bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiosurgery alone for solitary and multiple brain metastasis
Authors: Fox J. L. , Kleinberg L. , Kharkar S. , Clatterbuck R. E. , Wang P. , Wharam M.
Published: March 2020

1541

Background: Whole-brain radiation (WBRT) in the management of brain metastases treated with radiosurgery (RS) is controversial. Methods: Ninety-eight patients were treated for brain metastases with RS at Johns Hopkins between 4/03 and 7/05. Twenty-eight patients received RS alone after failing WBRT, 33 received RS alone for initial metastases and 37 received RS along with WBRT. Forty-five patients were women and 53 were men, with a median age of 56 (range, 18–92). Histology was: non-small cell lung cancer - 35, breast -14, melanoma -10, renal cell carcinoma - 9, and other - 30. Ninety-two (94%) pts had a KPS of ≥ 70 (median 80). The median number of metastases was 2 (range, 1–14). Results: Follow-up data from date of RS was available for 96 patients. Among those who received RS along with planned WBRT, median survival (MS) was 6.6 months with 1-yr overall survival (OS) 38%. Among patients treated initially with RS alone, MS was 9.7 months with 1-yr OS 42%. Among patients treated with RS for recurrent metastases after prior WBRT, MS was 6.8 months with 1-yr OS 24%. There were no significant differences in survival amongst these 3 treatment groups (p=0.73, log-rank test). For patients with 1–3 metastases (n=66), 1-yr OS was 38% versus 32% for those with ≥ 4 (n=32). Median survivals were 8.4 and 6.7 months, respectively (p=NS). Of patients treated with RS for recurrence, 7 of 25 (28%) with available follow-up data developed recurrent or new metastases whereas 11/27 (41%) treated with RS and planned WBRT and 15/27 (56%) who had RS alone as initial treatment had documented recurrent or new metastases. Conclusions: RS alone may be an effective treatment that preserves survival for those with single or multiple brain metastases at initial presentation or recurrence, but the tradeoff between the marginal increase in risk of brain recurrence versus toxicity and time commitment for WBRT needs further evaluation. The ongoing US Intergroup randomized trial, N0572/Z300, will address some of these questions.

No significant financial relationships to disclose.
Palliative whole brain radiation therapy (WBRT) for brain metastases (BM) revisited: The patient population in the modern era is different from the original patient cohort of the RTOG WBRT clinical trials
Authors: Savetsky S. RushM. , Vinokur A. , Mehta N.
Published: March 2020

1544

Background: RTOG trials in the 1970’s established WBRT (3000 cGy/10 fractions) as an effective palliative tool for symptomatic BM. This was in the era before CT/ MRI and effective systemic therapy. Inclusion criteria was based on clinical symptoms, and studies such as EEG and arteriography though not required. This study was undertaken to determine if pts. in the modern era are similar to those aforementioned, since it may not be appropriate to use accelerated WBRT (aWBRT) in these pts. based on the RTOG guidelines if the cohorts are different. (Other issues such as delayed cognitive dysfunction, alopecia and the impact of and integration with systemic therapy are pertinent to the application and prescription of aWBRT, but not the focus of this study). Methods: A retrospective chart review of 414 consecutive pts. with BM treated with radiation therapy in a single practice from 1990 through 2004 form the basis of this study. There were 256 females and 158 males. Lung cancer was the most common primary site (249/60%) and breast cancer next (75/18%). 121 pts (29%) had a single brain metastsis. 66 symptomatic patients underwent surgical resection of a brain metastasis prior to WBRT. The use of CT or MRI was determined. Results: Of the 414 pts, 105 were asymptomatic (25%). An additonal 66 pts. were rendered asymptomatic with surgical resection. Therefore, a total of 171 (40%) pts. were asymptomatic. All pts underwent imaging with CT (132) or MRI (282). Conclusions: Many pts. with BM seen in a modern radiation oncology practice are different from those in the RTOG series’ in which pts. were designated to receive aWBRT. 1. A notable proportion (40%) of a large number of pts. treated since 1990 for BM was asymptomatic vs. none of the pts. in the RTOG trials. 2. All pts. in this series underwent direct imaging vs. none in the RTOG series’. The systematic prescription of aWBRT for all pts. with BM as dictated by RTOG studies in the 1970’s may not be appropriate and alternative strategies and clinical trials are warranted.

No significant financial relationships to disclose.
Chemokine receptors seem to impact on patient survival in head and neck squamous cell carcinoma
Authors: Federico M. H. , Campofiorito C. M. , Mangone F. R. , Maistro S. , Pasini F. S. , Brunialti K. C. , Lehn C. N. , Walder F. , Carvalho M. B. , Brentani M. M. , Snitcovsky I.
Published: March 2020

15527

Background and Methods: Chemokine receptors seem to be involved in tumor spread to lymph nodes and influence outcome in cancer patients (pts). Here, we have determined the mRNA expression of CCR7, CX3CR1 and CXCR1 chemokines, by means of Ribonuclease Protection Assay, in 60 fragments of primary tumor and matched adjacent mucosa of pts with head and neck squamous cells carcinoma (HNSCC) submitted to curative surgery. For Kaplan Meier survival curves, pts were categorized for each chemokine as positive or negative if above or equal/below median densitometric value of the entire tumor group. Results: In the whole study population, CCR7 status did not impact on overall survival (OS) (P=0.118, Log Rank) and on disease free survival (DFS) (P = 0.102), neither. When the subgroup of oral SCC was considered (n = 19), the CCR7 negative pts (n = 10) presented a longer DFS and OS (median DFS and OS not reached) as compared to CCR7 positive pts (n = 9) (mDFS: 4.9 months, P = 0.001 and mOS 10.47 months P = 0.003). In the HNSCC group as a whole, the CX3CR1 negative pts presented a trend toward longer OS (mOS 26.60 months in negative group, n = 25 vs 15.43 months in the positive group, n = 35, P = 0.073) and a longer DFS (mDFS not reached in CX3CR1 negative vs 9.20 months in positive pts, P = 0.041). In the oral SCC subgroup, CX3CR1 negative pts (n = 8) presented significantly better DFS (mDFS not reached) as compared to CX3CR1 positive pts (n = 11, mDFS 4.9 months, P = 0.004). OS was also superior for oral SCC CX3CR1 negative (mOS not reached) as compared to positive pts (mOS 10.47 months, P = 0.008). Taking into account larynx SCC, mDFS and mOS were not reached for CX3CR1 negative pts (n = 5) as compared to positive pts (n = 11, mDFS 8.57 months, P = 0.016; mOS 12.37 months, P = 0.041). In larynx subgroup, the other receptor associated to an advantage in terms of both DFS and OS was the negativity for CXCR1 (mDFS not reached for negative vs 8.47 months for positive pts, P = 0.006; mOS not reached for negative vs 8.47 months for positive pts, P = 0.025). Conclusions: Even if the mechanisms are not clear, our data suggest that low expression of CCR7, CX3CR1 and CXCR1 mRNA may be markers of better outcome in Head and Neck Squamous Cell Carcinoma. Further studies are warranted to confirm these results.

No significant financial relationships to disclose.
Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-b2 targeted compound AP 12009
Authors: Bogdahn U. , Oliushine V. E. , Parfenov V. E. , Kunst M. , Mahapatra A. , Sastry K. V. , Venkataramana K. N. , Jachimczak P. , Hau P. , Schlingensiepen K.
Published: March 2020

1553

Background: In high-grade glioma (HGG), TGF-β2 expression strongly correlates with tumor grade and is highly predictive of disease outcome. The compound AP 12009 inhibits TGF-β2 expression. Preclinical results revealed strong multimodal activity including reversal of TGF-β induced immunosuppression, inhibition of tumor cell migration and proliferation. In 3 preceding phase I/II dose escalation studies, 24 HGG patients had been treated with AP 12009. Methods: G004 is an international open-label, actively controlled, dose finding phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy for efficacy and safety. 145 patients with histopathologically confirmed recurrent anaplastic astrocytoma (AA, WHO grade III) or glioblastoma (GBM, WHO grade IV) were randomized into one of 3 treatment arms. 134 patients received treatment AP 12009 10μM, AP 12009 80μM or standard chemotherapy (TMZ or PCV). AP 12009 was applied locoregionally by convection-enhanced delivery during a 6-month active treatment period with 7-day-on, 7-day-off cycles. Primary endpoint is tumor response by local and central MRI reading. All patients have completed active treatment. Follow-up for survival and tumor response assessed by local and central MRI reading is ongoing. Results: Here we report on patients with recurrent GBM (AA see separate Abstract). 96 GBM patients (37% female, 63% male; median age 51 years, range 20–74; median Karnofsky performance status 90, range 70–100) have been treated. 63 GBM patients received AP 12009 (28 pt. 10 μM, 35 pt. 80 μM), 33 patients received standard chemotherapy. Data were evaluated by an independent Data and Safety Monitoring Board. Up to now, in 89 patients treated with AP 12009 (AA and GBM patients) 6 SAEs possibly related to the study drug and 37 procedure related SAEs (92% mild or moderate) were documented. Several long-term tumor responses were observed by local MRI reading. Exact response rates are being determined by central reading. Conclusions: Responses in patients treated with AP 12009 in both AA and GBM patients are long lasting with a good quality of life. Phase III clinical trials in AA and GBM patients are currently in preparation.

[Table: see text]
Multimodal therapeutic approach in anaplastic thyroid cancer
Authors: Lee Y. , Jung J. , Hwang G. , Park H. , Im Y.
Published: March 2020

15533

Background: Anaplastic thyroid cancer (ATC) is a rare but highly aggressive neoplasm with a dismal prognosis. However, a few patients survive for a long time after treatment. We tried to identify prognostic factors of this disease and analyzed treatment outcomes in patients with ATC. Methods: We reviewed the medical records of 15 patients diagnosed with ATC in our institution between 1988 and 2003. The survival was compared by the Kaplan-Meier log-rank test. Results: The female-to-male ratio was 1.5:1 (9 women and 6 men), and the mean age at diagnosis was 63.9 years (range, 44–91). The mean tumor size was 6.3cm (range, 4–10 cm). Extrathyroidal invasion was present in 12 cases and distant metastasis at diagnosis was present in 6 cases. Surgery was performed in 8 cases. Radiotherapy was used for 10 cases and chemotherapy for 5 cases. The mean overall survival time of the 15 patients was 237 days (range, 28–717 days). The 6-, 12-, 18- and 24-month survival rates were 33%, 26%, 13% and 0%. No association was found between survival and presenting symptoms, age, gender, tumor size, previous goiter history, extrathyroidal invasion, distant metastasis, surgery, radiotherapy or chemotherapy. A significantly better outcome was observed in patients received triple modality treatment (surgery, radiotherapy and chemotherapy) than in those received single or dual modality treatment (P = 0.05). Conclusions: Although most patients with ATC had a poor prognosis, a multimodal approach including surgery, radiotherapy and chemotherapy, might improve survival.

No significant financial relationships to disclose.
Follow-up of concomitant treatment with gemcitabine/radiotherapy in locally advanced squamous cell carcinoma of head and neck
Authors: Bustamante F. , Villalobos R. , Castillo E. , Calva A. , Gallegos F. , Silva A. , Castruita A.
Published: March 2020

15537

Background: The stages of the locally advanced head and neck cancer have a negative prognosis, therefore, new treatments are continuously explored. One of these treatments consists of the use of Gemcitabine concomitant with radiotherapy. We previously evaluated the rate of response and the toxicity profile of this treatment in 15 patients and now we are reporting the follow up of such study. Methods: Fifteen patients, with histological report of locally advanced squamous cell carcinoma of head and neck, initiated treatment of Gemcitabine at intravenously doses of 50 mg\m2 per application weekly concomitant with radiotherapy. The radiotherapy consisted of an initial photons dose of 3960 cGy in 22 fractions of 180 cGy to the primary site and regional lymph with posterior increments of 2880 cGy in 16 fractions of 180 cGy excluding the spinal cord and electrons increments if necessary. Results: In 9 of the 15 patients complete response was obtained, achieving organ preservation. Four of the 15 patients presented a partial response and two presented progression. The principal severe toxicity presented was mucositis. The mean follow-up is 23 months with a range of 19–27 months. From the 9 patients that presented a complete response, one presented bone recurrence 13 months after achieving the total response; another one of them died because an infectious process without evidence of tumoral activity. The rest 7 patients are to the present date without evidence of tumoral activity. One of the patients with partial response is still alive with tumoral activity in central nervous system. The remaining patients died due to tumoral activity. Conclusions: In our study with 15 patients an overall response of 87% was obtained. With a follow up to 23 months only one recurrence has been presented. We concluded that the treatment is feasible and it could have an impact in the overall survival but studies with a greater number of patients and a larger follow up are needed.

No significant financial relationships to disclose.
Evaluation of combined modality treatment for advanced nasopharyngeal carcinoma by induction chemotherapy and radiotherapy
Authors: Tran T. Q. , Vu V. V. , Vo D. K. , Pham K. C.
Published: March 2020

15544

Background: We performed a retrospective investigation of the combined induction chemotherapy and radiotherapy for advanced nasopharyngeal carcinomas at Cancer Center-Ho Chi Minh City-Vietnam. Method: In the period 1998–2000, the treatment regimen induced 2 or 3 cycles of cisplatin and 5-Fluorouracile followed by radiation. Cisplatin was given in the dose of 100 mg/m2/day 1 and 5FU 1,000 mg/m2/d1–4. Radiotherapy included 2 lateral cervical portals and an anterior cervical portal with Cobalt 60. Results: One hundred sixteen patients (92 men and 24 women) with age ranging from 15 to 72 years were enrolled. The overall response rate to induction chemotherapy was 66% (15% complete responses (CRs) and 51% partial responses (PRs)). After combined treatment, overall response rates was 92% (82% CRs, 10% PRs). Toxicities in the chemotherapy were mainly myelosuppression (40%), nausea/vomiting (27%), mucositis (28%), and diarrhea (12%). There was 9 recurrences (2 local, 7 distant), 7 deaths and 1 refusal of radiotherapy. Conclusion: The immediate local response rates was rather high despite of the common of major myelotoxicities and expensive cost. The long-term survival benefit need to be reevaluated carefully later.

No significant financial relationships to disclose.
Phase I trial of bortezomib in adults with recurrent malignant glioma
Authors: Phuphanich S. , Supko J. , Carson K. A. , Grossman S. A. , Nabors L. B. , Mikkelsen T. , Lesser G. , Rosenfeld M. , Desideri S. , Olson J.
Published: March 2020

1567

Background: Bortezomib is a selective inhibitor of the proteasome that has been approved for the treatment of multiple myeloma and has also shown promising evidence of clinical activity against solid tumors. This study was undertaken to determine the maximum tolerated dose (MTD), toxicity profile, and biologic activity of bortezomib for the treatment of recurrent malignant glioma (MG). Methods: Eligible patients (pts) had supratentorial progressive MG upon radiotherapy and ≤ 1 prior regimen of chemotherapy. Dose escalation was conducted separately for pts taking enzyme inducing antiseizure drugs (EIASD+) and for those not (EIASD-). Bortezomib was given by bolus iv injection on weeks 1 and 2 of each 3 week cycle of therapy. The starting dose in both groups was 0.9 mg/m2. Cohorts of at least 3 patients were evaluated at each dose level. 20S proteasome activity was determined in whole blood lysates before and at 1 and 24 h after the first dose. Results: Fifty-nine evaluable pts (41 male/18 female) with a median age of 51 years and median KPS of 90% have been enrolled. All but 2 pts had received 1 prior chemotherapy regimen. In the EIASD- group, the weekly dose was escalated from 0.9 to 1.9 mg/m2 through 3 intermediate dose levels, with 1.7 mg/m2 established as the MTD. DLT experienced by 2 of 6 pts in the 1.90 mg/m2 dose level were grade 3 thrombocytopenia and grade 3 fatigue plus neurosensory toxicities. In the EIASD+ group, the dose has been escalated to 2.3 mg/m2 without the occurrence of any DLT. Ten additional EIASD- pts were treated at 1.7 mg/m2, with the most common adverse events being thrombocytopenia and peripheral neuropathy. The extent of proteasome inhibition in whole blood increased in a dose-dependent manner in both treatment groups. Mean proteasome inhibition in EIASD+ pts 1 h after receiving 2.1 mg/m2 of bortezomib (77 ± 12%) was similar to the 1.7 mg/m2 dose in EIASD- pts (79 ± 6%). Conclusions: The MTD for the weekly x 2 schedule of bortezomib in EIASD- patients, 1.7 mg/m2, is higher than the approved dose of 1.3 mg/m2 for the treatment of multiple myeloma. The enhanced tolerability of the drug when given together with EIASDs, for which the MTD is at least 2.1 mg/m2, is consistent with the diminished inhibition of 20S proteasome activity in these pts.

No significant financial relationships to disclose.
Multiparametric magnetic resonance imaging (MRI) of diffuse intrinsic pontine gliomas (DIPG) after radiation therapy (XRT)
Authors: Warren K. E. , Draper D. , Butman J. A.
Published: March 2020

1579

Background: The diagnosis and treatment of DIPG are based on typical MRI findings because of the inherent risk of biopsy. The standard treatment for this tumor is XRT. The limited ability of standard MRI to distinguish tumor from treatment effect hampers the determination of tumor response and time to progression. The objective of this study is to measure biochemical and physiologic MRI markers in DIPG after XRT that may aid in assessment of response. Methods: Fifteen pediatric patients (5 y, range, 1.8–12) with DIPG involving >50% of the pons and treated with XRT only were evaluated 12–64 days (median 38) following XRT (50.4–67.2 Gy, median 54 Gy) by MRI at 1.5 T. Standard T1, T2, and FLAIR MRI was performed in all cases. In addition, proton MR spectroscopy (MRS) was performed in 10 cases, MRS imaging (1H-MRSI) in 12, dynamic contrast enhanced MRI (DCE-MRI) in 14, and dynamic susceptibility weighted MRI (DSC-MRI) in 9. Ktrans and rCBV were measured using ROIs on enhancing portions of the tumor from the DCE- and DSC-MRI data after kinetic modeling. Results: Tumor area changed following XRT by a median of −29% (range, −61 to +37; SD, 33) and −17% (range, −65 to +101; SD, 45) on T2 and FLAIR, respectively. Enhancement was identified in 15 of 15 patients following XRT, and in only 6 of 15 prior to XRT (P = 0.0039 McNemar’s test). Following XRT, Choline: N-Acetyl Aspartate (CHO:NAA) ratio was 3.2 ± 1.9 by single voxel MRS, and the “worst voxel” CHO:NAA ratio was 3.5 ± 1.5 by 1H-MRSI. Overall, rCBV (1.98 ± 1.30) was elevated relative to normal cerebellum. However in 4 of these cases, rCBV was markedly elevated (>2), 4 were normal (1.0–1.3), and one was markedly reduced (0.6).Similarly, disruption of the blood-tumor barrier was variable across the group. Ktrans, a measure of permeability, ranged from 0.000 to 0.026 s−1, averaging 0.0086 ± 0.0085 s−1. Conclusions: Although all patients had a structurally similar tumor on MRI prior to XRT, significant variability in physiologic and metabolic response to XRT as measured by multiparametric MRI are noted. Presumably this variability represents real biologic differences resulting from differential responses to therapy. Determination of the prognostic significance is ongoing.

No significant financial relationships to disclose.
Demonstration of an expedited breast care (EBC) clinic
Authors: Lopez A. , Venker C. C. , Howerter A. , Barker G. P. , Bhattacharyya A. , Scott K. M. , Descour M. R. , Richter L. C. , Krupinski E. A. , Weinstein R. S.
Published: March 2020

16023

Background: Women report waiting for a breast biopsy result as a time of psychological distress. Waiting also delays entry into definitive oncology care, and patients in underserved communities may be lost to follow up. In this proof-of-concept demonstration, an Expedited Breast Care (EBC) clinic was developed to give patients the opportunity to receive same-day biopsy results. Methods: Patients requiring core breast biopsy at a community hospital were approached sequentially to participate. Following surgical biopsy, tissue underwent ultra-rapid fixation and processing. After paraffin sections were prepared and stained, the glass histopathology slides were imaged with a virtual slide scanner. Digital images were stored on a server and viewed on the Internet by a telepathologist at a tertiary care center. Light microscopy review was concurrently performed as the gold standard. After telepathology review and light microscopy confirmation, patients presented to the telemedicine suite to receive biopsy results. A teleoncologist at the tertiary care center presented all pathology results to the patient, whether benign or malignant. Time and patient satisfaction data were collected. Results: Nine patients have participated. Within 2 hours from the time the tissue arrived at the laboratory, digital images were available to the telepathologist. The teleoncologist presented results to patients within 3–5 hours after the biopsy procedure. Patients reported satisfaction with the same-day service, and stated they would seek EBC again in the event of a future breast biopsy. Many patients expressed relief at receiving results so promptly and felt they had avoided the stress of waiting longer for results. The elapsed time from mammogram to definitive oncology care was shorter for EBC patients compared to a control group of patients at a clinic not offering EBC, although the results did not reach statistical significance (Mann-Whitney U: Z = −1.804, p = 0.0713). Conclusions: These data indicate EBC can be successfully accomplished. Current studies to assess EBC’s role in facilitating prompt entry into definitive oncology care are underway. By incorporating rapid tissue processing with telepathology and teleoncology, EBC can improve access to breast care in underserved areas.

[Table: see text]
Status of geriatric oncology in India: A national multicentric survey of oncology professionals
Authors: Arora B. , Parikh P. M. , Nair R. , Vora A. , Gupta S. , Sastry P. , Menon H. , Bakshi A. , Kumar P. , Goyal L.
Published: March 2020

16035

Background: Elderly cancer patients are underrepresented in cancer services utilization and clinical research in India. National data on providers’ knowledge, attitude and practices with regard to elderly cancer patients is sparse and is urgently required to address needs of this vulnerable and growing population. Methods: A self administered questionnaire was mailed to nationally representative sample of practicing oncologists all over India. 112 Oncologists (Medical Oncologists-51%; Radiation Oncologists-25%; Surgical Oncologists-20%; allied fields-4%) responded out of 250 mailed Questionnaires. Results: A designated Geriatric Oncology unit is in existence in very few (<5%) centers. Majority (51%) considered patients with chronological age of >60 years as elderly for India. Although 75% of elderly patients receive some therapy, only 50% of potentially curable patients and a similar percentage of potentially incurable patients receive standard of care. Also, 50% patients require modification in their treatment and only two-third of treated patients complete therapy. The existent barriers to treatment included poor performance status (53%), advanced stage (16%), and co-morbidities (15%). Only 51% Oncologists always discussed and 28% always enrolled elderly patients in clinical trials. Standard of care and evidence based recommendations for elderly patients were felt to be lacking by 49% and 92% of respondents respectively. The need of separate trials for elderly and a separate discipline of Geriatric Oncology was voiced by 93% and 89% of respondents respectively. Major differences in treatment practice between medical oncologists and non medical oncologists are shown in table . Conclusions: Treatment practices and accrual of elderly cancer patients in clinical trials in India is far from optimal. Formation of a National Geriatric Oncology society and creation of designated Geriatric oncology services at key centers may enhance the understanding and clinical care of this population.

[Table: see text]

No significant financial relationships to disclose.
A humanized unconjugated antibody targeting CD33 (SGN-33; huM195) is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)
Authors: Raza A. , Galili N. , Jurcic J. G. , Roboz G. J. , Wood B. L. , Grove L. E. , Drachman J. G.
Published: March 2020

16500

Background: CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody has been developed that recognizes CD33 and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In prior clinical testing, this antibody led to significant reductions in blasts in patients with relapsed and refractory AML. Methods: A phase I single-arm dose escalation trial was initiated at multiple sites to assess the safety, immunogenicity, pharmacokinetics, and activity of SGN-33 at higher doses than previously tested. Cohorts of 3–6 patients with advanced MDS or AML will receive intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg over 5 weeks. Clinical response will be determined by bone marrow morphology and hematologic improvement. Responding patients will be eligible for 4 additional infusions. Results: Treatment of 6 patients at 1.5 mg/kg/wk has been well-tolerated, with no dose-limiting toxicity or related adverse events > grade 2. The median age is 79.5 years (range 52–88), and all patients were previously untreated. One patient discontinued treatment because of refractory thrombocytopenia, unrelated to SGN-33. CD33 saturation of the bone marrow blasts after 2 infusions ranged from 27% to 84% with an average of 55%. The mean change in bone marrow blasts by flow cytometry after 2 weeks was −9% (range −68% to +44%; N = 5), and the marrow monocytes changed by −39% (range −90% to +86%; N = 5). Two patients have completed re-staging after cycle 1. Blasts decreased from 29% to 12% in an 88 year-old woman with AML and from 11% to 9% in a 79 year-old man with RAEB. Conclusions: SGN-33 is well tolerated at 1.5 mg/kg/wk, and dose escalation is ongoing. Antitumor activity was seen in elderly patients with previously untreated AML and MDS. Incomplete saturation of the CD33 on bone marrow blasts suggests that higher doses may improve efficacy. SGN-33 holds promise for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy.

[Table: see text]
University of Wisconsin experience treating adult ALL with the BFM regimen
Authors: Medlin S. C. , Kahl B. , Longo W. , Williams E. , Lionberger J. , Kim J. , Kim K. , Juckett M.
Published: March 2020

16501

Background: Berlin-Frankfurt-Munster therapy (BFM) is an effective regimen for acute lymphoblastic leukemia (ALL) in children and young adults (Lancet 2:921–924,1988). Treating children and young adults at higher risk for relapse with an augmented BFM was shown to increase both event free and overall survival (NEJM 338:23,1663–1671,1998). Outcomes using standard BFM or augmented BFM in adults are unknown. Methods: This is a case-series of 29 adult patients treated with the BFM regimen. Patients were stratified into low, intermediate and high-risk groups based upon the following characteristics: age, white blood cell count, adverse cytogenetics and absence of CD 10. Low risk patients received the standard BFM regimen. Intermediate risk patients were given augmented BFM if less than 50 years old, standard BFM if older than age 50. High-risk patients received augmented BFM. Cranial irradiation was omitted in most patients (25/29). Events were defined as relapse, death from any cause, and stopping treatment for any reason. Results: Fifteen patients (median age 38, range 19–70) were treated with standard BFM and 14 patients (median age 37, range 21–72) with augmented BFM. Complete remission at day 28 was 93% (27/29). For the entire group, the 3-year overall survival was 60% with a 3-year event free survival of 45%. Patients treated with augmented BFM experienced a 3-year EFS, PFS, OS of 26%, 43%, and 48% respectively. Patients treated with standard BFM had a 3-year EFS, PFS, OS of 60%, 78%, and 78% respectively. Toxicity was common with significant neuropathy and neutropenic fever occurring in 83% and 48% respectively. Septic shock occurred in 17% of patients. Severe toxicity resulted in 1 death and discontinuation of BFM in 3 patients. The entire regimen was completed in 33 % of those treated with augmented BFM and 71% of those treated with standard BFM. Conclusion: Standard BFM is an effective and tolerable regimen for treatment of adult ALL. Augmented BFM is a difficult regimen for adult patients to complete. For both regimens, the 3-year PFS and OS compare favorably to other published regimens.

No significant financial relationships to disclose.
Alemtuzumab (ALZ) as treatment for severe paraneoplastic pemphigus (PNP) associated to B-cell chronic lymphocytic leukemia (CLL)
Authors: Nielsen R. B. , Steinicke T. , Peterslund N. A. , Hohwy T. , Bang K. , D′amore F.
Published: March 2020

16520

Background: ALZ is a monoclonal antibody used in the treatment of CLL. PNP is a mucocutaneous disease frequently associated with B-cell malignancies. PNP is often refractory to immunosuppressive drugs and is frequently fatal. Methods: We here report two cases, where ALZ induced a complete and sustained remission of both PNP and CLL and one case with a significant remission of PNP alone. Results: A 68-year old male with a 4-year CLL history developed blisters and ulcers on the extremities and trunk and severe stomatitis. Despite steroids, fludarabine, cyclophosphamide, ciclosporin A, and azathioprin, PNP exacerbated. A standard 12-weeks ALZ schedule was initiated. PNP lesions gradually regressed under the last weeks of treatment and resolved completely a few weeks later. A bone marrow biopsy showed morphologic and flowcytometric signs of remission. Now, 30 months after ALZ, the patient’s PNP and CLL are still in remission. Almost a year after this first case, a 77-year old male with a 3-year CLL history, presented with severe mucocutaneous lesions of the lips, oro-esophageal cavity, penis and extremities. PNP was diagnosed and a standard 12-weeks ALZ schedule was initiated. The lesions began to regress during the last weeks of treatment and normalized within the subsequent 8 weeks. This remission had a duration of 1½ year, after which the patient was hospitalized with evidence of PNP relapse. He is currently undergoing renewed ALZ therapy. An 80-year old female with a 4-year history of CLL, showed signs of disease progression after 2 treatment-free years.She then developed mucocutaneous lesions diagnosed as PNP. In spite of cytoreductive treatment, both PNP and CLL progressed and ALZ was given. All PNP lesions promptly disappeared, but recurred already 2 weeks after discontinuation of ALZ. Concomitantly, the patient developed a Legionella pneumonia. In spite of erythromycin, she deteriorated clinically and died one month later. At autopsy, marked CLL involvement of bone marrow and retroperitoneal lymph nodes was found. Conclusion: ALZ is an effective treatment in severe CLL-associated PNP. The observed duration of response was variable. A larger number of patient observations is necessary in order to identify patterns of response.

No significant financial relationships to disclose.
Skin reactions with imatinib in CML patients: An Indian experience
Authors: Attili S. V. , Anupama G. , Dadhich H. K. , Saini K. S. , Bapsy P. P. , Batra U.
Published: March 2020

16522

Background: Skin reactions are observed in up to 30–45% of all patients of CML on imatinib therapy. Owing to its low molecular weight it is less likely to be immunologically mediated. Therefore most of them can be managed without discontinuation of therapy. We tried to look into the spectrum of the skin reactions observed in CML patients receiving imatinib, and tried to see any change with the phase of the disease (chronic/accelerated/blast crisis) or difference in the brand of drug they are receiving. Methods: This retrospective study was conducted at Kidwai Memorial Institute of Oncology, Bangalore, India. A total of 235 patients were analyzed between Jan 2004 and Dec 2005. Clinical details were noted from the case records. Differences were calculated for the means using SPSS 13.0 for windows. Results: The age, total episodes of reactions, mean time to develop and to heal along with grade of reactions are summarized in the table . A total of 191 patients received the international brand and the total episodes of skin reactions observed were 68 with 4 grade III/IV toxicities. 54 patients received local brand and 17 of them developed skin reactions and 2 of which were grade III/IV. There is no difference in the time taken for resolution of skin reactions (23.8 + 6.7 vs. 25.2 + 7.5) (p = NS). Conclusion: There are no significant differences in skin reactions observed with brand of imatinib used. Patients with accelerated phase and blast crisis developed reactions at little earlier. As most of the patients in the later said conditions had a shorter survival, we could not comment conclusively on the time to heal according to phase of the disease.

[Table: see text]

No significant financial relationships to disclose.
Efficacy and feasibility of intensive induction therapy in very elderly patients with acute myeloid leukaemia
Authors: Biaggi G. , Santagostino A. , Manachino D. , Posca T. , Forti G. , Salva S. , De Marino E.
Published: March 2020

16528

Background: Intensive Induction Treatment (IIT) increases chances of longer survival in acute myeloid leukaemia (AML). Our aim was to improve outcome and to evaluate safety and tolerability of IIT in very elderly patients (pts). Otherwise they have a median surviving time of 11 weeks without treatment. Methods: From October 2003 to November 2005 we treated 23 pts, 16 Males (M) and 7 Female (F); median age 75.5 years (range 68–95). According FAB classification they were 1 M0, 10 M1, 5 M2, 6 M4, 1 M5. ECOG performance status (PS) was 0 in 6 pts, 1 in 5 pts, 2 in 7 pts and 3 in 5 pts. All pts underwent IIT with different schedules: only a female 95 years old had less intensive treatment. Immune-chemotherapy was also admitted. Schedules were: 3+7 IDA+ARA-C in 8 pts; MY-FLAI in 7 pts; VP+ARA-C 1 = ≥ 5 in 2 pts; IDA+ARA-C 1 = ≥ 2 in 4 pts; ARA-C + 6TG in 1 pt. Eleven pts underwent second line treatment. Results: Five pts are alive and 18 dead. We obtained 7 complete responses (CR) (32%) and 1 partial response (PR) (RR 36%);. The median CR duration was 7.5 months (range 1–12).Throughout IIT we observed 5 toxic deaths (23%) because of infections and 2 deaths not leukaemia therapy related (heart failure). The median Overall Survival (OS) was 9 months. Conclusions: Despite the toxic deaths due to the treatment, we obtained in 32% of the pts CR longer compared to palliative or best supportive care; also the median OS was longer than we can expected without chemotherapy. Our data support in our opinion the feasibility and the utility of an IIT in very elderly patients with good PS.

No significant financial relationships to disclose.
Biodistribution of paclitaxel poliglumex (PPX) in lung: Analysis of gender-related alterations in a preclinical model
Authors: Allievi C. , Strepponi I. , Bastrup U. , Piazzoni L. , Tavazzi S. , Pisano R. , Pezzoni G. , Fornasier M. , Bernareggi A. , Singer J. W.
Published: March 2020

17003

Background: PPX is a macromolecular drug conjugate that links paclitaxel with poly-L-glutamic acid; the release of paclitaxel is dependent on metabolism by lysosomal proteases, particularly cathepsin B. Cathepsin B is upregulated by estrogen in both reproductive and somatic tissues that express estrogen beta receptors, including normal lung epithelial cells. Cathepsin B mRNA is also increased by estrogen and decreased by anti-estrogens in the 201T NSCLC cell line (P. Hershberger, personal comm.). Clinical data from Phase III studies in NSCLC showed improved survival in women receiving PPX compared to women in the control-arm, particularly those that were pre-menopausal or with pretreatment estradiol levels >30 pg/ml. In contrast, men had similar survival regardless of treatment. Methods: To examine the effect of estrogen on PPX biodistribution and metabolism, male, sham-operated female, and oopherectemized (OPX) female adolescent rats were treated with [14C]PPX (25 mg paclitaxel eq/kg). Radioactivity, as well as total and unconjugated paclitaxel, were measured in plasma, liver, and lung weekly for 4 wks. Results: Plasma thalf values for radioactivity were appr. 3- and 1.5-fold higher in OPX females and intact females, respectively, compared to males; plasma AUCs were increased 1.8- and 1.5-fold, respectively. The lung AUC for radioactive PPX was similar for male and OPX females (11.8 and 15.1 hr*mgeq/g, respectively) but significantly higher for intact females (39.3 hr*mgeq/g). Total paclitaxel concentrations in the lung were 2-fold higher for females compared with either male or OPX rats (p < 0.05 at 1 wk, and p < 0.01 at 4 wks post dosing). No significant differences were observed in liver. Conclusions: OPX is associated with prolonged PPX plasma clearance compared to controls, and intact ovarian function is associated with enhanced distribution of PPX to lung tissue. These data provide the first evidence that ovarian function affects PPX pharmacokinetics and biodistribution; continued preclinical investigations will further characterize the mechanism for its apparent enhanced clinical efficacy in chemotherapy-naïve women with advanced NSCLC and intact ovarian function.

[Table: see text]
Factors affecting the risk of brain metastases after chemoradiotherapy for locally advanced non-small-cell lung cancer (LA-NSCLC)
Authors: Fujii M. , Segawa Y. , Nogami N. , Hamamoto Y. , Kataoka M. , Komori E. , Sawada S. , Yamashita M. , Shinkai T. , Takashima S.
Published: March 2020

17019

Background: With an improvement in treatment outcome in patients with LA-NSCLC undergoing radical chemoradiotherapy, brain metastasis has become a greater problem. We assessed the cumulative incidence of brain metastases and its risk factors in such patients with LA-NSCLC. Methods: Between 1993 and 2003, 85 consecutive patients with stage IIIA or IIIB NSCLC underwent chemoradiotherapy in our institution. The characteristics of these patients were as follows: median age, 64 years (range, 39 to 74 years); stage IIIA/IIIB, 30/55 patients; squamous-cell/nonsquamous-cell histologies, 39/46 patients. Concurrent and sequential chemoradiotherapy were administered for 78 and 7 patients, respectively. Only two patients underwent surgical resection after chemoradiotherapy. Fifty-seven patients received conventional thoracic radiotherapy with a total dose of 59.5 ± 1.4 Gy (range, 40 to 70 Gy), and 28 received twice-daily radiotherapy with a total dose of 71.5 ± 6.5 Gy (range, 43 to 86 Gy). Thirty-eight patients received a combination chemotherapy consisting of cisplatin and docetaxel, and the remaining 47 received the other platinum-based regimens. Results: At a median follow-up time of 51 months (range, 9 to 131 months), median survival time was 25 months, with a 3-year survival rate of 36.9%. The median disease-free survival time was 13 months. During treatment and observation periods, 21 (24.7%) patients had developed brain metastases. Thirteen (15.3%) patients experienced brain metastases as the first site of relapse, and in nine (10.6%), brain was the sole site of relapse. The cumulative risk of brain metastases was 15.4% at 1-year, 21.1% at 2-year, and 25.7% at 3-year, respectively. In a multivariate analysis using Cox proportional hazard model, T-factor (T4 vs. T1–3) was the most predictive of brain failure (hazard ratio, 3.51; 95% confidence interval, 1.35 to 9.13; p = 0.01). Conclusions: In patients with LA-NSCLC undergoing chemoradiotherapy, brain was one of the most common sites of failure when locoregional control was achieved. Although efficacy of prophylactic cranial irradiation (PCI) on survival remains unclear for such patients with NSCLC, identification of patients more likely to have a benefit from PCI would be useful.

No significant financial relationships to disclose.
Analysis of nerve growth factor (NGF) blood levels in patients with advanced non-small cell lung cancer patients (NSCLC): Its correlation with clinical outcome
Authors: Blasco A. , Sirera R. , Camps C. , Giner V. , Llobat L. , Safont M. J. , Berrocal A. , Taron M. , Sanchez J. J. , Rosell R.
Published: March 2020

17025

Background: Platinum compounds and taxanes have severe side effects in a dose and time-dependent manner, especially neurotoxicity. NGF plays an important role in growth and differentiation of neuronal components. Our goal was to study NGF levels in plasma and correlate it with patient’s clinico-pathologic characteristics. Methods: The study was performed with 451 patients with advanced NSCLC, stages IIIB-IV and treated with cisplatin and docetaxel. Peripheral blood was collected before therapy. NGF were assessed by commercial ELISA (detection limit, 5 pg/ml). Plasma from 32 age and gender-matched controls was used. Results: 91% of males, mean age 61 y [35–82]. 86 patients in ECOG PS 0–1 and 14 PS2. 71% in stage IV and 29% in IIIB. The histological subtypes were 38% squamous cell, 37% adenocarcinoma, 5% anaplasic large cell and 20% undifferentiated. 77.5% of the metastasis was out of the lung. Patients received a median of 6 cycles of chemotherapy [1–7]. 4% presented complete response (CR), 38% partial response (PR), 25% stable disease (SD) and 30% progressive disease (PD). Patient’s median plasma levels of NGF did not differ significantly from controls: 44 pg/ml [6–176] vs 31 pg/ml [14–144] respectively. There were not differences according to histology, site of metastasis and ECOG; however we could observe significant differences with stage: 25 pg/ml [10–70] in stage IIIB vs 47 pg/ml [6–176] in stage IV (p = 0.008). We could not observe any differences in response to therapy: CR+PR patients presented median NGF of 35 pg/ml [6–92] vs 39 pg/ml [10–165] in the SD+PD group. Splitting the cohort according to NGF median we found two significantly different groups in terms of Overall Survival (OS): patients with NGF <44 pg/ml had a median OS of 10.9 months (m) [7.9–13.9] vs 7.3 m [3–11.5] for patients with NGF >44 pg/ml (p = 0.03). In the multivariate analysis, NGF levels was not predictor for time to progression (TTP) and OS. Conclusions: NGF plasma levels did not differ in patients and controls. In our cohort with advanced NSCLC we have not found any relationship between NGF levels with histology, response, site of metastasis and TTP. By contrast NGF levels are higher in those patients in stage IV and in those presenting poorer OS.

No significant financial relationships to disclose.
Phase II trial of pemetrexed (P) and gemcitabine (G) as first-line chemotherapy for elderly and/or poor performance status patients with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Blakely J. , Schnell F. , Kaywin P. , Keaton M. , Fortner B. , Epperson A. , Schwartzberg L. S.
Published: March 2020

17031

Background: Pemetrexed and gemcitabine have shown to be active agents in the treatment of locally advanced or metastatic NSCLC with favorable toxicity profiles. A recent phase I study examined a biweekly schedule of P and G in combination in order to establish a maximum tolerated dose in solid tumors. (Dudeck, A. ASCO 2004 Abstract 2141.) This established the dose for this study. Methods: After informed consent all patients received biweekly cycles of P 500 mg/m2 IV 10 minutes before G 1500 mg/m2 IV. A maximum of 12 cycles was planned for stable or responding patients. All patients received vitamin B12 1000 μg and folic acid 1000 mg 7 days prior to the initiation of treatment and continued through treatment. Entry criteria include measurable stage IIIB/IV NSCLC by RECIST criteria, age ≥65 years and ECOG 0–2 or <65 years and ECOG of 2. A total of 40 patients are scheduled to be enrolled. Primary endpoint is objective response rate. Results: To date, 19 of 29 enrolled patients have data available for analysis. The median age is 71 (range 61–85). 2 had stage IIIB and 17 stage IV, median number of sites of disease is 2. Male/Female ratio was 10/9. Performance status was as follows ECOG 0 = 3 patients, 1 = 12 patients, 2 = 4 patients. 3 patients had grade 3 or 4 neutropenia with only 1 patient having neutropenic fever. There were no grade 3 or 4 anemias or thrombocytopenias. One patient had grade 3/4 nausea; there were no other severe non-hematologic toxicities. 14 patients were evaluable for response with 3 achieving PR (21%), 10 with SD (71%) (median number of cycles 7) and 1 with PD (7%). Conclusion: Pemetrexed and gemcitabine in combination biweekly has substantial activity with a favorable toxicity profile for patients with advanced NSCLC who are elderly or have poor performance status. The study is expected to be completed and fully evaluable by ASCO.

No significant financial relationships to disclose.
Tandem high-dose therapy with autologous stem cell support for small-cell lung cancer (SCLC)
Authors: Machatschek J. N. , Kobbe G. , Haas R. , Rohr U. P.
Published: March 2020

17033

Background: We evaluated the therapeutic efficacy of tandem high-dose chemotherapy followed by autologous peripheral stem-cell transplantation (PBSCT) in patients with newly diagnosed SCLC in complete remission or very good partial response after induction chemotherapy. Methods: Between 1996 and 2000, 19 patients with newly diagnosed SCLC in CR or very good PR after two cycles of induction chemotherapy (cisplatin 90 mg/m2 day 1, etoposide 120 mg/m2 day 1–3, ifosfamide 1500 mg/m2 day 1–4) received a tandem high-dose chemotherapy (cyclophosfamide 2000 mg/m2 day 1 and 2, etoposide 700 mg/m2 day 1–3, carboplatin 1200 mg/m2 day 1) followed by PBSCT. Following transplantation, patients received concurrent chest and cranial radiotherapy to a total dose of 45 Gy and 30 Gy, respectively. Results: Of 19 patients with SCLC, 18 had stage III and one stage IV disease. The median age was 50.7 years. Median time to leukocyte-recovery above 1000/μl and platelet-recovery above 20.000/μl was 12 days and 9 days, respectively. The median follow-up was 6.38 years (range 5.11–7.23) for surviving patients. There were no transplant-related deaths and toxicity was moderate. Using the Kaplan-Meier method, the 2- and 5-year survival rates after high-dose therapy were 42% and 32% respectively. Median time to relapse was 0.7 years (range 0.2–4.6). The mean survival was 36.8 months. This outcome compared favourably to a group of 77 patients who did not receive high-dose therapy but responded to conventional chemotherapy (mean survival 11.4 months). Using the Cox regression model, among all patients response to induction, normal LDH and PBSCT were associated with favourable outcome. Conclusions: Our findings suggest that patients with or near complete response after conventional therapy might benefit from tandem high-dose therapy with PBSCT with tolerable toxicicity.

No significant financial relationships to disclose.