bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of weekly docetaxel and carboplatin in patients with recurrent squamous carcinoma of the cervix after chemoradiation
Authors: Miller B. E. , Tait D. L.
Published: March 2020

15023

Background: Treatment for recurrent cervical cancer is palliative; therefore a low side effect profile is important. The combination of docetaxel and carboplatin has been used for the initial treatment of cervical cancer with success. We assessed the tolerance of a weekly schedule in patients with recurrent cervical cancer after chemoradiation. Methods: Patients with advanced recurrent squamous carcinoma of the cervix with a performance status of 2 or better were enlisted in a phase I study evaluating carboplatin at an AUC of 2 and docetaxel at the following dose levels: L1, 25 mg/m2; L2, 30 mg/m2; L3, 35 mg/m2; and L4, 40 mg/m2 i.v. for 3 consecutive weeks of a 4 week cycle. Results: So far 9 patients have been completely evaluated. The median age is 55 years. The median time to recurrence is 13 months. Previous treatment included chemoradiation and in 2 patients additional platinum based chemotherapy. Areas of metastasis included the lung, lymphnodes, abdomen, liver and the pelvis. Dose levels 1 to 3 are completed. A total of 34 courses were administered, an average of 3.6 per patient. One patient received 8 courses. Treatment was discontinued due to progressive disease in 7 patients and due to toxicity in 2 patients one with grade 3 onycholysis and another with a grade 3 allergic reaction to carboplatin. There were no treatment delays due to hematologic toxicity, no grade 2 or higher granulocytopenia, no thrombocytopenia. The mean hemoglobin level dropped from 12 g/dl prior to course 1 to 10.6 g/dl prior to course 3 and 10.2 g/dl prior to course 5. No grade 3 anemia was seen. The main non-hematologic side effects were fatigue, nausea and alopecia, none of which reached grade 3. Accrual on the L4 cohort is still ongoing. Conclusions: The combination of docetaxel and carboplatin given on a weekly schedule is well tolerated in patients with recurrent cervical cancer after chemoradiation. Dose levels similar to those reported for initial treatment can be reached.

[Table: see text]
Improvement in neurocognitive function (NCF) correlates with tumor regression after whole brain radiation therapy (WBRT) for brain metastases (BM)
Authors: Li J. , Bentzen S. M. , Renschler M. , Mehta M. P.
Published: March 2020

1504

Background: Few prospective trials have explored the neurocognitive impact of WBRT in BM patients (pts), complicated by competing effects between benefit from WBRT and deterioration due to disease progression. Methods: 208 pts from the WBRT alone arm (30 Gy) of a phase III trial (PCYC-9801) evaluating motexafin gadolinium in BM were analyzed. NCF was assessed by 8 tests of memory, executive function and fine motor coordination, and correlated to BM volume change by MRI, using Spearman’s rank correlation. Pts with tumor shrinkage below and above the median (45%) were compared for survival and NCF deterioration using Kaplan-Meier analysis. Results: 135 pts (65%) were evaluable for BM volume at baseline and 2 months (mo). Pts were divided into “good” and “poor” responders based on % volume reduction at 2 mo above or below the population median of 45%. The uni-directional hypothesis of improved survival in good responders was significant (P = 0.03, median survival (MS) 300±26 days (d) vs 240±19 d). For all 8 tests, the median time to NCF deterioration was longer in good responders than in poor responders. Largest gains were for an executive function test Trailmaking B (131 d gain, P=0.02), fine motor tests Pegboard non-dominant hand (110 d gain, P=0.05) and Pegboard dominant hand (93 d gain, P=0.02). In 15 mo survivors, statistically significant correlation between tumor shrinkage and NCF preservation was seen for 4/8 NCF tests (r = 0.68–0.88), especially for executive function and fine motor coordination. At early follow-up, the population mean NCF scores were dominated by pts with progressive disease, as reflected by a sharp drop in the mean NCF scores at 4 mo. 15-mo survivors had stable or improving scores, associated with greater reduction in BM volume in the 15 versus 4 mo survivors. Conclusions: WBRT-induced tumor shrinkage correlates with better survival and NCF preservation. NCF is stable or improved in long-term BM survivors. The adverse impact of tumor growth on neurocognitive function appears greater than that of WBRT.

[Table: see text]
Three-day regimen of fluorouracil and cisplatin combination chemotherapy for persistence, metastatic or recurrent uterine cervical cancer
Authors: Lee. M. , Yi H. , Song E. , Im M. , Im J. , Lee B. , Kim C.
Published: March 2020

15049

Background: The five-day infusion of FP(5-fluorouracil, cisplatin) combination therapy is one of the most popular regimens for advanced cervical cancer, which has yield a 50∼60% response rate. There is some variance in the FP combination, for example, longer infusion of FP requiring longer hospitalization as well as causing more discomfort to the patients. This study was designed to assess the therapeutic effect and toxicities of three day regimen of FP combination chemotherapy instead of five day regimen for disseminated or recurrent cervical cancer. Methods: From July 1996 through April 2001, 39 patients with advanced or recurrent cervical cancer were enrolled in the study. The regimen consisted of continuous 12-hour infusion of 5-FU(5-fluorouracil) at 1000 mg/m2/day plus bolus infusion of cisplatin at 25mg/m2/day for 3 days. The treatment was repeated every 3 weeks. Results: Thirty five patients with a median age of 53 years were evaluable for response during the median follow up of 21.5 months. The response rate was 45.7% (4 CR and 12 PR), and the median duration of the overall survival was 45 months. Toxicity was acceptable with no treatment related mortality. Neutropenia in grade 3 or more was seen in 16% with 4 febrile episodes throughout a total 232 cycles. It did not appear alopecia and gastointestinal trouble in grade 3 or more. Conclusions: These results revealed that the toxicity of 3 day regimen of 5-FU and cisplatin is acceptable and the efficacy comparable to that of 5 day regimen.

No significant financial relationships to disclose.
A retrospective review of metastatic or recurrent uterine sarcomas treated with ifosfamide and doxorubicin (IMA)
Authors: Guler N. , Hizli D. , Sarici S. , Ocalan R. , Kose M. , Aksoy S.
Published: March 2020

15053

Background: The prognosis of metastatic uterine sarcoma is poor with median survival reported between 4 to 26 months. We evaluated the efficacy and toxicity of ifosfamide (I) mesna (M) and doxorubicin (A) (IMA) chemotherapy regimen retrospectively in patients (pts) with metastatic, or recurrent uterine sarcomas. Methods: Eligible patients had measurable recurrent or metastatic disease, ECOG PS < 2, had adequate renal, hepatic and hematologic functions. The IMA regimen was ifosfamide 2500 mg/m2 days 1–3, mesna 2500 mg/m2 days 1–3, doxorubicin 60 mg/m2 day 1, repeated every 21 days. Patients were evaluated for response for each two cycles. Results: Thirty-five pts (17 leiomyosarcoma [LMS], 6 malignant mixed mesodermal tumor [MMMT], 5 endometrial stromal sarcoma, 4 carcinosarcoma, and 3 adenosarcoma) were enrolled in this study. The median age was 49 yrs (range, 18–72). Two pts were lost to follow up after the first cycle; one patient had ifosfamide encephalopathy on the third day of the first cycle. Thirty-two pts were assessable for response, toxicity, and survival. Nine pts had prior chemotherapy and 4 pts had radiotherapy. Most frequent metastatic sites were peritoneum, lung and liver. Median period of time from the diagnosis to starting IMA regimen was 14.5 months. A total of 132 cycles of chemotherapy were introduced and for each patient median number of chemotherapy cycles were 4 (range, 1–6). We observed CR in 2 pts; PR in 15 pts. Objective RR was % 48.6 (95% CI, 32% to 67%). Of 17 pts with LMS, 1 CR and 6 PRs were observed. The median progression-free survival time of the responders was 12.0 months. The median progression-free survival time of all patients was 7.0 months. NCI-CTC grade 3 or 4 leucopenia, neutropenia, thrombocytopenia, and anemia occurred in 40%, 55%, 12%, and 13%, respectively. There was no significant nausea/vomiting, nephrotoxicity. Febrile neutropenia was encountered in 6 pts. Dose modifications were required in 4 pts due to myelotoxicity. CNS toxicity was observed in one pts. Conclusions: IMA regimen has moderate anti-tumor activity (48.6%) with acceptable toxicity in pts with recurrent or metastatic uterine sarcomas.

No significant financial relationships to disclose.
Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas
Authors: Vredenburgh J. J. , Desjardins A. , Herndon J. E. , Quinn J. , Rich J. , Sathornsumetee S. , Friedman H. S. , Reardon D. , Gururangan S. , Friedman A.
Published: March 2020

1506

Background: The prognosis for recurrent malignant gliomas is poor, with a median survival <12 months, median progression-free survival <12 weeks and response rates <20%. Malignant gliomas have high concentrations of VEGF receptors, and the higher the VEGF receptor concentration, the worse the prognosis. Bevacizumab is a humanized IgG1 monoclonal antiblody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor, and has modest activity against recurrent malignant gliomas. Methods: We report a FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. 32 patients were enrolled, 23 with grade IV tumors (glioblastoma multiforme) and 9 with grade III tumors (anaplastic astrocytomas or oligodendrogliomas). All the patients had progressive disease and every patient had received prior radiation therapy and chemotherapy. Patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 for patients not taking enzyme inducing anti-epileptic drugs or 340 mg/m2 for patients taking enzyme inducing anti-epileptic drugs. Results: The regimen was well tolerated with no CNS hemorrhages or >grade 1 systemic hemorrhages. Four patients were taken off study for thrombotic complications, 2 pulmonary emboli, 1 deep venous thrombus, and one thrombotic stroke. Two patients were discontinued secondary to grade 2 proteinuria and three were discontinued because they required non-neurosurgical surgery, appendectomy, repair of anal fissures and hip stabilization. The response rate was 63% (19 PRs and 1 CR). The median progression-free survival is 24 weeks. The median overall survival has not been reached, and exceeds 6 months. There have been ten deaths due to disease progression. Conclusions: The combination of bevacizumab and irinotecan is safe and one of the most active regimens against malignant gliomas.

[Table: see text]
Cisplatin etoposide in heavily pretreated relapsed ovarian cancer
Authors: Basu D.
Published: March 2020

15061

Background: Ovarian Cancer is chemo sensitive but recurrence rate is high and patients who are platinum refractory have a poor outcome. Methods: 14 patients with histologically confirmed epithelial ovarian cancer that had relapsed after 3rd line chemotherapy (with platinum combination). Chemotherapy protocol - Cisplatin IVI 50 mg/m2 days 1,8 & 15, Etoposide PO 50 mg Days 1–15; Regime Cisplatin/oral Etoposide repeat 28 days total cycles 2, then oral Etoposide if appropriate. Toxicity Profile: Haematological - neutropenia WHO grade 3 in 20% requiring dose reduction, 64% experienced at least one haematological toxicity; Neutropenic sepsis in 14% of patients but no fatalities. Non-haematological: was mild; Nausea & vomiting - Grade I - II, 86%; Neurotoxicity - Grade I - II, 26%; Nephrotoxicity - Grade I - II, 18%; Fatigue - common, 70%. Results: CA 125 response in 82%; Clinical response with symptom control in 86%; Progression free survival median 6.1 months; Duration of response: 3 months to 18 months (median of 9 months); Stable disease in 7 patients, partial response in 4, complete response occurred in no patients, progression of disease in 2 patients; one patient unable to complete treatment. Conclusion: Chemotherapy for relapsed and heavily pre-treated ovarian cancer is essentially palliative. Symptomatic platinum sensitive patients have a favourable response to rechallenge. Cisplatin-etoposide has considerable activity with tolerable toxicity profile even in platinum refractory patients. Complete information about chances of response and adverse effects should be discussed with all relapsed patients.

No significant financial relationships to disclose.
Cyclin B1, D1 overexpression and its correlation with clinical prognostic factors in ovarian carcinoma
Authors: Kim J. W. , Kim Y. T. , Kim H. Y. , Kang M. H. , Kim J. H. , Kim S. H. , Kim S. W. , Yoon B. S.
Published: March 2020

15067

Background: The change of cell cycle is one of the characteristics of cancer. The various proteins related to the cell cycle have been revealed and their expression in ovarian carcinoma has been demonstrated. Therefore, this study was conducted to determine the expression of cyclin B1, D1 and evaluate the relationship between cyclin B1, D1 and clinical prognostic factors in patients with ovarian carcinoma. Methods: 41 fresh ovarian tissue samples including 36 ovarian carcinomas and 5 normal ovarian tissues were surgically obtained at YUMC from May 2002 to February 2005. Cyclin B1, D1 expression were detected using the quantitative real-time RT-PCR and Western blot analysis. For clinical prognostic factors, age, stage, grade, histopathology, LN metastasis, residual tumor size, CA 125 and DNA flow cytometry were evaluated. Results: By quantitative real time RT-PCR, the mean 2−ΔΔCT value of cyclin B1 and D1 mRNA in ovarian carcinoma was 5.83 ± 12.03, 17.60 ± 22.20, slightly higher than that of the control. (p = 0.67, 0.07). The mean value of relative protein levels of cyclin B1 and D1 in Western blot analysis was also higher in ovarian carcinoma (1.30 ± 0.73, 1.81 ± 1.28, respectively) (p = 0.76, 0.06). No significant relationship of cyclin B1, D1 expression and clinical prognostic factors was observed. Conclusions: The expression of cyclin B1, D1 in ovarian carcinoma was higher than that of the control, although there was no statistical significance. This suggests that cyclin B1, D1 might be involved in the tumorigenesis and the progression of malignancy. Even though there was no significant correlation between cyclin expression and prognostic factors, further studies are needed assessing the relationship between cyclin expression and survival rate to elucidate the role of cyclin as a prognostic factor in ovarian carcinoma.

No significant financial relationships to disclose.
Phase II study of extended schedule temozolomide in refractory gliomas
Authors: Berrocal A. , Perez-Segura P. , Gil M. , Balaña C. , Yaya-Tur R. , Yaya-Tur R. , Rodriguez J. , Reynes G. , Garcia-Lopez J. , Gallego O.
Published: March 2020

1516

Background: Temozolomide resistance is mainly mediated by the enzyme AGT that repair DNA damage in a suicide way. Inhibition of this enzyme is greater when temozolomide is administered in a extended schedule that also obtains higher exposure to the drug. Methods: Primary objective is to assess is extended schedule temozolomide can revert resistance. Patients with bidimensionally measurable high grade glioma refractory to temozolomide defined as either progression during treatment or in the following tree months of drug withdrawal were included. Temozolomide was administered at a dose of 85 mg/m2 daily for 21 consecutive days every 28 days until unacceptable toxicity or progression. Results: Up to now we have included 41 patients, 29 of them available for the first analysis. Mean age is 51.3 (23–77), male 22 (76%), ECOG 0/1/2 7 (24%)/13 (45%)/9 (31%), histology is glioblastoma 18 (61%), anaplastic astrocytoma 9 (31%), anaplastic oligodendroglioma 1 (3.4%) other high grade glioma 1. Fourteen patients received more than one line of chemotherapy before study entrance. 65% were on anticonvulsant therapy mainly with phenytoin 56% or valproic acid 42%. Response to treatment was partial in 2 (6.7%), stable in 9 (31%) progression in 13% (45%) and not assessed in 5. Response only in assessable patients was PR/SD/P 2 (8.3%)/9 (37.5%)/13 (54%). Responses were seen in oligodendroglioma and anaplastic astrocytoma. Median survival has been 5.9 months and time to progression 2 months. 80 courses have been administered with a mean per patient of 2 (1–7). Toxicity has been very mild mainly haematological and grade I and II. 7% of the patients experienced platelet toxicity grade III and 3.5% neutropenia grade III. Non haematological toxicity was mainly transaminase elevation grade I to II in 24% of patients and nausea and vomiting grade I to II in 31%. Conclusions: Extended schedule temozolomide is an active regimen in resistant patients with moderate toxicity. Resistance to temozolomide may be reverted by extended schedule of administration

[Table: see text]
Interaction between route of intra-CSF chemotherapy administration and efficacy of therapy in patients wtih neoplastic meningitis
Authors: Glantz M. J. , Chamberlain M. C. , Batchelor T. , Eric W. , Cavalli F. , Shapiro W. R.
Published: March 2020

1530

Background: NM is a devastating complication of solid tumor and hematologic malignancies. Although controversial, the current standard of care for patients with this disease includes intra-CSF chemotherapy. The importance of route of chemotherapy administration, however, remains controversial. Methods: 124 patients with NM from solid tumors (100 patients) or lymphoma (24 patients) were randomized to receive either sustained-release cytarabine—the study arm; or conventional intra-CSF chemotherapy (methotrexate for solid tumor patients; non-sustained-release cytarabine for lymphoma patients)—the control arm. The route of administration (lumbar vs. ventricular) was not specified. Results: Patients in the study and control arms were well-balanced for factors of known prognostic importance, including age, KPS, and extent of systemic tumor. Progression-free survival was identical between the study and control treatment arms for all patients (35 vs. 43 days, p = 0.73), for solid tumor patients alone (35 vs. 37.5 days, p = 0.79), and for lymphoma patients alone (34 vs. 50 days, p = 0.82). When outcome was examined in solid tumor patients as a function of route of chemotherapy administration, there was no difference in progression-free survival for patients treated with DepoCyt by the ventricular vs. lumbar routes (29 vs. 43 days, p = 0.35). For patients treated with methotrexate, there was a statistically significant difference favoring patients receiving intraventricular therapy (43 vs. 19 days, p = 0.048). Conclusions: Both the pharmacokinetic profile of the intra-CSF chemotherapeutic agent and the site of administration influence the outcome of patients treated for NM. Intraventricular administration, or the use of sustained-release chemotherapeutic agents if the lumbar route is used, appears to be critical to the success of treatment. The implications of this finding may also extend to patients (e.g. those with acute leukemias, high-risk NHL, or her2/neu-positive breast cancer) receiving prophylactic intra-CSF chemotherapy since, in the prophylactic setting, intra-lumbar chemotherapy administration is almost always employed.

[Table: see text]
Calculated versus measured creatinine clearance for the dosing of methotrexate in patients with primary CNS lymphoma
Authors: Gerber D. E. , Ye X. , Grossman S. A. , Batchelor T.
Published: March 2020

1536

Background: High-dose methotrexate (HDMTX) (8g/m2), the cornerstone of therapy for primary central nervous system lymphoma (PCNSL), is commonly dosed using a measured 24-hour creatinine clearance (CrCl) every 2–4 weeks. Because these collections are cumbersome, costly, and at times unreliable, the use of a calculated CrCl was evaluated. Methods: A retrospective analysis was performed on data from all 25 patients (287 treatments) with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Results: The 25 patients had a median age of 61 years (range 32–75 years). Seventeen patients (68%) were men. The patients received a median of 14 (range 2–21) HDMTX treatments. For 256 of 287 total treatments (89%), data were available to compare the measured and calculated (using the Cockcroft-Gault equation) CrCl. The average measured CrCl was 93±29 ml/min, and the average calculated CrCl was 107±43 ml/min. The correlation coefficient (r) was 0.66 (p<0.001) between the measured and calculated CrCl. Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48-hour serum MTX levels documented. Forty-eight levels (30%) were in the ideal range (0.3–1 μmol/L), 98 levels (62%) were lower (<0.3 μmol/L), 12 levels (8%) were higher (>1–3 μmol/L), and no levels were in the range associated with significant toxicity (>3 μmol/L). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 46 treatments (29%), a higher MTX dose for 62 treatments (39%), and a lower MTX dose for 50 treatments (32%). This distribution was not significantly different among the subsets of low, ideal, and high MTX levels (p=0.13). Conclusions: In this cohort of patients with PCNSL, there is a high correlation between the calculated and measured CrCl. For these patients, there is not a clear association between the method of determining CrCl and serum MTX levels. Therefore, the administered MTX doses using either method are likely to be similar. In this patient population, a calculated CrCl could be used to avoid the cost and inconvenience associated with measured CrCl.

No significant financial relationships to disclose.
Phase II study of capecitabine (X) plus reirradiation in patients (pts) with recurrent squamous cell carcinoma of the head and neck (SCCHN)
Authors: Kornek G. , Vormittag L. , Burian M. , Radonjic D. , Selzer E.
Published: March 2020

15504

Background: X has shown substantial activity in SCCHN [Pivot et al. 2004] and is replacing 5-FU as the backbone of chemotherapy in a wide range of solid tumors, particularly colorectal cancer. In addition, X has a unique survival benefit in breast cancer. There is substantial data to support using X in chemoradiation [Dunst et al. 2004]. We evaluated the therapeutic impact and safety profile of X plus reirradiation in SCCHN. Methods: Pts with locally advanced unresectable SCCHN who had prior radiotherapy (RT, with or without chemotherapy) received X 450 mg/m2 twice daily, 7 days a week. RT was delivered as a standard fractionated regimen (2 Gy/day, 5 fractions/week) up to a total dose of 50–70 Gy. The cumulative (life-time) dose within overlapping fields was not to exceed 120–130 Gy. Results: Currently, 20 male pts have completed treatment. Baseline characteristics were: median age 57 (42–72), ECOG PS 0/1 5/15. Six pts had previous chemoradiation followed by radical resection; 4 had surgery and postoperative RT; 10 had concomitant chemoradiation (accelerated and hyperfractionated). Twelve pts experienced locoregional recurrences, 4 developed secondary primaries, and 4 had a regional lymph node relapse. The median time since prior radiation therapy was 16 (8–244) months. Efficacy (as evaluated by WHO criteria): 7 pts (35%) had a complete (2) or partial (5) response; stable disease was observed in 11 pts, and tumor progression immediately after therapy was observed in 2 pts. Median duration of local control and median survival will be presented at the meeting. The most frequently observed toxicity was mucositis, which was grade 3 in only 2 pts; grade 1 or 2 skin reaction was seen in 9 pts. There was no evidence of systemic toxicity or myelosuppression, probably due to the very low dose of X. RT was completed without delay in all pts, and X was interrupted prematurely in 2 pts due to grade 3 mucositis. Conclusions: Our preliminary data suggest that X chemoradiation is a well-tolerated and effective treatment modality for previously irradiated pts with SCCHN. Based on available data, a higher dose of X should be feasible and potentially more effective. Earlier use of X in SCCHN could also be evaluated.

[Table: see text]
A trial of gemcitabine (gems) in combination with cisplatin for treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)
Authors: Yang M. , Wang H. , Wang W. , Chiou T. , Chen P.
Published: March 2020

15505

Aims: To determine the efficacy of gemcitabine in combination with cisplatin, and to assess the safety profile of the regimen as the first-line treatment in patients with recurrent/metastatic HNSCC. Methods: An open-label, non-comparative, multi-center phase II study for patients with histologically proven recurrent/metastatic HNSCC without prior treatment for their recurrent/metastatic disease. In this trial, 1250 mg/m2 gemcitabine was administered alone on day 1 and day 8 and 80 mg/m2 cisplatin would follow gemcitabine on day 8, to be repeated in cycles of 21 days until disease progression, intolerable toxicity, or consent withdrawal. Results: Between 04/2004 and 09/2005, 34 patients were enrolled in this study. 33 patients have completed the study treatment. Characteristics of the 33 patients: male- 33; median age- 51 years (range 38–65); 30 pts had a performance status (PS) of 0 or 1 and 3 had a PS of 2 (ECOG scale); histology: recurrent/metastatic HNSCC in all cases. Of the 33 patients, 25 were evaluable for response assessment. Partial response was observed in 8, stable disease in 10, and progressive disease in 7 patients. Overall response rate was 32% (95% Confidence interval 12%–52%). Grade 3/4 hematological toxicities included neutropenia in 12 pts, leukopenia in 11 pts, thrombocytopenia in 2 pts and anemia in 8 pts. Grade 3/4 nausea or vomiting was observed in 2 pts. Other toxicity was mild in the treatment. Patient treatment and follow-up are still ongoing. Conclusion: This study, with an overall response rate of 32% and a rate of stable disease of 40%, has shown a good activity with mild and acceptable toxicities of gemcitabine/cisplatin regimen in patients with recurrent/metastatic HNSCC. Survival and response analyses will be presented at the meeting.

No significant financial relationships to disclose.
AlteRCC phase I-II trial: Alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (HNC)
Authors: Merlano M. C. , Numico G. , Colantonio I. , Garrone O. , Gasco M. , Russi E. , Vigna Taglianti R. , Granetto C. , Di Costanzo G.
Published: March 2020

15515

Background: Pfister (ASCO 2003) added Cetuximab (C) to CT/RT to evaluate toxicity and activity of this combination in advanced HNC. The trial was early stopped due to an excess of toxicity including on treatment deaths. However, the treated pts achieved an excellent long term. Results: 76% of them were alive and disease free at 24 months. Therefore, a new, less toxic scheduling of CT/RT and C is highly attractive. Alternating CT/RT (ACR) may be less toxic than concurrent CT/RT (Haffty 2000; Merlano 2003). Therefore we designed a phase I-II trial, scheduling finding, combining ACR and C. Methods: The ACR regimen consists of cisplatin 20 mg/m2 and 5FU 200 mg/m2 days 1 to 5, weeks 1, 4 and 7; and RT, 2 Gy/day, days 1 to 5, weeks 2–3, 5–6, 8–10 to a total dose of 66 Gy. ACR remains unchanged during both phase I and phase II part of the study, whereas C is given to the first 6 pts (phase I, step I) weekly only in the weeks when RT is delivered. If no limiting toxicity is observed, C is combined also with CT, in a second group of six pts (phase I step II). If again no limiting toxicity is recorded, the trial will be continued as a phase II study (optimal two-stage design, 21+24 pts, Simon 1989). Results: At the time of the present report, the phase I step I is completed and 3 pts in phase I step II are on-going. All the pts had HNC stage IVa (8 pts) or stage III (1 pt). Two pts had disease recurrence after prior surgery, while the others had previously untreated cancers. All the tumors over-expressed EGFr (+++), but the percentage of cells expressing EGFr ranges between 10 to 100% (median 70%), One episode of neutropenic fever occurred in one pt enrolled in phase I step II. All the pts developed chemoradiation expected toxicities, including stomatitis and dysphagia requiring TPN. The only unexpected toxicity was a moist desquamation occurring within the irradiated field which was observed in all but one pts at a cumulative RT dose of 50–66 Gy. This toxicity did not interfere with ACR treatment but C was stopped until recovery. Recovery occurred in 5–7 days. Four pts out of the 6 evaluable for response, reached a complete response; the two remaining achieved a PR. One of them underwent surgical removal of a residual nodal mass without complications. Conclusions: The update of the AlteRCC trial will be presented.

[Table: see text]
The cytotoxicity of combined paricalcitol, docetaxel and radiation in head and neck squamous cell carcinoma
Authors: Huang T. W. , Northrup S.
Published: March 2020

15526

Background: Paricalcitol is a calcitriol analog used in the treatment of secondary hyperparathyroidism. It produces less hypercalcemia compared to calcitriol and has low clinical toxicity. We have shown previously that paricalcitol is antiproliferative in head and neck squamous cell carcinomas (HNSCC) in vitro. However, its interaction in combination with docetaxel and radiation has not been elucidated. The purpose of this study is to evaluate the combined effects of paricalcitol, docetaxel, and radiation in vitro in SCC-15 cells, a human tongue squamous cell carcinoma cell line. Methods: The cytotoxic effects were assessed using MTT assays. SCC 15 cells were plated, allowed to attach for 24 hours, and then treated with paricalcitol at 0, 12.5, 25, or 50 nM. After 24 hours, docetaxel at 0, 0.05, 0.15, or 0.3 nM was applied, followed in 24 hours by single treatment with radiation at 0, 2, 4, or 6 Gy. MTT assays were performed after incubation for 5 days. CalcuSyn analysis was used to determine if the interaction between paricalcitol, docetaxel, and radiation is synergistic, additive, or antagonistic. Results: Paricalcitol alone at 12.5, 24, and 50 nM produced growth inhibition of 30, 38, and 40%, respectively. Docetaxel alone at 0.05, 0.15, and 0.3 nM resulted in 33, 61, and 72% growth inhibition, respectively. Radiation at 2, 4, and 6 Gy produced 44, 57, and 62% inhibition, respectively. Sequential paricalcitol and docetaxel at the concentrations tested followed by 2 Gy radiation produced additive to synergistic cytotoxicity. Antagonism was seen with 4 Gy and all combinations of paricalcitol and docetaxel. Antagonism was also seen with 6 Gy and 0.15 or 0.3 nM of docetaxel. Conclusions: Sequential application of paricalcitol, docetaxel, and then radiation at moderate doses produced additive to synergistic cytotoxicity in SCC-15 cells. The results of this study provide support for further investigations of combined paricalcitol, docetaxel and radiation therapy in the treatment of head and neck cancers.

[Table: see text]
Weekly methotrexate in squamous cell cancers of head and neck
Authors: Pathak A. B. , Kulkarni H.
Published: March 2020

15539

Background: The aim was to evaluate response rates and toxicity of weekly methotrexate in locally advanced or recurrent squamous cell cancers of the head and neck region. Methotrexate, oldest non-platinum drugs active in squamous cell cancer of head and neck, was selected for its cost-effectiveness and ease of administration. Methods: Patients with locally advanced, inoperable or recurrent squamous cancers were selected. Sites included anterior two-third tongue, buccal mucosa, alveolus, base tongue, larynx and maxilla. Methotrexate 1 mg/Kg was given intramuscularly on outpatient basis once a week for 6 to 8 weeks along with hydration. Patients who responded well and became resectable were encouraged to undergo surgery. All patients were followed up in the clinic every monthly. Results: Total 19 patients were entered on the study over a duration of 24 months. 12 out of 19 patients had partial response (63%), 5 had stable disease (26%) and 2 patients had disease progression. Symptomatic relief ranged from 25% to 100%. Maximum response duration was 12 weeks. Treatment naïve patients had rapid response. In 5 patients disease became clearly resectable. Toxicity was grade II-III oral mucositis in patients with previous radiation. Sample size is small for a subset analysis. Conclusions: Weekly methotrexate is a simple, cost-effective regimen for palliation in advanced recurrent squamous cell cancers of head and neck region. It should also be evaluated further in large scale trials and especially in neo-adjuvant setting in locally advanced squamous cell cancers of the head and neck region given its rapidity of response and brief duration of therapy.

No significant financial relationships to disclose.
Induction chemotherapy with gemcitabine and cisplatin in paranasal sinus tumours
Authors: Hussain R. , Jamshed A. , Bilal M. , Shehzad K. , Azhar R. , Shah M. A. , Hameed S. , Arif M. , Faruqui Z.
Published: March 2020

15542

Background: There is no standard treatment for locally advanced carcinoma of paranasal sinuses. Induction chemotherapy is frequently used to down stage the disease. Surgery, radiotherapy and chemoradiation are all in use to treat the primary following neoadjuvant chemotherapy treatment. Cisplatin and gemcitabine are active agents in head and neck cancers. We evaluated the response of induction chemotherapy with cisplatin and gemcitabine in carcinoma of the paranasal sinuses. Methods: Between August 2005–November 2005, 5 patients with locally advanced carcinoma paranasal sinuses received induction chemotherapy at Shaukat Khanum Cancer Hospital and Research Centre. There were three males and two females, 19 to 65 (median 45) years of age. Three patients had maxillary and 2 patients had ethmoid sinus tumors. Four patients had Stage IVa and 1 patient had Stage IVb disease. All patients had biopsy proven carcinoma. Histologically the tumour was adenocarcinoma in 1 patient and squamous cell carcinoma in 4 patients. Four patients received 2 cycles and 1 patient received 1 cycle of cisplatin 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 day 1 and 8 (repeat day 22) before radical treatment. Response was assessed in all patients with pre and post induction chemotherapy with CT or MRI scan. Results: Overall response rate was 60%. Complete response was seen in one patient and over 50% tumor regression in 2 patients. Disease remained unchanged (no response) in 1 patient. One patient progressed following one cycle and did not receive the second cycle of chemotherapy treatment. The treatment was well tolerated and no grade III or IV toxicity was seen. Conclusions: The combination of gemcitabine and cisplatin in this schedule has low toxicity and significant activity in patients with locally advanced paranasal sinus tumors and is worthy of further study.

No significant financial relationships to disclose.
High dose rate brachytherapy with surface applicators: Treatment for nonmelanomatous skin cancer
Authors: Musmacher J. , Ghaly M. , Satchwill K.
Published: March 2020

15543

Background: To assess the use of HDR surface applicators as an alternative radiotherapy modality to external radiation (electrons or low-energy x-rays) for the treatment of skin lesions of the head and neck. Skin carcinomas require efficient and accurate delivery of HDR Brachytherapy, which can be precisely reproduced on an outpatient basis. Methods: Patients were treated to various sites, which included lesions of the face and scalp. Thermoplastic casts were fitted with Leipzig Surface Applicators and custom molded to the patient to treat squamous or basal cell carcinomas ≤ 2 cm in diameter. A custom surface mold applicator (Freiburg Flap) was used for lesions up to 4 cm. Planning target volume included the tumor plus a 5 mm margin. Biweekly photographs of the treatment volume were taken for documentation and monitoring of radiation reactions. Treatment was delivered by HDR Brachytherapy (Ir-192), 5 Gy per fraction, twice per week for four weeks to a 5 mm depth. TLD’s were placed at the center of the treated volume under the applicator and at critical structures (i.e. lateral canthus of the ipsilateral eye, auditory canal or gingivolabial sulcus) twice during the course of treatment. Results: Patients’ setup and reproducibility were accurate and treatment time was short which added great convenience for the patients. With the HDR surface applicators, dose distribution was uniform in the surface of the skin and at 5 mm depth in the whole area of the applicator. Differences between the areas of maximum and minimum dose at this depth did not reach values higher than 5% of the prescribed dose. At the edges of the applicators, the dose gradient was sharp, with the detected dose at 5 mm from the applicator being negligible. An exudative radiation reaction was noted in some patients, which reversed with appropriate therapy. Conclusion: High Dose Rate Brachytherapy offers a highly effective treatment of skin carcinomas. Surface applicators, used in conjunction with HDR brachytherapy equipment, make a uniform dose distribution and sharp dose gradient at the edge of the treatment field. Surface applicators are easy and safe to use, and they fit very accurately for each fraction. These applicators have the ability to become the standard treatment for skin carcinomas in the near future.

No significant financial relationships to disclose.
A phase I trial of intratumoral (i.t.) administration of reovirus in patients with histologically confirmed recurrent malignant gliomas (MGs)
Authors: Forsyth P. A. , Roldan G. , George D. , Wallace C. , Morris D. G. , Cairncross J. , Vallee Matthews M. , Coffey M. , Thompson B. , Hamilton M.
Published: March 2020

1563

Background: Reovirus is an oncolytic virus which replicates preferentially in transformed cells possessing activated Ras signaling pathways. Promising activity was found in in vivo models of MGs and in a phase I trial in patients (pts.) with cutaneous metastases from systemic cancer. We performed this dose-escalation trial of i.t. administration of reovirus to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in pts. with recurrent MG. Response, survival and time to progression (TTP) were secondary aims. Methods: Pts. were ≥ 18 yrs old, had a KPS ≥ 60, received prior radiotherapy ± chemotherapy, a histologically proven recurrence of MG and recurred ≤ 3 times. Reovirus was administered i.t. stereotactically at one of three dose levels (1 × 107, 1 × 108 or 1 × 109 TCID50) in a volume of 0.9 mls. Results: Twelve pts. were treated at 3 dose levels; seven were men, the median (mdn) KPS was 80, mdn age was 53.5 yrs, 10 had glioblastoma multiforme, one anaplastic astrocytoma and another anaplastic oligoastrocytoma. There were the 1st, 2nd or 3rd recurrences in 6, 5 and 1 pts., respectively. During i.t. viral administration all pts. were treated with prophylactic anticonvulsants and 6 (50%) were receiving corticosteroids. The 1st, 2nd and 3rd cohorts contained 3, 6 and 3 pts., respectively. There were no grade 3 or 4 adverse events definitely or probably related to the administration of reovirus. A transient increase in GGT was possibly related to reovirus administration and a patient experienced grade 3 motor weakness that could be related to post-injection edema. Viral shedding and systemic immune responses were examined but results are pending. There were no CR, or PR; a pt. had SD, 10 PD and one was not evaluable. The mdn survival was 20 weeks (range, 6–171), 6 pts. survived > 6 months and 3 are alive 6, 7 and 40 months from the reovirus injection. The mdn TTP was 4.3 weeks (range: 3.4–39). Conclusions: A MTD was not reached. The intratumoral administration or reovirus was well tolerated in patients with recurrent MGs. Phase 2 studies in MGs are planned.

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Phase II study of antiangiogenic (metronomic) chemotherapy for recurrent malignant gliomas
Authors: Kesari S. , Schiff D. , Doherty L. , Gigas D. , Batchelor T. , Muzikansky A. , O’Neill A. , Drappatz J. , Kieran M. , Wen P. Y.
Published: March 2020

1569

Background: There is preclinical evidence that continuous low-dose chemotherapy may inhibit tumor endothelial proliferation and prevent tumor growth (Browder et al Cancer Res 2000;60:1878). Methods: We conducted a phase II study of continuous low-dose etoposide (VP-16), alternating with cyclophosphamide (CP), in combination with thalidomide (T) and celecoxib (C) in adult patients with recurrent malignant gliomas. There was no limit on the number of prior therapies. Patients received VP-16 [35 mg/m2 (maximum 100 mg) daily for 21 days] alternating with CP [2 mg/kg (maximum 100 mg/day) for 21 days]. Thalidomide was started at 200 mg daily and increased by 100 mg weekly to a maximum of 1200 mg/day, as tolerated. Celecoxib was started at 200 mg twice daily and increased to 400 mg twice daily. MRIs were performed every 6 weeks. Patients were treated until tumor progression or development of unacceptable toxicity. Serum was collected for measurement of angiogenic peptides. Results: 48 patients were enrolled (15 female, 33 male). 28 had glioblastomas (GBM); 20 had anaplastic gliomas (AG). Median age was 53 years (range 33–74); median KPS was 70 (range 60–100). Patients had average of 2.1 prior chemotherapies; 33% had 3 or more prior chemotherapies. Toxicities included neutropenia (8 G3, 8 G4), leukopenia (13 G3, 8 G4), lymphopenia (26 G3), anemia (1 G3), thrombocytopenia (1 G3); nausea (1 G3), vomiting (3 G3), constipation (5 G3; 2 G4), colitis (2 G4), rash (1 G3), dizziness (1 G3); hypoxia (1 G3), and infection (2 G3). 2 patients had DVT and 6 had pulmonary emboli. There were no treatment related deaths. Fatigue was common but usually mild. 12% of patients had PR, 59% had SD, 29% progressed at their first scan. For GBM patients, median progression-free survival (PFS) was 11 weeks, 6 month-PFS was 9% and median survival was 21 weeks. For AG patients, median PFS was 14 weeks; 6 month-PFS was 26% and median survival was 41.5 weeks. Correlation of angiogenic peptide levels and response will be reported. Conclusions: Although there were some responders this regimen did not significantly improve survival in this heavily pretreated group of patients. However, further studies combining metronomic chemotherapy with more potent angiogenesis inhibitors such as lenalidomide or VEGFR inhibitors may be warranted.

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Regression of pre-established intracranial tumor growth by ON 01910.Na, a selective anticancer agent currently in phase I trials
Authors: Gondi C. S. , Kandhukuri N. , Yanamandra N. , Reddy M. , Reddy E. , Rao J. S.
Published: March 2020

1576

Background: Despite considerable progress in the treatment modalities used for brain tumors (surgery, radiation therapy and chemotherapy), local recurrence continues to be an important reason for treatment failure. Since multiple regulatory pathways are defective in these tumor cells, novel approaches must tackle more than one mechanism involved in the process of neoplasia. One approach is to effectively combine anti-tumor agents with anti-angiogenic assault. Onconova has developed agents that fit this profile. ON 01910.Na, an injectable product now undergoing Phase I studies at multiple centers, is a potent inhibitor of mitotic progression. It arrests cancer cells in mitosis by depleting cells of CDC25c and efficiently induces apoptosis in the irreversibly arrested cells. Methods: Here, we have evaluated the invasiveness, angiogenesis, and tumorigenicity of glioblastoma cells in both in vitro and in vivo models after treatment with ON 01910. Results: SNB19 cells treated with ON 01910 were significantly inhibited in migration, invasion, and angiogenesis in in vitro models compared to the control group. After treatment with ON 01910, SNB19 cells showed decreased levels of MMPs, uPA, pAKT and PI3 kinase levels compared to controls. Significantly increased levels of PARP, caspase 3 and caspase 9 were also shown. In addition, there was complete regression of pre-established intracranial tumor growth and angiogenesis in in vivo models. The effect was more significant in relation to invasion, angiogenesis and tumor growth when compared to other drugs such as BCNU and Gleevec. Toxicology studies, where ON 01910 was administered systemically or directly into the brain, demonstrate the safey and tolerability of this agent in animals and ongoing Phase I studies indicate that the agent is well-tolerated at dose levels generating pharmacologically relevant concentration of the drug in circulation. Conclusions: These studies validate the potential usefulness of this compound as a novel therapeutic agent for human glioblastoma.

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Frequency of treatment changes observed in chronic myeloid leukemia (CML) patients using imatinib mesylate (IM)
Authors: Devercelli G. , Schulman K. , Song X. , Cheng S. , Davis C. C.
Published: March 2020

16003

Background: Although the response rates in CML associated with IM treatment is well-documented, little research exists on actual practice patterns with IM. The objective of this study is to document treatment changes in a large CML patient population using IM. Methods: Patients ≥ 18 years of age diagnosed with CML (ICD9 = 205.1) between 2000 and 2004 and treated with IM were selected from the Medstat MarketScan Commercial, Medicaid and Medicare Research Databases. Disease phase was defined using a CML specific disease staging algorithm and was assigned at the time of imatinib initiation. A treatment change is defined as evidence of any of the following: any dose increase ≥50 mg, CML treatment added to IM, or IM discontinuation. Summary statistics reported are medians and interquartile ranges (IQR). Results: Four hundred adult IM-treated CML patients (mean age, 56 years; 50% male) were included. 81% and 18% were in chronic phase (CP) and accelerated phase (AP), respectively; with 1% in remission. IM 400 mg was most frequently used regardless of CML phase or year of treatment. The daily starting dose was 400 mg in 305 (78%) patients, 600–799 mg in 34 (9%) patients, ≥ 800 mg in 17 (4%), and the remaining 39 (9%) started at doses < 400 mg. Median follow-up of treatment duration was 9 (IQR: 4.6, 18.9) months. 158 (40%) patients on IM had at least one treatment change, with rates higher in AP patients than in CP (52% vs. 37%). Dose increases were reported in 108 (27%) patients, 3 (<1%) had additional CML treatment, and 64 (16%) discontinued IM altogether. Conclusions: 40% of patients treated with IM had at least one treatment change. The frequency of treatment change increased with longer duration of IM treatment.

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