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  • Feb 9, 2020
    Protons reduces adverse events for locally advanced cancers relative to photons

    In this retrospective nonrandomized study, the authors analyzed 1483 adult patients with nonmetastatic locally advanced cancers treated with concurrent chemotherapy between 2011 and 2016 at the University of Pennsylvania. 391 patients received proton therapy and 1092 received photon therapy. The main research question was whether proton therapy can reduce the risk of severe adverse events associated with unplanned hospitalizations compared to photon therapy for patients also receiving chemotherapy. The authors found that patients treated with protons tended to be older, with more medical comorbidities. Despite this, patients treated with protons had a lower risk of developing 90-day adverse events of at least grade 3, grade 2, and were less likely to have a decline in overall performance status. There was no difference in disease-free or overall survival. Although this does appear favorable for proton therapy, there are several important limitations. The study is retrospective and although the authors did use statistical techniques to try to account for potential sources of bias, there may be unmeasured differences between the groups, and randomize prospective studies are needed to confirm these results.

    Reference (PubMed Link): Baumann BC, Mitra N, Harton JG, et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol 2019;6:237-46.

    Key Institution: U Pennsylvania
    Keywords: Proton therapy, photon therapy, locally advanced cancer, concurrent chemoradiation 

  • Sep 20, 2019
    Protons may improve outcomes for HCC, perhaps by reducing post-treatment liver decompensation

    The purpose of this study was to compare clinical outcomes in patients with unresectable hepatocellular carcinoma (HCC) who receive ablative photon vs proton therapy.

    This was a single-institution retrospective study looking at patients treated between 2008-2017 with unresectable HCC not treated with prior RT. This study looked at OS (main endpoint) as well as incidence of non-classic radiation-induced liver disease.

    There were 133 patients on this study with a median follow-up of 14 months. There were 49 (37%) patients who received proton therapy. The study found that proton therapy was associated with a higher OS (HR 0.47, p=0.047). Proton therapy was also found to be associated with a lower risk of radiation-induced liver disease (OR 0.26, p=0.03). There was no difference in locoregional recurrence between the two arms.

    The results showed that proton therapy was associated with improved OS compared to photon therapy, possibly owing to a reduction in the incidence of radiation-related liver disease. The findings of this retrospective study support a prospective study comparing proton and photon therapy for treatment of unresectable HCC.

    Reference (PubMed Link): Sanford NN, Pursley J, Noe B, et al. Protons versus photons for unresectable hepatocellular carcinoma: Liver decompensation and overall survival. Int J Radiat Oncol Biol Phys 2019;105:64-72.

    Key Institution: Harvard
    Keywords: HCC, proton therapy, ablative radiation

  • Sep 20, 2019
    Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma

    There is substantial regional variation in the incidence of nasopharyngeal carcinoma worldwide, with the highest incidence in endemic populations in southern China, southeast Asia, northern Africa, and immigrant populations in the United States. Since the publication of the landmark Al-Sarraf trial (Intergroup 0099) in 1998, the standard of care for the vast majority of patients (all but M1 or T1N0) has been concurrent definitive chemoradiotherapy followed by adjuvant chemotherapy. An ongoing cooperative group trial in the United States is seeking to risk-stratify patients for selecting adjuvant chemotherapy, but the backbone of upfront chemoradiotherapy has remained the same for more than 20 years. More recently, however, there has been an interest in induction chemotherapy followed by chemoradiotherapy for patients with stage III-IVB disease; this month’s issue of the New England Journal of Medicine reports results from a phase III randomized-controlled trial reported by Zhang and colleagues.  

    Zhang et al. conducted a multicenter randomized-controlled phase III trial in China, enrolling patients with newly-diagnosed stage III-IVB nasopharyngeal carcinoma. Patients were randomized to standard upfront chemoradiotherapy (70 Gy, concurrent with cisplatin) with or without three cycles of every-three-week induction gemcitabine and cisplatin. The primary outcome was recurrence-free survival, with overall survival as a secondary endpoint. From 2013-2016, 480 patients were enrolled. In the induction chemotherapy arm, 97% of patients completed all three cycles of gemcitabine/cisplatin, and 94% of patients completed at least two cycles of concurrent cisplatin. In the control arm, 98% of patients completed at least two cycles of concurrent cisplatin. All but two patients in the trial completed radiotherapy. These results indicate good adherence to definitive concurrent therapy despite three cycles of induction, suggesting feasibility of such an approach.  

    The primary endpoint, recurrence-free survival, was statistically- and clinically-significantly prolonged with the addition of induction chemotherapy to chemoradiotherapy (3-year RFS, 85% vs 77%). Similarly, three-year overall survival was prolonged from 90% to 95%. This was primarily due to a reduction in distant recurrences, with no difference in locoregional recurrence-free survival. There were more grade 3+ adverse events in the induction therapy cohort (76% vs. 56%), primarily due to hematologic, gastrointestinal, and renal toxicity. There was no difference in the incidence of late effects except for grade 1-2 peripheral neuropathy.  

    This trial will likely change the decades-old standard of care for patients with stage III-IVB disease, and again calls into question the controversial use of adjuvant chemotherapy. As a result, radiation oncologists will need to learn to manage these patients after induction chemotherapy, with more complex decision-making regarding adaptive planning and treatment of pre-induction or post-induction volumes.

    Reference (PubMed Link): Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med 2019;381:1124-1135.

    Key Institution: Multi-Institutional (Southern China)
    Keywords: Nasopharyngeal Carcinoma, Chemoradiotherapy, Induction, Randomized, Intensity-Modulated Radiation Therapy

  • Jul 30, 2018
    Carotid Dosimetry and the Risk of Carotid Blowout Syndrome After Reirradiation With Head and Neck Stereotactic Body Radiation Therapy

    Patients with recurrent head and neck cancer have limited options for treatment, and generally poor outcomes.  The standard recommendation is for salvage surgery, but many patients are not eligible for this due to comorbidities, general medical deconditioning, or location of recurrence.  However, there has been concern with the role of reirradiation given retrospective reports of long term toxicity, and specifically the concern for carotid blowout syndrome (CBOS).  CBOS is defined as a complication of head and neck cancer in which the carotid artery or one of its major branches ruptures.  It is most often fatal.  SBRT is more attractive than conventionally fractionated treatment for a number of reasons including decreased acute toxicity and decreased treatment time.  Some small retrospective studies have previously suggested increased risk of CBOS for SBRT (8-17%) versus conventionally fractionated treatment (1-4%), as well as higher risk if >180 degrees of the carotid artery is encased.  This study examined whether there is any relation between SBRT and CBOS in the setting of reirradiation based on DMax, mean dose to the carotid, and additional risk factors such as degree of carotid encasement, skin involvement, and ulceration/necrosis. This is a single institution retrospective study of 75 patients and 150 carotid arteries.  All patients had previous conventionally fractionated head and neck radiation with a mean dose of 70Gy.  Their prior radiation doses, carotid hotspots, or carotid coverage were not accounted for in this study.  It only examined the SBRT reirradiation dose and hotspots.  Patients were treated to 40-50Gy in 5Fx delivered every other day.  A minority of patients (10.7%) had 2 or more courses of SBRT reirradiation and for these patients their cumulative SBRT dose was accounted for.  The median Dmax for the following volumes was: D0.1cc=40.8Gy, D1cc=26.8Gy, D2cc=15.4Gy.  The mean carotid dose was 15Gy, and median PTV size 39.3 cm^3. Interestingly this study only found a total of 4 carotid bleeding events (5.3%), which is lower than the previously reported 8-17% in the SBRT setting.  Of these, two were mucosal bleeds that were successfully embolized and 2 were truly fatal CBOS (2.6%).  This is within the range of 1-4% previously reported for conventional fractionation.  There was no true significant association between DMax, Dmean, or additional risk factors such as necrosis or carotid encasement.  There was however a trend (p=0.08) towards increased risk of bleeding with D0.1cc>47.6Gy.  Of note there was a true minority of patients who had carotid encasement >180 degrees (16%); the large majority (78.7%) had 0 carotid encasement.  The same is true for skin invasion (only 5.3%) and ulceration (9.3%).  These numbers are too small to form any real conclusions about safety of irradiating in these settings.  Additionally, it must be accounted for that this is a retrospective study that did not account for overlapping hotspots from previous radiation. Overall, this study does provide a preliminary reassurance that carotid reirradiation, especially in the SBRT setting, may pose less of a threat than previously thought for CBOS.  This opens the door for a modality of treatment that is often a head and neck patient’s only choice in a challenging setting of recurrence, especially if they have poor performance status or other comorbidities.  It cautions to proceed carefully and potentially limit D0.1CC to <47.6Gy.  More remains to be investigated for the true safety threshold of reirradiation, especially in the setting of overlapping hotspots from previous treatment, and carotid encasement. 


    Journal & Date: Int J Radiation Oncol Biol Phys, Vol. 101, No. 1, pp. 195-200, 2018
    Key Institution: UPMC Cancer Center, Pittsburgh PA
    Keywords: Carotid blowout, head and neck cancer, reirradiation, SBRT, maximum dose, mean carotid dose, carotid encasement, concurrent cetuxumab