Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain

Summary One hundred sixteen eligible patients with metastatic cancer to the brain were randomized to receive either radiotherapy 3000 rad/ 10 fractions (treatment 1) or the same radiotherapy plus metronidazole 6 gm/m² (treatment 2). One hundred eleven patients were either fully or partially evaluable. The response rates (CR + PR) and survival showed no significant differences between treatments. Treatment 1: CR + PR 24%, median survival 14 weeks, Treatment 2: CR + PR 27%, median survival 12 weeks. There were no differences observed in response rates based on primary tumor site, neurologic performance status, or extent of metastatic disease. Metronidazole therapy was associated with substantial nausea and vomiting but no neurotoxicity was observed. Oral metronidazole given every other day during radiation therapy provided no clinical benefit for patients with brain metastases compared to radiotherapy alone. Address for reprints: Southwest Oncology Group (SWOG-7811), Operations Office, 4450 Medical Drive, San Antonio, TX 73229, USA     

Prognostic Significance of Endothelial Surface Score and MIB-1 Labeling Index in Glioblastoma

The aim of this study is to investigate the usefulness of a vascular endothelial surface score (VESS) and MIB-1 labeling index (MIB-1 LI), in a defined series of glioblastomas, as biological markers with prognostic significance of survival. Tumor tissue and survival were studied in a series of 38 patients with glioblastoma, previously treated by surgical resection and radiotherapy. For each tumor, immunohistochemical and morphornetric studies were performed in order to study MIB-1 LI, and VESS, expressed as the CD-34 immunostained endothelial surface per 1000 tumor cells. The survival for the entire patient population of the series was 48.1 ± 14.1 weeks, and the mean VESS for the tumors of the series ranged from 16.7 to 107µm² per 1000 tumor cells (mean: 38.7 ± 18.2). Factors such as age or MIB-1 LI were not significatively associated with survival, but the median survival for the 18 patients with a VESS less than 35 was 50.7 ± 3.7 weeks, versus 45.9 ± 2.8 weeks for the 20 patients showing a VESS higher than 36 (p < 0.05). Our present results suggest that tumor VESS, expressed as the CD-34 immunostained endothelial surface per each 1000 tumor cells, may have usefulness, as angiogenic-related factor influencing survival, in patients with glioblastoma.     

Feasibility study of intraarterial vs intravenous cisplatin,BCNU, and teniposide combined with systemic cisplatin,teniposide, cytosine arabinoside,glycerol and mannitol in the treatment of primary and metastatic brain tumors

Sixteen patients with intracerebral tumors received intraarterial cisplatin, teniposide, and BCNU combined with intravenous cisplatin, teniposide, and cytosine arabinoside. Oral glycerol and intravenous mannitol were given along with the intravenous chemotherapy in an attempt to increase drug delivery to tumor by augmenting tumor blood flow. Thirteen additional patients were treated with the same regimen, but received all the chemotherapy intravenously. Of the 16 patients receiving intraarterial chemotherapy (median survival, 14 weeks), none responded, 5 (31%) were stable for > 8 weeks, 8 (50%) failed, and 3 (19%) were unevaluable due to early death. Of the 13 patients receiving all their treatment intravenously (median survival, 13 weeks), 3 (23%) responded, 1 (8%) was stable, 7 (54%) failed, and 2 (15%) were unevaluable due to early death. In the patients receiving intraarterial chemotherapy, toxicity included ipsilateral retinal toxicity (2 patients), ocular pain or headache (10), periorbital swelling and flushing (6), increased brain edema with focal neurological deficits and drowsiness (5), and catheter-related carotid artery thrombosis followed by fatal herniation (1). Myelosuppression was worse in patients who received all their treatment intravenously than in those receiving intraarterial chemotherapy (p < 0.05). Neutropenic sepsis developed in 4 patients on the intraarterial arm (1 fatal) and in 5 patients on the intravenous arm (2 fatal). Other toxic effects were similar whether or not patients received intraarterial treatment or only intravenous treatment. Overall, toxicity of this regimen was excessive, and response rates were lower than would have been expected with single agent therapy.     

Multiple fraction-per-day radiotherapy for patients with brain stem tumors

Brain stem tumors are among the most resistant brain tumors to therapy. The majority progress within 18 months of diagnosis and treatment. Multiple-fraction-per-day (MFD) radiotherapy would theoretically allow higher total doses of radiotherapy to be delivered in order to improve local tumor control without increasing neurotoxicity secondary to treatment. Seventeen patients with brain stem tumors were evaluated and treated at Duke University Medical Center (DUMC) from 1985 to 1991 with a MFD regimen. Six patients were accrued to Pediatric Oncology Group (POG) Protocol 8495 and were not included in this analysis, leaving eleven patients for review. Local fields were treated with fraction sizes of 110 or 117 cGy twice daily. There were 3 patients who received a total of 60.5–68.2 Gy and 8 who received 70.2–71.5 Gy. Initial and follow-up CT and/or MRI studies were available for review on all but one patient. All patients had progression of disease and have died. Median time to tumor progression was 5.8 months. Median overall survival was 11.2 months. There was no significant influence upon time to tumor progression or survival by total radiation dose received. Patients were classified by imaging group per the criteria of Stroinket al. based on review of their pre-treatment CT or MRI scans. One patient had no initial films available, 2 were in Group II (no contrast was given to separate A or B), 3 in IIA, 4 in IIB, and 1 in III. Autopsy in 3 patients failed to demonstrate histologic evidence of injury attributable to radiotherapy. The results of this study fail to demonstrate a positive impact of MFD radiotherapy on the outcome of children with unresectable brain stem tumors.     

Breast cancer subtypes and response to systemic treatment after whole‐brain radiotherapy in patients with brain metastases

BACKGROUND:

The aim of this study was to assess the role of systemic treatment after whole‐brain radiotherapy (WBRT) in immunohistochemically defined biological subsets of breast cancer patients with brain metastases.

METHODS:

The group of 420 consecutive breast cancer patients with brain metastases treated at the same institution between the years of 2003 to 2009 was analyzed. Patients were divided into 4 immunohistochemically biological subsets, based on the levels of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors, and labeled as luminal A, luminal B, HER2, and triple‐negative. Survival from brain metastases with and without systemic treatment after WBRT was calculated in 4 subsets.

RESULTS:

In the entire group, the median survival from brain metastases in patients without and with systemic treatment after WBRT was 3 and 10 months, respectively (P < .0001). In the triple‐negative subset, the median survival from brain metastases with and without systemic treatment was 4 and 3 months (P = .16), and in the luminal A subset, it was 12 and 3 months, respectively (P = .003). In the luminal B subset, the median survival without further treatment, after chemotherapy and/or hormonal therapy, and after chemotherapy and/or hormonal therapy with targeted therapy was 2 months, 9 months, and 15 months, respectively (P < .0001). In the HER2 subset, the median survival was 4 months, 6 months, and 13 months, respectively (P < .0001). No significant response to systemic treatment was noted in the triple‐negative breast cancer population.

CONCLUSIONS:

Systemic therapy, ordered after WBRT, appears to improve survival in patients with the luminal A, luminal B, and HER2 breast cancer subtypes. Targeted therapy was found to have an additional positive impact on survival. In patients with triple‐negative breast cancer, the role of systemic treatment after WBRT appears to be less clear, and therefore this issue requires further investigation. Cancer 2010. © 2010 American Cancer Society.     

Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma

Objectives The optimal treatment for elderly patients (age >70 years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. Patients and methods Forty-three patients 70 years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS) ≥ 60 were treated with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2 weeks) followed by up to 12 cycles of adjuvant temozolomide (150–200 mg/m² for 5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. Results The median OS was 9.3 months and the median PFS was 6.3 months. The 6 and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3–4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. Conclusions Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.     

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18–93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m²/dose; 375 mg/m²/dose) for 4–6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m²/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4–10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6–10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months.     

Effect of surgical modality and hypofractionated split-course radiotherapy on local control and survival from sinonasal mucosal melanoma

Aims

To assess the efficacy of surgery and high-dose split-course radiotherapy in sinonasal head and neck mucosal melanoma (SHNMM).

Material and methods

Between 1991 and 2006, 23 patients (median age 73 years, male:female ratio 0.4) with non-metastatic SHNMM underwent surgery and postoperative radiotherapy, two had exclusive radiotherapy. Radiotherapy consisted of three series of 18 Gy (3 × 6 Gy every other day for 1 week) with 3 week planned treatment breaks. Chi-squared tests, Kaplan–Meyer method and Log-rank test were used to assess prognostic factors for survival and local control.

Results

There were 20 nasal cavity tumours; 12 of these involved more than one sinonasal site. One patient (4%) had lymphadenopathies at diagnosis. Six SHNMMs (24%) were amelanotic. The median follow-up was 39 months. Fourteen patients had en bloc surgery, 16 underwent radiation (14 postoperative, two exclusive). Eleven patients had local relapse, three had regional relapse and three had bone or liver metastases. Five year local control was 49 ± 12%. Five year overall and SHNMM-specific survival was 38 ± 12% and 62 ± 12%, respectively. Five patients were alive without disease after 5 years and three after 10 years. En bloc excision (tumour removed in one piece) was prognostic for survival.

Conclusions

En bloc surgery was a prognostic factor on outcomes for local control and survival in this series. Data from the literature have shown that postoperative radiation therapy improves local control. Most series were carried out with conventional fractionation. The effect of planned breaks (split-course radiotherapy) may be deleterious, as suggested in this series. Therefore, split-course radiotherapy cannot be recommended for SHNMM.     

Clinical trial of folinic acid to reduce vincristine neurotoxicity

Summary In a murine model system, folinic acid demonstrated host-protective properties during administration of repetitive and lethal doses of vincristine (VCR). Subsequently, folinic acid was evaluated in patients receiving VCR during an adjuvant chemotherapy program for stage II carcinoma of the breast. The toxicities, cumulative VCR dosage, and percentage of ideal dosage observed in 18 patients receiving folinic acid have been compared with those observed in 70 patients who previously received VCR without folinic acid in the same chemotherapy program. All patients ideally were intended to receive VCR 1.0 mg/m² weekly for 6 weeks, with dose modification for neurotoxicity. Treatment patients received folinic acid 800 mg PO daily in three divided doses during the 6-week course. The degree of neurotoxic manifestations of VCR was similar in the treatment and comparison patients. Absent to mild neurotoxicity was observed in approximately 70% of patients in both groups; moderate or greater neurotoxicity occurred in about 30% of patients in both groups. Full dosage (6.0 mg/m²) was attained in 7 (39%) treatment patients and 17 (24%) comparison patients (P=0.21). The mean percentage of the ideal dosage of VCR was 73.7±28.7 in patients receiving folinic acid and 76.1±20.5 in those given only VCR (P=0.69). Hematologic toxicities were similar in both groups, but nausea occurred more frequently in the folinic acid group. Folinic acid in this dose and schedule afforded no protection from the neurotoxic side effects of VCR.Supported in part by National Cancer Institute grants CA24740 and CA12197     

Phase II study of a radiotherapy/etoposide combination for patients with newly malignant gliomas

Purpose: Etoposide, a semisynthetic derivative of podophyllotoxine, is a topoisomerase II inhibitor. This drug is currently used in several types of human cancer. The aim of this study was to evaluate the efficacity and tolerance of a near-concurrent association of radiotherapy and etoposide for newly malignant gliomas. Methods: From May 1995 to December 1996, 30 malignant glioma patients were included in this phase II study; 16 patients underwent surgical tumor resection, and a stereotactic biopsy was performed in 14 patients. Standard cranial irradiation and six courses of etoposide (100 mg/m², ×days 1–3) were administered. The first course of etoposide was administered on days 1–3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. Results: Only 26 patients could be evaluated for the purpose of our study. The median age was 60.1 years, and the median Karnofsky performance score (KPS) was 80.2. The rate of objective response for evaluable patients was 34.6%, and four complete responses (CR) and five partial responses (PR) were noted. The median survival (MST) was 12 months, and the average overall survival was 12.5 months. Hematological toxicity was mild, and grade 3 or 4 neutropenia (white blood cell count <1500/ml) was noted in three patients, without any sepsis or bleeding. Conclusions: The results obtained in this study are comparable to the best reported results on the combination of radiotherapy and nitrosoureas. The near-concurrent combination of radiotherapy and etoposide seems to be effective and well tolerated in the treatment of newly malignant gliomas. Received: 7 December 1998 / Accepted: 5 February 1999     

All-trans retinoic acid in relapsing malignant gliomas: clinical and radiological stabilization associated with the appearance of intratumoral calcifications

(1) Purpose: To evaluate the therapeutic effect ofall-trans retinoic acid (ATRA) with and without cytosinearabinoside in relapsing malignant gliomas.(2) Patients and methods: 9 patients (8 male,1 female, age 53.9 ± 11.2) with relapsingmalignant gliomas (grade IV:6; grade III:3) were treatedby ATRA 1 to 21 months after theend of their initial treatment. ATRA was givenunceasingly during 2 to 17 months at 90mg/d. In 6 patients it was associated tocytosine arabinoside (4 g/course, 1 to 9 coursesevery 4 weeks).(3) Results: 4 non-responder patients died 2.5 to4 months after starting therapy. One patient whohad been reoperated before receiving ATRA and cytosinearabinoside (5 courses) had no sign of tumorrecurrence after 17 months of treatment. In 4responder patients (2 glioblastoma and 2 anaplastic astrocytoma)a clinical and radiological stabilization (time to progression)during 9 ± 2.5 months was observed. Thisstabilization was associated in 3 of them withthe appearance of intra tumoral calcifications visualized onrepeated CT scans and confirmed in one patientby post-mortem examination. All of them had receivedcytosine arabinoside (1 to 9 courses) with ATRA;however small calcifications were also observed in onenon-responder patient who did not receive aracytine.(4) Conclusion: These results suggest: a) a therapeuticeffect of ATRA in combination with cytosine arabinosidein patients with relapsing malignant gliomas b) thatintratumoral calcifications are related to the effects ofATRA on differentiation and/or on endothelial t-PA productionand that these effects explain the tumor progressionarrest in responder patients. The transient efficiency isprobably related to the pharmacokinetics of ATRA orto changes of cellular mechanisms that modulate thecell response to the drug and is acritical issue for this therapy.     

Soft tissue sarcomas: Preoperative versus postoperative radiotherapy

External beam radiation may be given either before or after excision of a primary soft tissue sarcoma. This study was undertaken to determine whether or not the timing of radiotherapy was associated with any difference in either local control, survival, or incidence of complications. The files of 112 patients with a primary, nonmetastatic, extremity soft tissue sarcoma, treated with limb salvage surgery and irradiation were evaluated. Data regarding tumor stage, grade, site, surgical margin, dosage and timing of radiotherapy, treatment complications, disease relapse, and relapse-free survival (RFS) were analyzed. Kaplan-Meier lifetable analysis was used to determine survival estimates. There was no significant difference in the 5-year RFS between patients receiving radiotherapy (RT) preoperatively versus postoperatively; 56 ± 15% and 67 ± 12% (P = 0.12, Mantel-Cox), respectively. There was no significant difference in the overall survival between patients receiving RT preoperatively versus postoperatively; 75 ± 15% and 79 ± 11% (P = 0.94), respectively. Actuarial local control at 5 years for preoperative versus postoperative RT patients was not statistically different; 83 ± 12% versus 91 ± 8% (P = 0.41), respectively. Wound complications were more frequent in preoperative RT patients (31%) compared to postoperative RT patients (8%) (P = 0.0014, chi-square). Preoperative irradiation was not associated with any benefit in terms of relapse-free survival, overall survival or actuarial local control in this series. A higher incidence of major wound complications was found among patients treated with preoperative irradiation. We recommend that patients with a resectable extremity soft tissue sarcoma be treated with postoperative irradiation, reserving preoperative irradiation for those situations in which either the tumor is initially thought to be unresectable or the original tumor boundaries are obscured. © 1996 Wiley-Liss, Inc.     

Delay in radiotherapy shortens survival in patients with high grade glioma

Fractionated external beam radiotherapy is an important component of standard treatment for high grade glioma. Due to resource constraints, patients may experience delays in receiving treatment. The purpose of this study was to evaluate the effect of radiotherapy waiting time on survival in patients with high grade glioma. A retrospective analysis was performed of 172 patients with a histological diagnosis of WHO Grade 3 or 4 Astrocytoma who had undergone surgery at Wellington Hospital between 1993 and 2003, and who subsequently underwent radiotherapy. Time to radiotherapy after surgery varied from 7 days to over 16 weeks. Multiple Cox regression analysis showed that age, performance status, tumour grade, extent of surgical resection, radiotherapy dose, and time to radiotherapy from day of surgery were all independently related to survival. Every additional week of delay until the start of radiotherapy increases the risk of death (hazard ratio) by 8.9% (95%CI 2.0%–16.1%). A 6 week delay in starting radiotherapy (from 2 weeks post-op to 8 weeks) reduces median survival by 11 weeks for a typical patient. Delay in radiotherapy results in a clinically significant reduction in survival. These findings have implications for resource allocation and for the design of clinical trials. This study was approved by the Central Regional Ethics Committee, New Zealand.     

Impact of radiotherapy delay on survival in glioblastoma

Background

Previous studies in glioblastoma have concluded that there is no decrease in survival with increasing time to initiation of RT up to 6 weeks after surgery. Unfortunately, the number of glioblastoma patients who start RT beyond 6 weeks is not small in some countries. The aim of our study was to evaluate the effect of RT delay beyond 6 weeks on survival of patients who have undergone completed resection of a glioblastoma.

Methods

We reviewed 107 consecutive glioblastoma patients who had a complete surgical resection at our hospital. Clinical data, including delay in initiation of RT, were prospectively collected. The impact of single parameters on overall survival was determined by univariate and multivariate analyses.

Results

According to univariate analysis, variables that had a prognostic influence on survival were age (p = 0.036), KPS (p = 0.031), additional treatment with CHT (p < 0.0001), and initiation of RT before 42 days (p = 0.009). Multivariate analysis indicated that Karnofsky performance scale, additional treatment with chemotherapy, and initiation of RT before 6 weeks after surgery were favorable, independent prognostic factors of survival.

Conclusions

Survival is significantly reduced in glioblastoma patients if RT is not initiated within the 6 weeks after complete resection of the tumor.     

Radio-chemo-immunotherapy (CCNU plus Levamisole) for treatment of metastatic brain tumors

Summary Thirty-one patients with metastatic brain tumors were treated with Radiotherapy (RT) and CCNU or with RT, CCNU and Levamisole (LMS) in a randomized clinical trial. Twenty-seven were evaluable. All patients were submitted to whole brain radiation (50 ± 5 Gy) and CCNU (130 mg/ m² p. o. every 8 weeks). 15 also received Levamisole (2.5 mg/ kg p.o. daily for 3 weeks in the first month, for 2 weeks in the second, and then once a week monthly until progression). Primary tumor was predominantly lung cancer (22/27) and brain lesions were generally multiple (24/27). The overall response rate was 35% in the RT plus CCNU treated group and 38% in the RT plus CCNU plus LMS treated group. The median survival time was similar and not statistically different in both groups (7 versus 6 months). No important side effects were observed either in the RT + CCNU or in the RT + CCNU + LMS treated groups. The absence of combined depression of T-cell levels and responsiveness of lymphocytes to mitogens suggests that thymus dependent immunity could be improved by LMS administration. However, such improvement had no impact on duration of survival in patients with metastatic brain tumors.     

Gliosarcomas: analysis of 11 cases do two subtypes exist?

Summary There are conflicting reports regarding gliosarcomas. The goal of this study is to examine clinical, radiological, surgical and therapeutic aspects of 11 patients with gliosarcoma. Between 1993 and 2001, 11 patients with cerebral gliosarcoma were treated at our Institute. Ten patients underwent surgery and one patient had stereotactic biopsy. Four patients received whole brain radiotherapy with ⁶⁰Co, five underwent radiotherapy with LINAC extended 2 cm beyond the edema margins. One patient refused any additional treatment after surgery and one patient was not treated postoperatively for poor clinical conditions (KPS 40). Chemotherapy (temozolomide) was administered to four patients. Four patients had a prevalence of sarcomatous component that corresponded to surgical and radiological aspects similar to meningioma while six patients showed a prevalence of gliomatous component and radiological and surgical aspects similar to those of glioblastomas. Surgical resection was total in six and subtotal in four patients. Patients with prevalent sarcomatous component showed median survival time more prolonged than patients with prevalent gliomatous component (71 ± 6 weeks vs. 63 ± 6; P=0.0417). Moreover, the survival rate differed in relation to the therapy: patients treated with multimodality therapy (surgery, radiotherapy and chemotherapy) had a longer survival time than patients treated in single or bimodality. Despite prognosis of gliosarcomas remains poor, a multidisciplinary approach (surgery, radiotherapy and chemotherapy) seems to be associated with slight more prolonged survival times.     

The effect of delays in treatment for breast cancer metastasis on survival

It is generally accepted that delay in receiving treatment for breast cancer results in adverse outcomes. The purpose of this study was to evaluate the impact of delay in treatment after the diagnosis of metastatic disease on survival measured from metastatic breast cancer diagnosis and from first treatment while controlling for immortal time effect among patients with metastatic breast cancer. A total of 553 patients with breast cancer metastasis diagnosis from one large urban practice have been followed between January 1, 1999 and June 30, 2008. Prognostic factors and outcomes of these patients were analyzed using log-rank test and Cox regression model. Backward stepwise selection of covariates was conducted to assess the association of treatment delay with survival. The median survival was 40 months (range 1–114 months), with 265 (47.9%) women alive and 288 (52.1%) having died at the end of the follow-up period. Treatment delays of more than 12 weeks had impact on poor survival from first treatment than the delays of 4–12 weeks with borderline significance level (HR 1.76, 95% CI 0.99–3.13, P = 0.056) in multivariate analysis, adjusted by BMI, history of hypertension, ER/PR status, HER2 status, number of metastatic sites, and liver metastasis. Moreover, the interval of 12–24 weeks, compared to the interval of 4–12 weeks was associated with greater risk of death from first treatment (HR 2.39, 95% CI 1.19–4.77, P = 0.014). The treatment delay interval of >12 weeks was not related with survival since metastatic breast cancer diagnosis, compared to the 4–12 weeks of treatment delays. This study demonstrated that delays of over 12 weeks in receiving treatment for metastatic breast cancer were related to adverse survival outcomes measured from initiation of first treatment. The findings of this study support targeted efforts to ensure prompt treatment initiation in patients diagnosed with metastatic breast cancer.     

Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial

BackgroundHippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function.MethodsThis single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test–Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method.ResultsFrom March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was −8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well.ConclusionPatients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.     

Prognostic index to identify patients who may not benefit from whole brain radiotherapy for multiple brain metastases from lung cancer

Palliative whole brain radiotherapy (WBRT) is often recommended in the management of multiple brain metastases. Allowing for WBRT waiting time, duration of the WBRT course and time to clinical response, it may take 6 weeks from the point of initial assessment for a benefit from WBRT to manifest. Patients who die within 6 weeks (‘early death’) may not benefit from WBRT and may instead experience a decline in quality of life. This study aimed to develop a prognostic index (PI) that identifies the subset of patients with lung cancer with multiple brain metastases who may not benefit from WBRT because of ‘early death’. The medical records of patients with lung cancer who had WBRT recommended for multiple brain metastases over a 10-year period were retrospectively reviewed. Patients were classified as either having died within 6 weeks or having lived beyond 6 weeks. Potential prognostic indicators were evaluated for correlation with ‘early death’. A PI was constructed by modelling the survival classification to determine the contribution of these factors towards shortened survival. Of the 275 patients recommended WBRT, 64 (23.22%) died within 6 weeks. The main prognostic factor predicting early death was Eastern Cooperative Oncology Group (ECOG) status >2. Patients with a high PI score (>13) were at higher risk of ‘early death’. Twenty-three per cent of patients died prior to benefit from WBRT. ECOG status was the most predictive for ‘early death’. Other factors may also contribute towards a poor outcome. With further refinement and validation, the PI could be a valuable clinical decision tool.