The principle of salvage in the context of COVID-19.

The prioritisation of scarce resources has a particular urgency within the context of the COVID-19 pandemic crisis. This paper sets out a hypothetical case of Patient X (who is a nurse) and Patient Y (who is a non-health care worker). They are both in need of a ventilator due to COVID-19 with the same clinical situation and expected outcomes. However, there is only one ventilator available. In addressing the question of who should get priority, the proposal is made that the answer may lie in how the pandemic is metaphorically described using military terms. If nursing is understood to take place at the 'frontline' in the 'battle' against COVID-19, a principle of military medical ethics-namely the principle of salvage-can offer guidance on how to prioritise access to a life-saving resource in such a situation. This principle of salvage purports a moral direction to return wounded soldiers back to duty on the battlefield. Applying this principle to the hypothetical case, this paper proposes that Patient X (who is a nurse) should get priority of access to the ventilator so that he/she can return to the 'frontline' in the fight against COVID-19.

Assessing the Best Surgical Template at Salvage Pelvic Lymph Node Dissection for Nodal Recurrence of Prostate Cancer After Radical Prostatectomy: When Can Bilateral Dissection be Omitted? Results from a Multi-institutional Series.

The best surgical template for salvage pelvic lymph node dissection (sLND) in patients with nodal recurrence from prostate cancer (PCa) after radical prostatectomy (RP) is currently unknown. We analyzed data of 189 patients with a unilateral positive positron emission tomography (PET) scan of the pelvic lymph node areas, who were treated with bilateral pelvic sLND after RP at 11 high-volume centers. The primary endpoint was missed contralateral disease at final pathology, defined as lymph node positive for PCa in the side opposite to the positive spot(s) at the PET scan. Overall, 93 (49%) and 96 (51%) patients received a 11C-choline and a 68Ga prostate-specific membrane antigen (PSMA) PET scan, respectively, and 171 (90%) and 18 (10%) men had one and two positive spots, respectively. The rate of missed contralateral PCa was 18% (34/189), with the rates being 17% (29/171) and 28% (5/18) in men with one and two positive spots, respectively. While the rate of contralateral disease did not differ between 68Ga-PSMA and 11C-choline (29% and 27%, respectively) among men with two positive spots, the rate of contralateral PCa was only 6% with 68Ga-PSMA versus 28% with 11C-choline in patients with a single positive spot. This finding was confirmed at multivariable logistic regression analysis predicting missed disease at final pathology after accounting for confounders (odds ratio: 0.24; p = 0.001). However, in men with a single positive spot at 68Ga-PSMA PET/computed tomography, the rate of single confirmed lymph node metastasis at final pathology was only 33%, suggesting the need for extended template even if unilateral dissection is performed. Awaiting confirmatory studies, patients diagnosed with a single positive spot at the 68Ga-PSMA PET scan might be considered for unilateral extended pelvic sLND. PATIENT SUMMARY: We assessed the risk of missing contralateral disease in patients with a positron emission tomography (PET) scan suggestive of unilateral nodal recurrence from prostate cancer (PCa) after radical prostatectomy and who were treated with bilateral salvage lymph node dissection (sLND). Variability exists according to the number of positive spots and PET tracer, with the lowest rate of missed PCa in men diagnosed with a single positive spot at a 68Ga prostate-specific membrane antigen PET scan (6%). If replicated, our data suggest that these patients might be considered for unilateral extended pelvic sLND.

Pathologically Node-Positive Prostate Cancer: Casting for Cure When the Die Is Cast?

The postoperative management of men with lymph node involved prostate cancer (pN+) remains a challenge as there is a general lack of randomized trial data and a range of management strategies. Retrospective studies suggest a variable clinic course for patients with pN+ prostate cancer. Some men progress rapidly to metastatic disease despite further therapies, whereas other men can have a period of prolonged quiescence without adjuvant androgen deprivation therapy (ADT) or radiation therapy (RT). For men who have undergone radical prostatectomy, randomized trial data indicate that the addition of ADT in pN+ disease extends metastasis-free, prostate cancer-specific, and overall survival. Additional retrospective studies suggest that adding RT is potentially beneficial in this setting, improving overall and cancer-specific survival especially in men with certain pathologic parameters. Conversely, men with lower disease burden in their lymph nodes have longer times to progression and may be candidates for observation and salvage therapy as opposed to adjuvant ADT/RT.

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Inotuzumab ozogamicin versus standard of care in Asian patients with relapsed/refractory acute lymphoblastic leukemia.

Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population.Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.

[The efficacy and safety of salvage surgery for local recurrent nasopharyngeal carcinoma: a systematic review and Meta-analysis].

Objective: To assess the current evidence regarding the efficacy, safety, and potential advantages of endoscopic compared with open salvage surgery for patients with local recurrent nasopharyngeal carcinoma. Methods: A systematic search of Pubmed/Medline, Embase, and Cochrane databases ranged between 2000 and 2017 was conducted. Included studies reported specific residual or local recurrent nasopharyngeal cancer survival data. Proportional Meta-analysis was performed on both outcomes with a random-effects model and the 95% confidential intervals were calculated by Stata 12.0 software. Results: A total of 24 case series studies were included in the Meta-analysis.The pooled 2-year overall survival rates of endoscopic and open group were 84% (95%CI:72%-93%), 68%(95%CI:59%-77%),respectively.The pooled 2-year disease-free survival rates of endoscopic and open group were 68%(95%CI:53%-81%), 65%(95%CI:54%-75%),respectively. The pooled 5-year overall survival rates of endoscopic and open group were 72%(95%CI:37%-97%), 48% (95%CI:40%-56%),respectively.The pooled 5-year disease-free survival rates of endoscopic and open group were 65%(95%CI:29%-93%), 50%(95%CI:43%-57%),respectively.The combined outcome of endoscopic was higher than open procedure. In addition, less severe complications, lower local recurrence rates(27%vs32%).The 2-year overall survival rates of endoscopic was higher than open procedure in the staging of rT1, rT2, and rT3 (93%vs87%; 77%vs63%; 67%vs53%) , but was equal to open in the staging for rT4 (35%vs35%) .Meta-regression showed that the heterogeneity was correlated with advanced tumor ratio. Conclusions: The present Meta-analysis reveals that endoscopic approach offers a safe and efficient alternative to open approach with better short-term outcome and fewer postoperative complications in selecting patients strictly.

Adjuvant and Salvage Radiotherapy after Prostatectomy: ASTRO/AUA Guideline Amendment 2018-2019.

PURPOSE: The purpose of this amendment is to incorporate newly-published literature into the original ASTRO/AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guideline and to provide an updated clinical framework for clinicians. MATERIALS AND METHODS: The original systematic review yielded 294 studies published between January 1990 and December 2012. In April 2018, the guideline underwent an amendment and incorporated 155 references that were published from January 1990 through December 2017. Two new key questions were added. One on the use of genomic classifiers and the other on the treatment of oligo-metastases with radiation post-radical prostatectomy. RESULTS: A new statement on the use of hormone therapy with salvage radiotherapy after radical prostatectomy was added and long-term data was used to update an existing statement on adjuvant radiotherapy. The balance of the guideline statements were re-affirmed and references were added to the existing literature base. A discussion on the use of genomic classifiers as a risk stratification tool was added to the future research discussion. No relevant data on oligo-metastases was found. CONCLUSIONS: Hormone therapy should be offered to patients who have had radical prostatectomy and who are candidates for salvage radiotherapy. The clinician should discuss possible short- and long-term side effects with the patient as well as the potential benefits of preventing recurrence. The decision to use hormone therapy should be made by the patient and a multi-disciplinary team of providers with full consideration of the patient's history, values, preferences, quality of life, and functional status.

Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND: Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. METHODS: Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. RESULTS: Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. CONCLUSIONS: In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Radiotherapy for recurrent prostate cancer: 2018 Recommendations of the Australian and New Zealand Radiation Oncology Genito-Urinary group.

The management of patients with biochemical, local, nodal, or oligometastatic relapsed prostate cancer has become more challenging and controversial. Novel imaging modalities designed to detect recurrence are increasingly used, particularly PSMA-PET scans in Australia, New Zealand and some European countries. Imaging techniques such as MRI and PET scans using other prostate cancer-specific tracers are also being utilised across the world. The optimal timing for commencing salvage treatment, and the role of local and/or systemic therapies remains controversial. Through surveys of the membership, the Australian and New Zealand Faculty of Radiation Oncology Genito-Urinary Group (FROGG) identified wide variation in the management of recurrent prostate cancer. Following a workshop conducted in April 2017, the FROGG management committee reviewed the literature and developed a set of recommendations based on available evidence and expert opinion, for the appropriate investigation and management of recurrent prostate cancer. These recommendations cover the role and timing of post-prostatectomy radiotherapy, the management of regional nodal metastases and oligometastases, as well as the management of local prostate recurrence after definitive radiotherapy.

Policies for reirradiation of recurrent high-grade gliomas: a survey among Italian radiation oncologists.

PURPOSE: To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach. METHODS: In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach. RESULTS: A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy. CONCLUSIONS: Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.

Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline.

PURPOSE: This guideline presents evidence-based recommendations for stereotactic body radiation therapy (SBRT) in challenging clinical scenarios in early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing: (1) application of SBRT to operable patients; (2) appropriate use of SBRT in tumors that are centrally located, large, multifocal, or unbiopsied; (3) individual tailoring of SBRT in "high-risk" clinical scenarios; and (4) SBRT as salvage therapy after recurrence. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength. RESULTS: Although few randomized trials have been completed for SBRT, strong consensus recommendations based on extensive, consistent publications were generated for several questions, including recommendations for fractionation for central tumors and surgery versus SBRT in standard-risk medically operable patients with early-stage NSCLC. Lower quality evidence led to conditional recommendations on use of SBRT for tumors >5 cm, patients with prior pneumonectomy, T3 tumors with chest wall invasion, synchronous multiple primary lung cancer, and as a salvage therapy after prior radiation therapy. These areas of moderate- and low-quality evidence highlight the importance of clinical trial enrollment as well as the role of prospective data registries. CONCLUSIONS: SBRT has an important role to play in treating early-stage NSCLC, particularly for medically inoperable patients with limited other treatment options. Shared decision-making with patients should be performed in all cases to ensure the patient understands the risks related to SBRT, the side effects, and the alternative treatments available.

Beam distortion due to gold fiducial markers during salvage high-intensity focused ultrasound in the prostate.

PURPOSE: High intensity focused ultrasound (HIFU) provides a non-invasive salvage treatment option for patients with recurrence after external beam radiation therapy (EBRT). As part of EBRT the prostate is frequently implanted with permanent fiducial markers. To date, the impact of these markers on subsequent HIFU treatment is unknown. The objective of this work was to systematically investigate, using computational simulations, how these fiducial markers affect the delivery of HIFU treatment. METHODS: A series of simulations was performed modelling the propagation of ultrasound pressure waves in the prostate with a single spherical or cylindrical gold marker at different positions and orientations. For each marker configuration, a set of metrics (spatial-peak temporal-average intensity, focus shift, focal volume) was evaluated to quantify the distortion introduced at the focus. An analytical model was also developed describing the marker effect on the intensity at the focus. The model was used to examine the marker's impact in a clinical setting through case studies. RESULTS: The simulations show that the presence of the marker in the pre-focal region causes reflections which induce a decrease in the focal intensity and focal volume, and a shift of the maximum pressure point away from the transducer's focus. These effects depend on the shape and orientation of the marker and become more pronounced as its distance from the transducer's focus decreases, with the distortion introduced by the marker greatly increasing when placed within 5 mm of the focus. The analytical model approximates the marker's effect and can be used as an alternative method to the computationally intensive and time consuming simulations for quickly estimating the intensity at the focus. A retrospective review of a small patient cohort selected for focal HIFU after failed EBRT indicates that the presence of the marker may affect HIFU treatment delivery. CONCLUSIONS: The distortion introduced by the marker to the HIFU beam when positioned close to the focus may result in an undertreated region beyond the marker due to less energy arriving at the focus, and an overtreated region due to reflections. Further work is necessary to investigate whether the results presented here justify the revision of the patient selection criteria or the markers' placement protocol.

Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. Recurrent cancers present some of the most challenging management issues in head and neck surgical and oncological practice. This is rendered even more complex by the poor evidence base to support management options, the substantial implications that treatments can have on the function and quality of life, and the difficult decision-making considerations for supportive care alone. This paper provides consensus recommendations on the management of recurrent head and neck cancer. Recommendations • Consider baseline and serial scanning with computed tomography and/or magnetic resonance (CT and/or MR) to detect recurrence in high-risk patients. (R) • Patients with head and neck cancer recurrence being considered for active curative treatment should undergo assessment by positron emission tomography combined with computed tomography (PET-CT) scan. (R) • Patients with recurrence should be assessed systematically by a team experienced in the range of management options available for recurrence including surgical salvage, re-irradiation, chemotherapy and palliative care. (R) • Management of patients with laryngeal recurrence should include input from surgeons with experience in transoral surgery and partial laryngectomy for recurrence. (G) • Expertise in transoral surgery and partial laryngectomy for recurrence should be concentrated to a few surgeons within each multidisciplinary teams. (G) • Transoral or open partial laryngectomy should be offered as definitive treatment modality for highly-selected patients with recurrent laryngeal cancer. (R) • Patients with OPC recurrence should have p16 human papilloma virus status assessed. (R) • Patients with OPC recurrence should be considered for salvage surgical treatment by an experienced team, with reconstructive expertise input. (G) • Transoral surgery appears to be an effective alternative to open surgery for the management of OPC recurrence in carefully selected patients. (R) • Consider elective selective neck dissections in patients with recurrent primaries with N0 necks, especially in advanced cases. (R) • Selective neck dissection (with preservation of nodal levels, especially level V, that are not involved by disease) in patients with nodal (N+) recurrence appears to be as effective as modified or radical neck dissections. (R) • Use salivary bypass tubes following salvage laryngectomy. (R) • Use interposition muscle-only pectoralis major or free flap for suture line reinforcement if performing primary closure following salvage laryngectomy. (R) • Use inlaid pedicled or free flap to close wound if there is tension at the anastomosis following laryngectomy. (R) • Perform secondary puncture in post chemoradiotherapy laryngectomy patients. (R) • Triple therapy with platinum, cetuximab and 5-fluorouracil (5-FU) appears to provide the best outcomes for the management of patients with recurrence who have a good performance status and are fit to receive it. If not fit, then combinations of platinum and cetuximab or platinum and 5-FU may be considered. (R) • Patients with non-resectable recurrent disease should be offered the opportunity to participate in phases I-III clinical trials of new therapeutic agents. (R) • Chemo re-irradiation appears to improve locoregional control, and may have some benefit for overall survival, at the risk of considerable acute and late toxicity. Benefit must be weighed carefully against risks, and patients must be counselled appropriately. (R) • Target volumes should be kept tight and elective nodal irradiation should be avoided. (R) • Best supportive care should be offered routinely as part of the management package of all patients with recurrent cancer even in the case of those who are being treated curatively. (R).

Reconstructive considerations in head and neck surgical oncology: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. The reconstructive needs following ablative surgery for head and neck cancer are unique and require close attention to both form and function. The vast experience accrued with microvascular reconstructive surgery has meant a significant expansion in the options available. This paper discusses the options for reconstruction available following ablative surgery for head and neck cancer and offers recommendations for reconstruction in the various settings. Recommendations • Microsurgical free flap reconstruction should be the primary reconstructive option for most defects of the head and neck that need tissue transfer. (R) • Free flaps should be offered as first choice of reconstruction for all patients needing circumferential pharyngoesophageal reconstruction. (R) • Free flap reconstruction should be offered for patients with class III or higher defects of the maxilla. (R) • Composite free tissue transfer should be offered as first choice to all patients needing mandibular reconstruction. (R) • Patients undergoing salvage total laryngectomy should be offered vascularised flap reconstruction to reduce pharyngocutaneous fistula rates. (R).