Chemotalk Newsletter

Chemotalk Newsletter, Vol. 115 November 1, 2017

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End of the year...



By Dave Levitan

Treatment with hyperthermia improved survival when added to neoadjuvant CHEMOTHERAPY for patients with localized high-risk soft-tissue SARCOMA, according to results of a new study.

    It has previously been established that regional hyperthermia, where localized tissue is heated to the 40 to 43 degrees Celsius range, could help in cancer therapy. Lars H. Lindner, MD, of University Hospital Medical Center Grosshadern in Munich, Germany, described an antenna coupling technique that can deliver the heat to a specific small region by modulating the intensity, phase, and frequency of several antennae.

    Lindner presented long-term results of the trial, which included 329 high-risk soft-tissue sarcoma patients randomized to neoadjuvant chemotherapy plus hyperthermia or alone at the Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting, held November 8­11 in Wailea, Hawaii.

    Patient characteristics were well balanced between the groups. Slightly more than half of the patients had soft-tissue sarcoma in a non-extremity location, and the rest had tumors in the extremities. The most common histologic types included liposarcoma (30 patients in each group), leiomyosarcoma (25 in the hyperthermia group and 27 in the neoadjuvant chemotherapy­alone group), and synovial sarcoma (24 and 19 patients, respectively).

    The addition of hyperthermia to neoadjuvant chemotherapy resulted in significantly improved cancer-specific survival after a median follow-up period of 11.3 years, with a hazard ratio (HR) for death from the disease or its treatment of 0.73 (95% CI, 0.54­0.98; P = .037). A multivariate analysis confirmed this, with an HR of 0.70 (95% CI, 0.52­0.95; P = .024).

    When stratified by extremity vs non-extremity soft-tissue sarcoma, there were trends toward improvement with hyperthermia in both cases, but these did not reach significance. Other factors that were found to be significantly prognostic on multivariate analysis included tumor grade and tumor size.

    Patients who received hyperthermia treatment and radiotherapy following R0- and R1-resection fared better than those who did not receive radiotherapy, with an HR for local progression-free survival of 0.35 (95% CI, 0.13­0.93; P = .035). This effect was not seen in the neoadjuvant chemotherapy­alone group.

    "Among patients with localized high-risk soft-tissue sarcoma, the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival," Lindner concluded. "For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted." He said that other related approaches are also under investigation, including a phase II trial combining trabectedin with regional hyperthermia.

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By Leah Lawrence

    Treatment within 30 days of MELANOMA diagnosis was associated with improved outcomes, according to the results of a study published in the Journal of the American Academy of Dermatology. Overall survival decreased in patients waiting longer than 90 days for surgical treatment, regardless of the stage of disease.

    "The ideal timing for melanoma treatment, predominantly surgery, had yet to be determined‹until now," said primary investigator Brian R. Gastman, MD, director of melanoma surgery at Cleveland Clinic. "Patients and referring physicians are not only concerned with how a melanoma is removed, but also when it¹s removed. We saw significantly worse prognoses and outcomes for those surgically treated after 30 days of stage I melanoma diagnosis. Knowing for certain that a more expedient time to surgery to remove an early melanoma improves the chances of survival is a game-changer in treating this life-threatening skin cancer."

    The study was designed to assess the impact of time to definitive melanoma surgery on overall survival. It included more than 150,000 patients with stage I to III cutaneous melanoma from the National Cancer Database from 2004 to 2012.

    Multivariate analysis showed that compared with surgical treatment within 30 days of biopsy, those patients in all stages treated between 90 and 119 days (hazard ratio [HR], 1.09; 95% CI, 1.01­1.18) and after more than 119 days (HR, 1.12; 95% CI, 1.02­1.22) had a higher mortality risk.

    The researchers conducted a subgroup analysis of only those patients with stage I disease and the trend remained with higher mortality risk seen in patients treated within 30 to 59 days (HR, 1.05), 60 to 89 days (HR, 1.16), 90 to 119 days (HR, 1.29), and more than 119 days after biopsy (HR, 1.41). Delay of surgery did not affect survival for patients with stage II or III disease.

    "We hypothesize that the negative effect of prolonging time to treatment initiation on early-stage melanoma is visible as a result of the lower baseline mortality found in these patients," the researchers wrote. "However, in stages II and III, the potential benefits of a shorter time to treatment initiation are likely overshadowed by a higher metastatic potential and baseline mortality. In other words, it appears that prompt initiation of definitive treatment is beneficial in stage I melanoma but likely not in stage II or III."

    Based on these results, the researchers suggested that greater efforts be made to improve the entire process "from suspicion of melanoma to its ultimate treatment."

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By Leah Lawrence

`The off-label use of the beta-blocker propranolol significantly reduced disease recurrence among patients with non-metastatic MELANOMA, according to the results of a prospective, non-randomized study published as a brief report in JAMA Oncology.

    "This study is the first we know of to evaluate the administration of a beta-blocker to patients as adjuvant therapy at the time of diagnosis of melanoma," wrote Vincenzo De Giorgi, MD, of the University of Florence, Italy, and colleagues. "These results provide the basis for larger trials of longer duration to measure the clinical efficacy of propranolol."

    The prospective study included patients with histologically confirmed stage IB to IIIA cutaneous melanoma without metastasis. Patients were asked to take propranolol 80 mg daily. Those who accepted were part of the propranolol arm (PROP; n = 19); those who agreed to participate in the study but not to take propranolol were part of the non-propranolol arm (No-PROP; n = 34).

    The two arms were well balanced except that the PROP arm had more cases of ulcerated melanoma, which the researchers noted presents a greater risk for disease progression.

    After a median follow-up of 3 years, 41.2% of patients in the No-PROP arm had disease progression compared with 15.8% of patients in the PROP arm.
The 3-year disease-free survival was 89% in the PROP arm compared with 64% in the No-PROP arm (P = .04).

    Adjusted analyses showed an 80% risk reduction for recurrence when propranolol was used from the time of diagnosis (hazard ratio, 0.18; 95% CI, 0.04­0.89; P = .03).

    "This result is important because in the propranolol cohort histopathological examinations showed a greater number of cases with ulceration, which is considered a poor prognostic factor," the researchers wrote. "Even overall survival, although not significant, showed a trend toward decreased mortality in the propranolol group after 3 years of follow-up."

    There were no adverse events in the PROP group.

    The researchers acknowledged that the study has limitations including the small sample size and its prospective nature.

    "The development of randomized placebo-controlled clinical trials is necessary to clarify a definitive role for beta-blockers in protecting against the risk of progression of melanoma and to potentially identify the receptor subtype involved in the protective effect," they wrote.

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By Dave Levitan

An intense dose-dense CHEMOTHERAPY approach offers better survival than standard therapy, extending out to 10 years in women with BREAST CANCER and extensive axillary lymph node involvement, according to the long-term results of the AGO study.

    "Dose-dense, intense dose-dense regimens, or tailored dose-dense regimens have shown superior clinical outcomes when compared with conventionally dosed chemotherapy," wrote study authors led by Volker J. Möbus, MD, of the Academic Hospital of the Goethe University Frankfurt in Germany. "However, clinical follow-up has been relatively short in these studies, and long-term clinical outcome data are missing."

    This analysis was a 10-year follow-up report from the AGO trial, which included 1,284 patients with high-risk breast cancer. All patients had four or more involved axillary lymph nodes, and were randomized to receive either 3 courses each of intense dose-dense sequential epirubicin, paclitaxel, and cyclophosphamide (iddEPC; 658 patients), or standard epirubicin/cyclophosphamide followed by paclitaxel (EC-P; 626 patients).

Results were published in Annals of Oncology.

    After a median follow-up of 122 months, both event-free survival (EFS) and overall survival (OS) were better with iddEPC. The EFS rate for iddEPC was 56% at 10 years, compared with 47% with EC-P, for an adjusted hazard ratio (HR) of 0.74 (95% CI, 0.63­0.87; P = .00014). The OS rates at 10 years were 69% with iddEPC and 59% with EC-P, for an HR of 0.72 (95% CI, 0.60­0.87; P = .0007).

    This effect was more pronounced with more lymph node involvement. Patients with more than 10 positive axillary lymph nodes had an OS rate at
10 years of 62% with iddEPC and 48% with EC-P, for an HR of 0.66 (P = .0016); for those with 4 to 9 positive lymph nodes, the OS rates were 74% and 66%, respectively, for an HR of 0.77 (P = .061). The authors noted that the benefit seen with iddEPC was independent of HER2 and estrogen receptor status.

    A secondary neoplasm was observed in 46 patients. There were 11 cases of acute myeloid leukemia or myelodysplastic syndrome, including 9 in the iddEPC group and 2 in the EC-P group (P = .065).

    Hematologic toxicity was more frequent in the iddEPC group‹7% vs 2% in EC-P patients (P < .0001). Only 6 EC-P patients needed a red blood cell transfusion, compared with 127 (20%) in the iddEPC group (P < .0001). Nonhematologic toxicity was also more frequent in the intense dose-dense group, but grade 3/4 toxicities were relatively rare and "clinically acceptable."

    "Independently of known molecular breast cancer subtypes, dose-dense chemotherapy remains an important treatment option for high-risk breast cancer patients," the authors concluded. "Future research will need to focus on identifying biomarkers that predict treatment response and will need to evaluate combination therapies with novel targeted agents to further improve treatment outcomes for patients diagnosed with high-risk primary breast cancer."

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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