bluuebunny/crossref_metadata_2025 huggingface dataset:
Docetaxel in advanced breast cancer (BC) in the community setting: Analysis of treatment and prognostic factors in 129 South African patients
Authors: Ruff P. , Pienaar R. , Gudgeon A. , Michaelis F. , Neethling H.
Published: March 2020

10715

Background: Docetaxel has become a standard of care in BC, initially as salvage therapy, then as front line therapy for advanced disease and now in the adjuvant setting. Patients and Methods: A survey of the use of docetaxel in advanced BC in the community setting included 129 patients (128 females; 1 male) treated by 29 oncologists from 27 centers in South Africa from August 2002 until October 2003. Median age was 51 years (range 25–82 years). Median time between initial diagnosis and treatment was 27 months (range 6 days - 22 years). Although the survey was planned for advanced disease, 10 patients received adjuvant therapy; 59 received 1st line docetaxel and the rest 2nd line or more; major metastatic sites were bone (n = 57), liver (n = 45) and lung (n = 37); 47% patients were ER+, 30% ER- and 23% ER unknown; most had good PS (63 ECOG PS 0, 53 PS 1); 19 patients had no prior chemotherapy, 58 prior adjuvant therapy and 52 prior non-taxane chemotherapy for advanced disease. 62% patients received single agent docetaxel including 75–100mg/m2 3–4 weekly (38%) and 20–50mg/m2 weekly (19%) with 38% receiving docetaxel plus another drug. Results: At 1 year, 88 patients (68.8%) were alive. Log rank analysis showed age >40 years (p = 0.025) and PS 0 (p = 0.0000) were prognostic factors for survival, while post docetaxel chemotherapy (p = 0.062), 1st line vs more advanced disease (p = 0.3557), weekly vs 3–4 weekly docetaxel (p = 1.00), ER status (p = 0.1527) and menopausal status (p = 0.997) were not. Of 59 1st line patients, 40 (67.8%) were alive at 1 year. Age >40 years (p = 0.0015) and PS 0 (p = 0.031) as well as ER status (p = 0.011) and post docetaxel chemotherapy (p = 0.0436) were prognostic factors for survival, while menopausal status (p = 0.0609) and weekly vs 3–4 weekly docetaxel (p = 0.248) were not. 115 patients had 655 adverse events (AEs) including 111 serious AEs (SAEs) in 55 patients. 470 AEs were drug related with 54 SAEs including neutropenia (8), diarrhea (6) febrile neutropenia (5), emesis (5), cellulitis (3) and pneumonia (3). There were no treatment related deaths. Conclusions: Docetaxel alone or in combination is effective and well tolerated therapy in advanced BC especially in patients over 40 years of age with good PS (ECOG 0). Sponsored by Aventis Pharma (South Africa).

No significant financial relationships to disclose.
Trastuzumab prolonged administration: Safety and toxicity profile in heavily pre-treated patients
Authors: Tomadoni A. E. , Wainstein R. C. , Rondinón M. N.
Published: March 2020

10742

Background: HER2 over-expression was found to be an independent prognostic predictor of overall survival and time to relapse in breast cancer patients. Trastuzumab binds to the extracellular domain of HER2 cell receptor, thereby inhibiting the growth of breast cancer cells that over-express HER2. Objective: examine safety and toxicity profile of trastuzumab prolonged treatment (> 6 months) in heavily pre-treated HER2+ metastatic breast cancer patients. Methods: Between February 1999 and April 2005, 20 patients received weekly standard trastuzumab infusion until disease progression or serious adverse events. Population characteristics: median age: 46.6 years (30–65 years), ER+: 47.6%, PR+: 42.8%. Previous treatment: hormonotherapy: 12 patients (60%), two or more lines: 5 patients: (41.6%). All patients received previous chemotherapy: one line: 7 patients (35%), two lines: 10 (50%), three or more lines:3 (15%). Median trastuzumab treatment time was 11 months (6–36 months) Trastuzumab was administered as monotherapy in 5 patients (25%) and in combination in 15 patients (75%): 60% with docetaxel, 26.6% with paclitaxel, and 13.3 % with gemcitabine or vinorelbine Safety was primary trial end point, hence pre-treatment cardiac (baseline LVEF ≥55% by Echo or MUGA scan) and liver function assessment were required; and then, repeated each two months. Results: As regards cardiac adverse events, 2 patients (10%) receiving also docetaxel, developed supraventricular tachycardia reversible with 1 week treatment arrest. After 17 months, trastuzumab was discontinued in one of these two patients due to asymptomatic decrease in LVEF to 35 % (baseline LVEF:65%). An increase in transaninases (per 3ULN) was noted in one patient (5%) after 12 months of treatment. Liver function normalized after two weeks trastuzumab interruption. Allergic phenomena, as hot flashes or chills during first infusion was described in 3 patients (15%). In combination therapy, asthenia (20%), nausea (10%), anemia (10%), foot and hand syndrome (5%) and myalgia (5%) were observed. Conclusions: Prolonged tratuzumab administration in heavily pre-treated patients seems to be a safe approach with predictable profile and reversible toxicity with trastuzumab discontinuance and standard medical care.

No significant financial relationships to disclose.
Pathological complete response (pCR) in stage II and III breast cancer patients treated with neoadjuvant chemotherapy (CT): Dose dense ACx4 followed by AT/Tx4 (weekly paclitaxel)
Authors: Alarcon-Rozas A. E. , Melendez R. , Ramirez J. , Salas F. , Ramirez J. , Guevara J. , Galarreta A. , Hernandez E. , Viayrada F. , Torres J.
Published: March 2020

10746

Background: This is a prospective study of a single Institution to determine the pCR in stage II and II breast cancer patients after dose dense and sequential CT using the most active drugs. Patients and Methods: Between June/2004 and July/2005 we collected 28 patients, they have echocardiogram and needle biopsy for IHC before starting the treatment. All of them received Adriamicin 60mg/m2 in 3hrs infusion and Cyclophosphamide 600mg/m2 x4 in dose dense schedule (every 2 weeks) with G-CSF support and then Adriamicin 60mg/m2 and Taxol 80mg/m2 days 1,8 every 3 weeks. Once the treatment was finished they went to surgery. Results: Six (21%) patients were stage II and 22 (79%) were stage III; 8 (35%) patients achieve pCR, 50% of them had Her2/neu positive and 7/8 (90%) were ER/PR negative; 60% (5) had T more than 5cm and 75% were post menopausal. 12 patients had clinical complete remission. Eight patients had progressive disease with 50% ER/PR negative, 37% Her2/neu positive and all of them with T more than 5cm. 50% were premenopausal. Conclusion: This is one of the highest pCR of the literature (35%) achieved and it is interesting to note that 90% of them were ER/PR negative, so this is a potential target group for CT intensification. There is a group of patients (with progressive disease) that will never respond to CT, and it would be worst in the adjuvant setting (blindly treatment) because the great toxicity. We need more studies to confirm this hypothesis.

No significant financial relationships to disclose.
Docetaxel versus paclitaxel and “paclitaxel” versus paclitaxel: The optional therapy in breast cancer
Authors: Sulemanjee G. , Ristzert S. , Cao T. L.
Published: March 2020

10758

Background: For the past fifteen years many clinical trials have demonstrated that paclitaxel therapy could generate 30% to 60% response rate in patients with breast cancer. Recent clinical trials indicated that when used as control, paclitaxel therapy only produced 20% response rate in patients with breast cancer. Methods and Results: Using Medline study, data from early clinical trials indicated that paclitaxel, as first-line or second-line therapy, could generate 30% to 60% response rate in patients with breast cancer and the response rate was dose-dependent and toxicity-limited (Seidman, 1994; Perez, 1998). Therefore, paclitaxel is considered superior to older chemotherapeutic agents in treating breast cancer. When used as control to compare with two newer agents, docetaxel and nanoparticle albumin-bound paclitaxel (“paclitaxel”), data from recent clinical trials indicated that paclitaxel therapy only produced 19% to 25% response rate in patients with breast cancer. Many questions remain because the response rate from any chemotherapeutic agent is dose-dependent and toxicity-limited. Nishimura et al (2005) recently reported that weekly placlitaxel as second-line therapy in breast cancer resulted in 41.2% response rate which is much higher than the rates from either docetaxel or “paclitaxe” therapy (33% and 32%, respectively). The cost of paclitaxel dropped from $5000 per three-week therapy when it could produce 30% to 60% response rate years ago to $300 in recent years while the other agents such as docetaxel and “paclitaxel” cost about $3000 to $5000 per therapy. Conclusion: The role of inferior control in clinical trials is no longer a puzzle. Whether the quality of the low-cost paclitaxel or other factors could alter the response rate in clinical trials requires future research.

No significant financial relationships to disclose.
Combined modality treatment for breast cancer: Justification for integration of transplants at diagnosis
Authors: Hupperets P. , Van Hoef M. E.
Published: March 2020

10760

  >Introduction: In acute leukemia best therapy consist of fast remission-induction, consolidation of complete response and allogeneic transplantation to eradicate residual malignant cells. This therapeutic plan at diagnosis consists of three treatment combinations that have been proven to be most efficacious when administered consecutively according to protocol. Methods: The three treatment combinations were defined as independent entities and literature search was pursued to identify equivalent components for high risk and metastatic breast cancer. Results were tabulated. Results: First line combination treatment induces complete response rates that can be enhanced by dose density. This type of intensification does not change the risk of relapse although time to relapse may vary by a few months; survival in high risk breast cancer is about 50% and in early metastatic 10%. Failure to treat more aggressively induces respectively 50% and 90% relapse mortality. It is hidden treatment-failure related mortality. High-dose autologous transplants (HD-auto-tx) add a survival advantage of about 10% but this is statistically not considered significant. In large series treatment related mortality (TRM) of HD-auto-tx is 0–3%. Treatment integrating autologous transplantation reduce relapse mortality to respectively 60% and 80%. Allogeneic transplants induce an immune response in breast cancer that is comparable to the response observed in leukemia; micrometastatic bone marrow disease can be eradicated. After an autologous transplant risk of relapse is 80% and after an allogeneic transplant in first consolidated remission 20%. Allogeneic transplants make the combination attractive, despite the risk of TRM, mainly attributable to graft versus host disease. Selection of right treatment schedules and adequate prophylaxis for and treatment of graft versus host disease is emerging and may minimize the risk of TRM as result of this side effect to <5%. Discussion: Optimization of treatment by integration of transplants in treatment at diagnosis is warranted to offer breast cancer patients the choice of cure at certain risks versus the standard chemotherapy resulting in remarkably higher disease driven mortality. Details will be presented.

No significant financial relationships to disclose.
Axillary lymph node metastases from papilloma of the breast
Authors: Singh T. , Tso E. , Kumar A. , Ahrens P.
Published: March 2020

10764

Background: To report a unique case of papilloma of the breast with metastases to the axillary lymph node. Methods: Case report and review of literature. Results: 80 year old Caucasian male presented with right gynacomastia of 3 months duration. The lesion was resected. Pathology was consistent with intraductal papilloma with hyperplasia and no evidence of malignancy. Subsequently, after 2–3 weeks a mass was noted in the right axilla. This mass was resected and was found to be consistent with papilloma of the axillary lymph node and had the pathological characteristics of the original breast papilloma. Conclusion: Solitary papillomas are generally lesions of the large ducts usually located in the subareolar region of the breast. They are among the commonest cause of spontaneous nipple discharge. After resection of the primary lesion, local recurrence is fairly common. Recurrence is especially common if hyperplasia is associated with the papilloma. There is also an increased incidence of carcinoma in the affected breast. Due to the benign nature of papillomas, they do not metastasize. We did an extensive review of literature and did not find any cases of metastatic lesions from a papilloma of the breast. The underlying reason and pathogenesis for the metastases is not known.

No significant financial relationships to disclose.
Cost-effective treatment with half year of trastuzumab and chemotherapy as adjuvant treatment for overexpression of Her2/neu breast cancer patients: Two institutional experiences in Taiwan
Authors: Tai C. J. , Pan C. K. , Wu C. H. , Chen C. S.
Published: March 2020

10765

Background: In this study, we are evaluating the utilizing trastuzumab as an adjuvant combination with chemotherapy in an half year interval for breast cancer (1–3). Methods: Patients after October 2000 with HER2-positive (3+ by immunohistochemistry; if 2+, should fit over expression by FISH) stage II/III breast cancer who received adjuvant trastuzumab (4mg/kg ×1, then 2mg/kg/wk ×22, equals 6 bottles of trastuzumab) in combination with chemotherapy. The chemotherapy utilized for stage II breast cancer patients received CEF only and for those patients with LN(+) but ER/PR(−/−) also added paclitaxel for another 4 cycles besides CEF with interval of 3 weeks, and for those with stage III breast cancer patient with ER or PR(+), the docetaxel was given with CEF for 6 cycles). Clinical response rates were followed by using imaging studies with chest films, CT scanning, bone scan and sonography. Results: Overall, there were 37 patients enrolled in this study. The median age was 43 years old (22–74 y/o). Two patients (including the youngest one) were found to have bilateral breast cancer on diagnosis but both were still alive without disease so far. There were 3 patients developed disease progression after adjuvant chemotherapy with trastuzumab and 2 of them died thereafter and all these 3 patients were stage III disease. The oldest patient was one of the exception without receiving adjuvant chemotherapy and received monotherapy of trastuzumab only and so far, she was still alive without disease. The side effect including chills (24.32%), dizziness (8.10%), cough (2.10%), cold sweating (2.10%). Conclusions: For her2/neu overexpression patients, trastuzumabwith chemotherapy may have positive role in adjuvant therapy. In this study, our main goal is to achieve patient’s treatment outcome in disease free status. Nonetheless, the cost was high if we applied trastuzumab as adjuvant therapy with 1- or 2-year interval (4–6). Even if this required further time to demonstrate this study’s final outcome, I suppose that utilization of trastuzumab as adjuvant treatment plus chemotherapy in a half interval will be a good alternative treatment option.

No significant financial relationships to disclose.
Rapid and prolonged palliation of symptoms with improved quality of life (QOL) with endocrine therapy (anastrazole) in metastatic breast cancer (MBC)
Authors: Samuel J. , Osafo D.
Published: March 2020

10767

Background: Efficacy of anastrazole in receptor positive post-menopausal MBC; rapid palliation of symptoms with improved QOL. Methods: Case Report: A 62 year old woman diagnosed with right breast cancer in 1995, stage IIB, underwent surgery, adjuvant chemotherapy, and tamoxifen for 5 years. In February 2004, a left supraclavicular lymph node (1 cm) was felt. Chest x-ray (CXR) showed blunting of right cardiophrenic angle. CT scan of the neck showed multiple left cervical lymph nodes. In April 2004, her condition deteriorated rapidly needing hospitalization. She developed 15 pound weight loss, anemia, anorexia, shortness of breath, dyspnea on exertion, dry cough, and chest pain. CXR showed large right pleural effusion needing multiple thoracentesis. Hemorrhagic exudative effusion was seen with negative cytology and cultures. She also developed multiple palpable left cervical and left axillary lymphadenopathy. Breast exam was normal. Mammogram was not diagnostic but ultrasound of breast showed a 2.5cm left breast mass, axillary lymphadenopathy and additional lesions in the breast. Left cervical lymph node biopsy showed metastatic adenocarcinoma favoring primary breast cancer. A diagnosis of 2nd primary breast cancer with metastasis was made. Within 1 week of palliative capecitabine, she was readmitted with significant mucositis, diarrhea, dehydration, dysphagia, electrolyte imbalance, and reaccumulation of right pleural effusion. She lost 35 lbs. in 4 months. She was aggressively resuscitated and also needed thoracocentesis. Markers from prior biopsy showed Estrogen receptor 20%, Progesterone receptor <5%, and HER 2 (Herceptest) 3+. Palliative hormonal therapy with anastrazole was started in July 2004. Results: Within 4 weeks, she improved significantly with disappearance of lymphadenopathy and resolution of effusion. Performance status improved to ECOG 0. She is continuing anastrazole, 17 months since the diagnosis of debilitating metastatic breast cancer. Conclusions: Anastrazole is approved for the treatment of hormone receptor positive post-menopausal MBC. We describe the efficacy of endocrine therapy (anastrazole) leading to rapid and meaningful palliation of symptoms with improved QOL.

No significant financial relationships to disclose.
Five years update of sequential high dose doxorubicin, cyclophosphamide and docetaxel in inflammatory breast cancer; PEGAGE05 trial on behalf of FNLCC
Authors: Palangie T. , Pouillart P. , Roche H. , Viens P. , Linassier C.
Published: March 2020

10773

Background: Inflammatory breast carcinoma is a distinct clinicopathologic entity with poor survival outcome. Early response to initial chemotherapy was reported as predictive for survival and complete pathological response is considered as a major prognostic factor. This study was conducted to determine the safety and to estimate the efficacy of sequential high dose chemotherapy with doxorubicine (D) + cyclophosphamide (CPM) and docetaxel (Doc), in terms of pathological response, disease-free and overall survival Methods: Fifty-four patients entered into the trial from July 1997 to March 1999; treatment consisted in four 3 weekly cycles of D75 mg/m2 + CPM 6 g/m2 in C1 and C2; Doc 100 mg/m2 q 2w in C3, C4 and C6; D75 mg/m2 + CPM3 g/m2 in C6 and C7. Mastectomy with axillary dissection was performed for responding patients, followed by radiotherapy. Results: An interim analysis showed the same efficacy reported in previous high dose chemotherapy trial Pegase 02, without Docetaxel, and unexpected toxicity with 2 toxic deaths that warranted an early closure of the trial The overall 35% [22.5%–47.9%] grade 1 or 2 pathological response according to Chevallier as compared to the 32% reported in the Pagase 02 trial, suggest no greater efficacy for additionel Docetaxel to high dose D + CPM Five-year disease-free survival and overall survival showed a better tendency in Pegase 05 trial, with respectively 42% and 62% as compared to Pegase 02 trial with 33% and 50% Conclusions: these results suggest some benefit from dose intensified CT in terms of complete pathological response rate with improvment of the disease- free and survival outcome. The positive impact of additional docetaxel will be assessed in the last randomized multicenter Pegase 07 trial.

No significant financial relationships to disclose.
Multiple primary neoplasms involving the breast
Authors: Maddali L. S. , Maddali S.
Published: March 2020

10786

Background: Multiple Primary Neoplasms (MPN) are being identified with increasing frequency in Breast cancer patients. We studied MPN involving Breast cancer as at least one primary for (1) incidence and (2) identifying. subsets with special features. Methods: 83 patients with MPN were identified among 3378 patients seen between January 1st 1999 and 31st December 2005. (2.15%). 40 of these had Breast primary (48.19%). which form the basis of the present report. One or both primaries were identified during this period. But in some cases with primaries in remote past, available documentation was accepted. Results: Breast cancer was the Index cancer 31/40 (77.50%)and second primary in 9/40 (22.50%). Among the index cancers, 4/31 cases (12.90%) were synchronous and 27/31 (87.10%) were metachronous. 100% of the second primary in breast group were metachronous. Breast-Breast MPN 15/40 (37.50%) and Breast-Non breast MPN 25/40 (62.50%). Mean ages for Breast-Breast MPN 47.33 years, Synchronous tumors 38.66 yrs, metachronous tumors 58.20 yrs, Breast-Non Breast MPN 55.44 yrs. Mortality for Breast-Breast MPN as a group was 73.33%, synchronous tumors (2/3) 66.67%, metachronous tumors (10/12) 83.33%, Breast-Non Breast MPN, metachronous tumors (13/24) 54.17%. When the interval between index and second primary was studied, the Breast-Breast MPN mortality was (7/9) 77.78% for 2 yrs or less duration, (3/3) 100% for more than 2yrs. For Breast-NonBreast MPN, mortality was (6/9) 66.67% for duration of 2 yrs or less and (7/15) 46.67% for more than 2 yrs. The common malignancies associated in the index Breast cancer group were from Ovary (6),Thyroid (2),pancreas (2), Hematologic neoplasms (3) Upper Aero Digestive Tract (2). The second primary Breast cancer group had primaries in ovary (2), colon (2), hematologic (3) neoplasms. Conclusions: Breast-Breast MPN are seen in younger patients with higher mortality than Breast-Non Breast MPN. In the Breast-Non Breast MPN group, longer interval between the primaries is associated with lower mortality. There were no major differences between the Index Breast cancer group and Breast Second Primary group. Mortality appeared to be determined by the nature of the Non Breast Primary.

No significant financial relationships to disclose.
Trastuzumab-containing therapies: Activity beyond disease progression in M.B.C.—A pivotal experience
Authors: Del Bianco S. , Rondinelli R.
Published: March 2020

10788

Background: To evaluate Trastuzumab containing successive therapies activity in patients with overexpressing metastatic breast cancer (MBC). To determine the response rate (RR), time to progression (TTP) and overall survival (OS). Methods: Pivotal study of Trastuzumab (TZB) activity in HER-2 overexpressing MBC patients enrolled in our institution from 2000 to 2005. Results: 12 pts have been evaluated. Median age: 56; 8/12 postmenopausal,. 10/12 received adjuvant chemotherapy. Hormonal receptors: 8/12 positive, 4/12 negative. 8/12 pts had visceral disease. 11/12 had metastases in ≥ 2 locations. 5/12 pts received TZB as front line for MBC. Median previous lines: 2 (0–5). TZB was first time combined as follows: paclitaxel 7/12, docetaxel 4/12, (1/12 TZB alone). Asintomatic cardiac disfunction (LVEF reduction >10%) or CHF occurred in 1/12 pts (=CHF) after 46 months of TZB-treatment, with cardiac function progressively improving after standard medical care. RR for the 1st line (TZB containing): 11/12 (CR 3/12, PR 8/12), stable disease (S): 1/12, Clinical benefit (CB) 12/12, Median TTP 9.5 m (3–61+). 9/12 pts received a 2nd TZB containing therapy. RR for 2nd TZB-containing line: 4/8 (CR 0/8), SD 4/8, CB: 8/8; Median TTP: 8 months (3–14). All the 8/8 pts received a 3rd TZB- containing therapy. RR for 3rd TZB-containing line: 5/8 (CR 1/8), SD: 3/8, CB:8/8; Median TTP: 9 months (1–11). 4/8 pts have received a 4th or more TZB containing therapy with some long-lasting RR still presents at this time. Median overall survival is 33.5 months (9–61+). Conclusions: TZB-containing therapies beyond disease progression in MBC shows an interesting activity even in heavily pre-treated women. Small number of patients perhaps, do not allow to draw any final conclusion.

No significant financial relationships to disclose.
A phase II study of gemcitabine (G), peghilated liposomal doxorubicin (PLD) and docetaxel (D) in locally advanced breast cancer (LABC): An interim analysis
Authors: Artioli G. , Bozza F. , Cartei G. , Zovato S. , Mencarelli R. , Zavagno G. , Michelotto M.
Published: March 2020

10789

Background: On the basis of general and our own experience neoadjuvant therapy is justified in patients with locally advanced breast cancer to reduce cancer and to perform a conservative surgery. In this study we evaluated the efficacy of G plus D and PLD as first-line therapy in LABC. Methods: To date sixteen consecutive patients with LABC have been enrolled into the study. All patients before neoadjuvant treatment, underwent biopsy for hormonal receptors and c-erb-B2 assessment. Patients received G 1250 mg/m2 on day 1 and G 1000 mg/m2, T 75 mg/m2 and D 25–30 mg/m2 on day 8 (escalation dose was 25 mg/m2 at first cycle, 27.5 mg/m2 at second cycle and 30 mg/m2 at third cycle), every 21 days with G-CSF support on day 3, 10, 12 and 14. Tumor response was evaluated on the basis of surgeon consultation and breast MRI after 4 cycles. If tumor response was higher than 50% patients underwent 2 more cycles; if it was 50% ore less or because of unacceptable toxicity they underwent surgery after 4 cycles. Microscopic assessment of the extent and type of residual tumour was made. Results: 16 patients were enrolled comprehensive of 2 with no symptomatic bone metastases. Median age was 50 years-old, and 100% had a WHO performance status (PS) of 0 and EORTC QoL was submitted. Four patients were submitted to surgery after 4 cycles, one after 5 cycles of CT with 5 pPR more than 50%. Three patients had a pathological complete response, 2 partial response more than 50% and 1 stable disease after 6 cycles. (a total of 70% of pPR, 30% of pRC, 10% of pSD). Five patients are still on treatment. One patient died because of acute respiratory distress syndrome. Major toxicity was mucositis G3–4 in one patient. PPE was G3–4 in 3 patients, one discontinued chemotherapy with PLD and continued with Epirubicin. 2 patients received Epirubicin after the first cycle of PLG because of acute allergic reaction. Conclusions: This regimen of chemotherapy seems feasible and active in LABC. At the interim analysis results it has been noted that the best response to chemotherapy was among patients having worse prognostic factors (histology and staging).

No significant financial relationships to disclose.
Multivariate analysis identifies factors that affect survival after stereotactic radiosurgery for brain metastases
Authors: Diluna M. L. , King J. T. , Knisely J. P. , Bond J. E. , De Lotbiniere A. C. , Chiang V. L.
Published: March 2020

11500

Background: Stereotactic radiosurgery (SRS) has become a standard for the treatment of brain metastases. We attempted to determine if specific tumor- or patient-related factors in our population independently predicted better survival. Methods: Survival data for all 334 patients with brain metastases treated with SRS between Jan 1998 and Dec 2004 were analyzed. Clinical data were abstracted retrospectively from treatment records; survival data were obtained from the Connecticut Tumor Registry. Kaplan-Meier plots and Cox proportional hazard multivariate regression models were used to identify the factors that independently affected survival. Variables analyzed included age, sex, race, histology, number, location and total volume of metastatic lesions, surgical resection, WBXRT, chemotherapy, and systemic disease control. Results: Median age of our patient population was 57.3 years. The median number of lesions treated in a single session was 2 (range 1 to 36). Tumor histologies included non-small cell lung carcinoma (36%), breast (17%), melanoma (16%), small cell lung carcinoma (8%), renal cell (8%), esophageal (2%), and other (16%). Three hundred patients (90%) had confirmed deaths, with a median survival after SRS of 8.1 months. Increased survival was independently associated with systemic control (HR = 0.51, P<0.001), breast cancer (HR = 0.60, P=0.003), and total tumor volume <5cc (HR = 0.68, P=0.003). Decreased survival was independently associated with the presence of four or more cerebral metastases (HR = 1.50, P=0.005) and a trend toward decreased survival was associated with esophageal cancer (HR = 2.24, P=0.055). There was no difference in survival associated with age, race, sex, location of metastases, surgical resection, WBXRT before or after SRS, or chemotherapy. Conclusions: Breast cancer, systemic control, and fewer metastases were all significant independent predictors of improved survival. Of note, histological diagnosis, other than breast or esophageal cancer, did not affect patient survival, and a total tumor burden of 5cc or more was associated with worse survival independent of the number of metastases. These results should assist in survival prognostication in patients with cerebral metastases considering SRS.

No significant financial relationships to disclose.
Measurement of multidrug resistance in acute leukemia with three methods (Pgp expression, dnr accumulation & rho accumulation)
Authors: Alimoghaddam K. , Alamsamimi M. , Tootoonchian M. , Nadeali F. , Ashori A. , Ghavamzadeh A.
Published: March 2020

12001

Background: Multidrug resistance (MDR) is one of the most important causes of treatment failure in chemotherapy specially in acute leukemias. One of the MDR resistance mechanisms is mdr1 gene expression that causes P-glycoprotein (Pgp) expression on cell surface. Its expression and function is detected by flowcytometry. we decided to measure its expression by three method in our leukemias patients. Then we studied correlation of each of these tests with relapse, resistance, survival and some other parameters. Methods: before chemotherapy bone marrow. Pgp expression was detected with MRK16 Ab. For interpreting of Pgp we use D-value. D-value >0.15 was considered positive for Pgp. For dnr accumulation & rho accumulation D-value >0.2 was considered positive. Informations was colleced from patient chart. Correlation of OS, DFS, resistance to therapy with Pgp expression by each method was studied. Results: there were 84 patients (52 male & 32 female). 18 cases of ALL & 66 cases of AML were included. Mean age was 30 ± 13 and mean of follow up was 168 ± 106 days. Mean of dPgp was 0.35 ± 0.05, mean of ddnr was 0. 5 ± 0.28 and mean of drho was 0. 5 ± 0.28 too. There was significant correlation between patients presented with first relapse and dPgp (p-value < 0.009).But there was not true for ddnr or drho.Sensitivity and specifity of Pgp for resistance to therapy was 35% & 75% respectively. Sensitivity and specifity of dnr accumulation for resistance to therapy was 11% & 76% respectively. Sensitivity and specifity of Pgp for resistance to therapy was 11% & 76% respectively. There is on significant correlation between Pgp and OS. It was true for dnr accumulation & rho accumulation. RFS was longer for patients with negative Pgp, but there was not significant correlation. In patients with positive Pgp probability of relapse was 9 times more than negative Pgp. Conclusions: among these three tests Pgp expression is more useful for predicting resistance to therapy. There is no difference between dnr accumulation and rho accumulation in detecting resistance to therapy. But sensitivity of Pgp expression in detecting resistance to therapy is more than the two other tests. We can use Pgp expression as a helpful test for recognizing more resistant disease.

No significant financial relationships to disclose.
Pharmacokinetic (PK) and pharmacodynamic (PD) study of the effect of imatinib (Ima) on tumor (T) vascularity (V) and on gemcitabine (Ge) uptake (U) using non-invasive dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) and spectroscopy (MRS)—Study BUS228
Authors: Wolf W. , Presant C. A. , Waluch V. , Chen E. J.
Published: March 2020

12006

Background: Ima has been reported to increase T U of other chemotherapy drugs and to reduce interstitial fluid pressure (IFP) in experimental animals. Poplin et al performed a phase 1 analysis of Ima plus Ge in solid tumors (AACR 95:405, 2004). We tested ImaGe to determine the T PK and PD effects of Ima, Ge, and the ImaGe combination using DCE-MRI and MRS. Methods: Patients (pt) with measurable and MRI-imagible refractory solid T possibly responsive to Ge were randomized to receive either: one course of Ima with PK/PD, followed by one course of Ge with PK/PD, followed by the combination ImaGe; or one course of Ge with PK/PD followed by one course of Ima with PK/PD, followed by ImaGe. Ge was given at 900 mg/m2 IV over 30 min. for PK/PD and at 10 mg/m2/min. for continued therapy. Ima was given at 400 mg daily for 5 d. with Ge given on day 3. Doses were adjusted for toxicity. T V was measured by the use of DCE-MRI, as described previously (AACR 95:490,2004), where the initial contrast accumulation rate (ICAR) was calculated as the slope of the influx curve, and the delayed contrast accumulation rate (DCAR), measured between 2–20 min post contrast administration, as an approximation of IFP. Ge U was measured by serial 19F-MRS for ∼ 1hr post Ge administration. Results: To date 7 pts have been evaluated for the trial. Two pts have entered the trial and completed one cycle of therapy for PK/PD evaluation. Ima produced moderate nausea in both pts. Other toxicity was negligible. In the first pt Ima produced an 18% increase in the ICAR and a 72% increase in the DCAR but there was no significant change observed in the Ge uptake. In the second pt, Ima produced a 60% increase in the ICAR and a 21% increase in the DCAR. Neither of the 2 pts responded to treatment. Further pts are under study and their PK/PD results will be presented. Conclusions: PK and PD can be measured using DCE MRI together with MRS to determine the clinical affects of Ima, Ge, and the Ima-Ge combination. Current results indicate that Ima has a measurable effect on T V, but its relation to drug U and pt response require further pt evaluations to be definitive.

[Table: see text]
Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose
Authors: Kosloff R. A. , Wright J. , Ivy P. , Escalon J. , Norwood B. , Levinson B. , Pavlick A. C. , Beric A. , Muggia F. M. , Hochster H.
Published: March 2020

12007

Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX.

[Table: see text]

[Table: see text]
A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation
Authors: Hwang J. J. , Marshall J. L. , Malik S. , Chun H. , Ahmed T. , Pilia P. A.
Published: March 2020

12008

Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues.

[Table: see text]
Phase I study of gemcitabine (GEM) and premetrexed (ptx) in the treatment of advanced solid tumors
Authors: Kalykaki A. , Agelaki S. , Kalbakis K. , Kotsakis A. , Kentepozidis N. , Christophyllakis C. , Giassas S. , Vamvakas L. , Vardakis N. , Mavroudis D.
Published: March 2020

12025

Background: GEM has activity against a wide range of tumors and ptx is a multitargeted antifolate agent with activity in mesothelioma and non small lung cancer (NSCLC). A phase I study of a combination of GEM plus ptx for advanced malignancies was conducted. Methods: Patients with advanced malignancies were enrolled in this accelerated dose escalation trial. Both patients with or without prior chemotherapy were also eligible. They were treated with Gem followed by ptx on days 1 and 15 every 4 weeks. The starting dose was GEM 1250 mg/m2 and ptx 300 mg/m2. The dose of each drug was escalated alternately by 250 mg for GEM and 50 mg for ptx at each dose level. Results: A total of 41 patients (9 female/32 males) with median age of 60 years were enrolled at 6 dose levels. A total of 93 cycles were conducted with a median number of 2 cycles/pt. 35 patients were assessable for efficacy and all courses were assessable for toxicity. Grade 3/4 neutropenia was observed in 8 cycles whereas grade 3 /4 anemia and grade 3/4 thrombocytopenia in 3 and 2 cycles respectively. Grade 3 febrile neutropenia occurred in 1 cycle. Other ≥ grade 3 non-hematological toxicities were observed in only 3 cycles [grade 3/4 asthenia: in 2 cy; grade 3 edema: in 1 cy). The MTD was 1750 mg/m2 for GEM and 450 mg/m2 for ptx. Dose limiting toxicities were grade IV neutropenia, grade III thrombocytopenia and febrile neutropenia. Two partial responses (1 patient with ovarian cancer and 1 with NSCLC) were observed and stable disease in 4. Conclusions: The recommended doses for further phase II studies are GEM (1750 mg/m2) followed by ptx (450 mg/m2) biweekly.

No significant financial relationships to disclose.
Lung deposition of aerosolized anticancer drugs with a novel inhalation system: AKITA
Authors: Hofstetter E. , Ehlich H. , Muellinger B. , Scheuch G.
Published: March 2020

12037

Background: Inhalation of anticancer drugs might be a helpful route of delivery in cancer therapy, particularly for lung tumors and metastasis in the lungs. In this experimental setup 12 different drugs (including antineoplastic drugs and immunotherapeutics) were nebulized with two different jet nebulizer systems. Aerosol particle size (MMD) and mass output were characterized. Methods: MMD was measured using a laser diffraction system (Sympatec, Clausthal-Zellerfeld, Germany). Mass output measurements were performed after CEN Standard using a Flow/volume simulator with radiolabelled (99m Tc) solution/suspension. The amount of radioactivity on the filters was detected with a scintillation counter. For aerosolization two nebulizer systems were used: Pari LC Plus with Pari compressor (PARI) and Pari LC Star with AKITA compressor (AKITA). To determine lung deposition a lung deposition model (International Commission of Radiological Protection, ICRP66, 1994) was used, taking into account: mass output, particle size and breathing pattern of patients. The AKITA guides the patient with a positive pressure through the inhalation maneuver, it is breath activated and delivers the medication only during inspiration. The PARI nebulizes continuously and the patient inhales with different individual breathing pattern. Results: MMD with PARI was found to be 4.2 ± 0.4 μm compared to 3.40 ± 0.3 μm for AKITA. After filling 2.5 ml into the nebulizers we found 1.4 ml residual volume with PARI and 1.0 ml for AKITA. The output rate was 0.15 ± 0.02 ml/min for PARI and 0.29 ± 0.03 ml/min for AKITA. Lung deposition relative to the emitted dose was determined to be 28 ± 10% for PARI and 85 ± 4% for AKITA. This is because the AKITA nebulizes only during inspiration and guides the patient through the inhalation maneuver, where as the PARI is running continuously and patients inhale with different breathing pattern. The result is that from 2.5 ml filled into the nebulizer, on average 0.3 ml will be deposited in the lungs with the PARI and 1.3 ml with the AKITA. To deposit 1 ml in the lungs with AKITA it will take 7 min, with PARI about 24 min. Conclusions: By use of modern inhalation devices with controlled inhalation lung deposition for cancer therapy can be optimized.

[Table: see text]
Plasma kinetics, uptake by neoplastic breast tissue and preliminary toxicity data of a cholesterol-rich microemulsion (LDE) associated to a paclitaxel (PCT) derivative
Authors: Pires L. A. , Hegg R. , Graziani S. R. , Rodrigues D. G. , Maranhão R. C. , Deus D. F.
Published: March 2020

12038

Background: Previously we described the association of PCT to a cholesterol-rich microemulsion (LDE) that binds to low-density lipoprotein (LDL) receptors and concentrates in neoplastic tissues. The association is stable, preserves the anti-proliferative activity and reduces the toxicity to animals. The present study was designed to provide preliminary toxicity data on the LDE-PCT oleate formulation, to determine its plasma kinetics compared to that of commercial PCT and to verify the complex ability to concentrate in malignant breast tissue. Methods: To determine the plasma kinetics [3H]-PCT oleate associated to LDE labeled with [14C]-Cholesteryl oleate was intravenously injected into 3 pts and [3H]-commercial PCT into 2 pts 24 h before surgery. Blood samples were collected over the 24 h to quantified radioactivity and the pharmacokinetic parameters. Tumoral and normal breast tissue were excised during the surgery. Other 3 heavily pretreated pts with breast cancer were included in this study to assess toxicity. LDE-PCT (175 mg/m2) was administered as a 1-hour infusion at 3 week interval, without pre medication. Results: Fractional clearance rate (FCR) of LDE and of the drug were similar (0.030 ± 0.026 e 0.018 ± 0.018, respectively, P = 0.5742). The uptake of both [14C]-LDE and [3H]-paclitaxel oleate by breast malignant tissue was 2 and 3 fold greater than that of the normal breast tissue. The PCT oleate T1/2 (h) was greater than the commercial PCT (T½ = 18.97 ± 7.7 and 7.34 ± 0.40) and the clearence (L/h) of PCT oleate was lesser than the commercial (CL = 1.51 ± 0.18 and 7.95 ± 4.32). No hematological or neurotoxicity was found. Nausea and anorexia grade 1 was found only in one patient. Conclusion: Most of the drug is retained in the microemulsion until its removal from the circulation. The complex is stable and has greater plasma half life and lesser clearance than those for commercial one and can be concentrated in malignant breast tissue. Furthermore, LDE-PCT showed no considerable toxicity events in the 3 patients. Although data regarding response rates were not assessed, our preliminary results suggest that LDE-PCT may be a suitable and powerful weapon to treat breast cancer patients.

No significant financial relationships to disclose.
A phase I study of antitumor vaccination using tumor cells genetically modified to express alpha(1,3)galactosyltransferase (αGT) in patients with refractory or recurrent non-small cell lung cancer (NSCLC)
Authors: Morris J. C. , Janik J. E. , Vahanian N. , Mertes S. , O’Hagan D. , Tennant L. , Pittaluga S. , Albert P. , Seregina T. , Link C.
Published: March 2020

12503

Background: Despite new treatments, lung cancer remains the leading cause of cancer death. We examined the safety and activity of antitumor vaccination using genetically altered human non-small cell lung cancer cells (HAL; HyperAcute Lung Cancer Vaccine) engineered to express xenotransplantation antigens through retroviral transfer of the murine αGT gene in patients (Pts.) with NSCLC. Methods: A single institution Phase I trial. Eligibility: Stage IV, recurrent or progressive NSCLC, Age ≥18, ECOG PS ≤2, prior chemotherapies ≤2, AGC ≥1,500/μL, Plts. ≥100,000/μL, adequate hepatic/renal function and informed consent. Cohorts of Pts. received intrademal injections of 3 × 106, 10 × 106, 30 × 106, or 100 × 106 HAL vaccine cells every 4-weeks × 4, or 500 × 106 HAL cells followed by 300 × 106 HAL cells every 2-weeks × 7. Toxicity was assessed using CTCv3.0 and response by RECIST criteria. Immunological responses included anti-αGal antibody titers, interferon-γ ELISPOT and vaccine site skin biopsies. Results: Seventeen Pts., 9 men and 8 women, median age 57 years (range, 34–85), median number of prior chemotherapies 1 (range, 1–2) were vaccinated. There were no Grade 3/4 adverse events attributable to the study vaccine. Adverse events (≤grade 2) attributable to vaccination include injection site urticaria, pain/discomfort, local skin reaction, fatigue, herpes zoster, arthralgias/myalgias and hypertension. Six Pts. had stable disease ≥16 weeks duration (range, 16–85+ weeks), 9 Pts. progressed and 2 Pts. were not evaluable for response. Skin biopsies 48-hrs after vaccination demonstrated vaccine cells in the dermis with acute infiltration of lymphocytes, granulocytes and eosinophils. Serum anti-αGal titers increased 10–14 fold with vaccination. Conclusions: Xenogeneic antitumor vaccination with genetically altered allogeneic human lung cancer cells expressing αGT is safe and feasible. A phase II trial is planned.

No significant financial relationships to disclose.