maximal tolerated dose of this novel anti-angiogenic combination for future renal cell carcinoma studies. Supported by the NCI/Clinical Therapeutic Evaluation Program Grant U01 CA62502.

No significant financial relationships to disclose.
A phase II trial of 13-cis retinoic acid, interferon, docetaxel, and estramustine (RITE) for the treatment of hormone refractory prostate cancer (HRPC)
Authors: Mehta A. , Stein M. N. , Goodin S. , Doyle-Lindrud S. , Todd M. , Rubin E. , White E. , Jeyamohan C. , Metzger D. , DiPaola R. S.
Published: March 2020

15542

Background: Efficacy of chemotherapy for the treatment of HRPC is limited secondary to the development of multiple mechanisms of resistance. In our prior studies, we demonstrated the safety and activity of docetaxel (T) 40 mg/m2 given with 13-cis retinoic acid (R), interferon alpha (I) and estramustine (E), along with a decrease in the expression of the anti-apoptotic protein Bcl-2. To test whether this regimen had clinical activity in HRPC, we conducted a phase II trial with the combination of these drugs. Methods: Eligible patients (pts) received 13-cis retinoic acid 1 mg/kg on days 1 to 4, interferon alfa 6 million units/m2 on days 1 to 4, estramustine 280 mg three times a day on days 1 to 5, and docetaxel 40 mg/m2 on day 2, all repeated every 21 days. Pts had peripheral blood mononuclear cells (PBMCs) obtained prior to therapy and on days 2 through 4 of the first cycle to assess the effect of therapy on the expression of Bcl-2. Results: Nineteen of 20 registered pts (mean age 66) have been treated in this trial. The median pre-treatment PSA was 33.3 ng/mL. A PSA decrease was seen in 13/19 pts (68%) with a mean decrease of 50.3%. A PSA decrease ≥ 50% was seen in 7/19 pts (37%), with an average PSA decrease of 70.4% in these pts. One patient had an objective response (partial remission). The median time to progression (TTP) was 16.3 weeks (range: 3.1 - 132.6 weeks). Three pts remain on study with a median TTP of 25.1 weeks (range: 6.1 - 132.6 weeks). Grade 3 toxicities included 2 pts with hypophosphatemia, 1 patient with neutropenia, and 1 patient with flu-like symptoms. One patient experienced a pulmonary embolism and one patient had a portal vein thrombosis. Common Grade 2 toxicities included fatigue (21%), cytopenias (21%) and GI side effects (16%). There was no treatment-related mortality. Conclusions: These data support the efficacy of the RITE regimen, and the possibility of using alternative Bcl-2 modulating agents in combination with docetaxel in future studies. In addition, long term treatment with low dose docetaxel may be feasible. The assessment of an effect on PBMC Bcl-2 expression is ongoing.

No significant financial relationships to disclose.
Predictive value of PSA halving index (PSAHI) in patients (pts) with hormone refractory prostate cancer (HPRC): Results from a randomized phase II trial with docetaxel (D) ± estramustine phopshate (E)
Authors: Sava T. , Comploj E. , Fariello G. , Zustovich F. , Segati R. , Sacco C. , Perin A. , Mandarà M. , Cetto G. , Caffo O.
Published: March 2020

15548

Background: D-based chemotherapy represents the standard treatment for HRPC pts. For several years PSA has been considered as a surrogate endpoint for studies involving pts with HRPC. The possibility of predicting a clinical advantage through the biochemical response rate is controversial. The PSAHI may represent a predictive parameter more than the simple PSA trend. We retrospectively evaluated the role of PSAHI in a consecutive series of patients affected by HRPC and treated in a randomized phase II trial with D±E. Methods: 95 pts affected by HRPC were randomized to D 70 mg/m2 IV d1 q3w (arm A: 49 pts) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B: 46 pts). The treatment continued until best PSA response achievement or PSA progression. PSAHI was calculated comparing basal value (the day before first D administration) with those reached after every cycle at 21, 42, 63 and 84 days: each median value was then correlated across all pts. Correlations were made with response, time to progression (TTP) and overall survival (OS). Results: Responses, in terms of PSA? >50% were: 40% in arm A and 75%in arm B with PSA normalization in 5% and 32% respectively. After a median follow-up of 17 months, 65 patients are died (31 in Arm A and 34 in Arm B). Progression free survival (biochemical) was 20 weeks in arm A and 30 in B. Median PSAHI was 2.1 (0.8–8.8) and resulted significantly related to response and TTP: pts with PSAHI less than 1 and more than 1 had a median TTP of 14 and 34 weeks respectively. Between the 4 PSAHI analyzed (after 21, 42, 63 and 84 day), those at 42 and, particularly, 63 day resulted statistically related to response, TTP and OS. After 3 cycles, the PSA decline (63-PSAHI) was highly predicyive of OS which was 63, 72 and 90 weeks respectively (p=0.03), for pts with PSAHI of less than 1, between 1 and 3 and more than 3. Conclusions: PSAHI seems to be highly predictive of TTP and OS. 63-PSAHI seems to be a good surrogate marker of D response and may help in discriminating pts who need to be further treated with D and those who do not.

No significant financial relationships to disclose.
Health status in senior adult prostate cancer patients: Limits for active treatment and clinical trials inclusion
Authors: Droz J. , Albrand G. , Chaladaj A. , Fléchon A. , Terret C.
Published: March 2020

15550

Background: Two-third of patients (pts) with prostate cancer are older than 70 years. Patients are likely to receive active treatments in the curative and palliative settings if they have good health status, moreover they are likely to be offered to participate to clinical trials. Health status evaluation is performed by Comprehensive Geriatric Assessement (CGA). Methods: We have prospectively performed a mini- CGA (Terret C, Expert Rev Anticancer Ther. 2004; 4 : 469–75.) in 69 patients with prostate cancer : 33% pts had localized disease, median age was 78.7 years (68–92). Mini-CGA was based on a careful clinical examination with analysis of physical function, nutritional status (MNA), functional domain (ADL, IADL), cognitive and emotional domains (MMSE, GDS), identification and grading of comorbid conditions (CIRS-G), and a medication review. Social and familial evaluations complete the procedure. Results: Dependancy: only 12% pts are fully independant for ADL and 11% for IADL; 20% pts experienced falls and 32% were at risk of fall. Cognitive functions and depression: 60% pts had normal cognitive funtions, 46% and 4% were moderately and deeply depressed respectively. Nutrition: 22% pts had severe weight loss, 23% were mal nourished and 41% at risk of denutrition. Comorbidities: median CISR-G score was 8 (3–12), 80% and 21% pts had at least one grade 3 and one grade 4 comorbidity respectively. The most frequent comorbidities were by decreasing order of incidence : psychologic, hematologic, endocrine and osteo-articular pathologies. Polymedication: median number of drugs taken by pts was 5 (0–14) and iatrogenicity was observed in 30% pts. A caregiver was identified in 83% pts and 16% pts were living alone. None of the pts were fully independant with no major comorbidity. Conclusions: Health status of prostate cancer patients older than 70 years must be evaluated with the objective to either tailor specific clinical trials or apply adapted standard treatments. Task forces of the International Society of Geriatric Oncology (SIOG) are on the process to establish specific guidelines for prostate cancer treatment in the senior adults and for selection of manageable CGA procedures.

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