Quality and Quantity: Dual Benefits of Ablative Radiation in Oligometastatic Pancreatic Cancer.

Systemic therapy with or without local intervention for oligometastatic oesophageal squamous cell carcinoma (ESO-Shanghai 13): an open-label, randomised, phase 2 trial

MP62-03 HIGH-INTENSITY FOCUSSED ULTRASOUND IN THE TREATMENT OF LOCALISED PROSTATE CANCER: FOCAL SALVAGE TRANSITION RATES

BackgroundPrevious studies have shown the feasibility and effectiveness of local aggressive thoracic therapy (surgery and radiotherapy) for oligometastatic non-small cell lung cancer compared with systemic therapy, but with small sample. This study aims to perform a pooled analysis to explore whether LT could improve outcomes of oligometastatic patients with non-small cell lung cancer.MethodsProtocol of present study was registered on PROSPERO as number: CRD42021233095. PubMed, Embase and Web of knowledge were searched, and eligible studies investigating local therapy for non-small cell lung cancer with 1–5 metastases regardless of organs were included. Linear regression between survival and clinical characteristics were conducted. Hazard ratios of survival and adverse effects were merged. Pooled survival curves were carried out.ResultsThree randomized controlled trials and 5 cohort studies enrolling 499 patients were included. There was a trend that median overall survival declined with the increasing proportion of N2–3 positive patients in local therapy group, but with no statistical difference (P=0.09, R2=0.98). Undergoing local therapy for oligometastatic non-small cell lung cancer achieved reduction of 47% and 60% in the risk of death and cancer progression (P<0.001), respectively. In subgroup analysis, patients receiving local therapy including surgery showed hazard ratio of 0.33 on progression-free survival and 0.55 of these excluding surgery. Patients receiving consolidative local therapy (local therapy after systemic therapy) obtained hazard ratios 0.33 and 0.45 on progression-free and overall survival vs. systemic therapy, respectively. Hazard ratios of those receiving upfront local therapy (local therapy first) were 0.62 and 0.68 on progression-free and overall survival vs. systemic therapy. Pooled survival analysis showed median overall and progression-free survival of local therapy (21.6 and 14 months) group were both longer than systemic one (14.3 and 6.5 months). Odds ratio of adverse effects were no difference between 2 groups (P=0.16).ConclusionsLocal aggressive thoracic therapy could prolong 7 months overall and progression-free survival compared with systemic therapy in patients with oligometastatic non-small cell lung cancer. Consolidative local therapy might be a more favorable choice of local therapy. Benefits of local therapy for N2–3 positive patients should explored further.

BackgroundThe 5-year overall survival (OS) for stage IV pancreatic cancer is dismal despite aggressive systemic therapy. Stereotactic body radiation therapy (SBRT) involves delivering precise, highly conformal, and biologically effective doses of radiation via a linear accelerator to the tumor region. Clinical trials have shown improvement in OS and progression-free survival (PFS) with SBRT plus standard chemotherapy in oligometastatic (<5 metastatic lesions) solid tumors such as breast, lung, colorectal, and prostate cancers, when compared to chemotherapy alone. Factors predicting response to SBRT need to be further explored in oligometastatic pancreatic cancer (oPC). The study aims to assess the role of SBRT in the management of patients with oPC.MethodsWe conducted a retrospective cohort study of oPC patients treated at the Mayo Clinic during the period from January 2012 to January 2022, who underwent SBRT to at least one site, including the primary site and/or sites of metastases, received at least 4 months of chemotherapy, and had a minimum of 1-year follow-up. Pertinent data were collected from the electronic health records after institutional review board (IRB) approval. The response rates (RRs) were assessed using the RECIST v1.1 criteria, and the PFS and OS were calculated using the Kaplan-Meier method. Multivariate Cox regression was used to determine a statistically significant correlation between treatment and genomic characteristics with OS and PFS.ResultsSixty-one patients with oPC were identified, among whom 38% were female. Eighty-seven percent were Caucasian, and 13% were other ethnicities (African American, Hispanic, and Asian). The median age was 66 years. Patients received gemcitabine (gem) or 5-fluorouracil (5-FU) based chemotherapy. Eight-five percent of patients received chemotherapy within 3 months of SBRT and the median follow-up time of 16 months. The RR was 25% in the primary lesion and 17% in metastatic lesions. SBRT to primary pancreas lesion correlated with higher OS [hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.082–0.89, P=0.03] but showed no difference in PFS (HR: 0.97, P=0.95) when compared to SBRT to any other metastatic site. SBRT to liver metastases had no improvement in OS (P=0.92) or PFS (P=0.70) versus SBRT to other metastatic sites. The type of chemotherapy (gem vs. 5-FU based) alongside SBRT within 3 months did not influence OS (P=0.47) or PFS (P=0.62) in these patients. Among 30 patients who underwent circulating tumor deoxyribonucleic acid (ctDNA) testing, SMAD4 gene alteration correlated with significantly higher PFS (HR: 0.23, 95% CI: 0.065–0.87, P=0.03) but had no relation with OS (HR: 0.60, 95% CI: 0.18–2.03, P=0.41) compared to patients with undetectable SMAD4 alteration.ConclusionsSBRT plus chemotherapy may have benefits in some patients with oPC. SBRT to primary pancreas lesion led to better OS compared with SBRT to other metastatic sites. SMAD4 alteration in ctDNA testing correlated with higher PFS in oPC patients who received SBRT. This implies a potential role for genomic biomarker-based patient selection in oPC. These findings are currently being studied in a randomized clinical trial evaluating SBRT plus chemotherapy in oPC (NCT04975516).

Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a4 mm expansion of the internal target volume. In C2, asubvolume was additionally created, asimultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed areduced dose. In all, 18patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1patient in C1 experienced agrade ≥3 late toxicity. The SIP approach is auseful prescription method for abdominal SBRT with afavorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) constitute a diverse range of conditions including posttransplant lymphoproliferative disorders, other iatrogenic IA-LPDs, and lymphoproliferative disorders associated with an underlying primary immune disorder or HIV infection. IA-LPDs are clinically and pathologically heterogeneous, and there is a lack of standardization of diagnostic terminology. They can represent a potential serious diagnostic pitfall because the histological features of clinically indolent proliferations may mimic those of high-grade lymphoma. However, correct identification of these entities is essential given that complete remission may occur upon reversal of the underlying cause of immunosuppression without the need for systemic therapy. IA-LPDs presenting in the skin are rare but well documented. One form of iatrogenic IA-LPD, methotrexate-associated lymphoproliferative disorder (MTX-LPD), can present with cutaneous nodules, plaques, or ulcers. Predominantly, MTX-LPD develops in the context of long-term treatment of autoimmune conditions, such as rheumatoid arthritis, dermatomyositis, and Sjögren syndrome, and may be associated with underlying Epstein-Barr virus (EBV) infection. We present 4 cases of cutaneous EBV-positive B-cell MTX-LPD and describe their clinical and morphological findings. Comparison of our histological findings to the diagnostic criteria for EBV-positive mucocutaneous ulcer (EBVMCU) revealed significant overlap, highlighting the intersection between MTX-LPD and EBVMCU. Withdrawal of methotrexate resulted in healing of all lesions at a mean time of 2 months. In summary, close clinicopathological correlation is vital to identify MTX-LPD presenting as cutaneous EBVMCU given that the initial treatment strategy is that of withdrawal of methotrexate without the need for immediate systemic therapy.

Pancreatic cancer is the tenth most common cancer and is the fourth leading cause of cancer mortality. While surgery remains the current potentially curative treatment of choice, few cancers are resectable at presentation. Chemotherapy and radiation play a vital role in locally advanced non-metastatic pancreatic cancer. Systemic therapy is vital in these patients and often, when they remain non-metastatic after induction therapy radiation improves local control. Conventional chemoradiation is delivered in 5–6 weeks. Stereotactic body radiotherapy (SBRT) has been used in patients with locally advanced pancreas cancer, in fewer treatments, without significantly affecting systemic therapy, thereby maximizing systemic and local control. SBRT has also been used to boost positive margins, local recurrences after prior radiation, and in oligometastatic pancreatic cancer.

Role of Local and/or Metastasis-directed Therapy in Patients with Hormone-sensitive M1a Prostate Cancer—A Systematic Review

Head and neck squamous cell carcinoma (HNSCC) has a reported average of around 15% metastases at presentation with chemotherapy being the mainstay of treatment for widely metastatic disease. However, in select patients with oligometastatic disease, local ablative therapy (commonly including surgery or radiotherapy) can be utilized with the possibility of improving survival, decreasing morbidity from the metastases, and obviating the need for systemic therapy with its possible side effects. However, most research has been of ablative therapy has been performed for pulmonary and hepatic oligometastatic lesions. In this case, we present a patient who initially presented with a metastatic base of tongue malignancy with left axilla metastases who was treated palliatively with systemic therapy with an initial complete response. She subsequently progressed on maintenance therapy with a locoregional recurrence that was treated with definitive chemoradiation with complete response. There was a subsequent recurrence again in the left axilla that was treated as well with chemoradiation with complete response. Next, there was a recurrence in the right occipital lobe and left parotid gland with treatment with surgical resection, plus stereotactic radiotherapy boost and stereotactic ablative body radiotherapy (SABR), respectively. This all occurred over a 30-month time frame from initial therapy to her last treatment, with an additional 42 months at the present time with no recurrence. This case highlights the future of care of oligometastatic disease of HNSCC with potential long-term survival in appropriately selected patients treated with stereotactic ablative body radiotherapy. Furthermore, this is one of the first reported cases in the literature of SABR for an oligometastatic lesion of the parotid gland, especially from squamous cell carcinoma (SCC) of the oral cavity, with no recurrence of disease over 40 months removed from treatment.

PC08.01 Debate #1: Locally Ablative Therapies Should Be Standard Treatment for Patients with NSCLC Oligometastese (PRO)

The use of IRE in multi-modality treatment for oligometastatic pancreatic cancer

The Role of Stereotactic Radiotherapy in Deferring the Need for Systemic Therapies in Patients with Progressive Oligometastatic Iodine-Refractory Thyroid Cancer

Background: Stage IV breast cancer was considered to be an incurable disease with a poor survival outcome. Among them, patients with de novo stage IV breast cancer (BC) account for approximately 25%. Systemic therapy has remained the cornerstone of treatment, and the role of local therapy (Surgical resection of the primary tumor and/or radiotherapy) for de novo stage IV BC remains controversial. Aim: This study was conducted to examine the clinical and pathological profile and survival outcomes of patients with de novo stage IV BC treated with local therapy at our institutions. Settings and design: The study was conducted at two Chinese tertiary hospitals and was retrospective in nature. Methods and patients: All de novo stage IV BC patients (all female) treated with local therapy and systemic therapy alone at our hospitals between March 2007 and November 2016 were enrolled in the study. Data were retrospectively extracted from the patients’ case records. Data were analyzed according the clinicopathological features and treatment outcomes. Overall survival was used as the primary study outcome. Univariable and multivariable Cox regression analysis were used to assess the association between local therapy and overall survival. Further stratified survival analysis was used to assess the effect of surgical resection of the primary tumor before or after systemic therapy on survival outcomes. Kaplan-Meier method was used for survival analysis and the outcome variables were compared using the log-rank test. Results: A total of 138 cases of de novo stage IV BC patients admitted to our institutions were included, of whom 80 underwent local treatment. There was no significant difference in age, primary tumor N-stage, Ki-67 index, ER/PR status, and HER-2 expression between local treatment group and systemic therapy group. But there were differences in tumor size and metastatic site between the two groups. Surgical resection of the primary tumor was performed in 71/138 (51.4%) patients and 26 cases of the patients had combined radiotherapy. The median duration of follow-up was 31±20.6 months. Median survival time of all patients was 32.1 months, and the 3-year and 5-year survival rates were 36.2% and 12.3%, respectively. The median survival time of local treatment group and systemic therapy group were 38.0 and 19.0 months (HR 0.50; 95% CI 0.34-0.73; p&amp;lt;0.0001), and the 3-year and 5-year survival rates were 53.5% versus 20.9% and 16.9% versus 7.5%, respectively. Similarly, patients who had surgery were found to have a better survival outcome than the patients with non-surgery therapy (HR 0.53; 95% CI 0.36-0.77; p&amp;lt;0.0001). While receipt of radiotherapy alone to either the primary and/or metastatic sites had no impact on overall survival (p=0.24). Interestingly, surgical resection of the primary tumor, whether before or after systemic therapy (p=0.0004; p=0.0005), was independently associated with improved overall survival when compared to systemic therapy alone. Conclusions: Our data support that local therapy mainly based on surgical resection of the primary tumor can improve overall survival in patients with de novo stage IV BC, but fail to demonstrate the survival benefit from radiotherapy alone. However, prospective evidence from phase-3 randomized controlled trials on the feasibility of local therapy in de novo stage IV BC is required before its routine use can be recommended. Key words: De novo stage IV breast cancer; Local therapy; Surgical resection of the primary tumor; Survival outcomes Research protocol number: 2017-AF29-058 Citation Format: Ren Chongxi, Sun Jianna, Kong Lingjun, Liu Hong. Local therapy and its association on survival outcomes in patients with de novo stage IV breast cancer: Results from a retrospective cohort study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-19.

Osteosarcoma and Ewing sarcoma represent the 2 most common cancers of bone seen in pediatric patients. Given that patients with such tumors can frequently present to nononcologist providers reporting nonspecific symptoms such as musculoskeletal pain or swelling, an understanding of these disease entities by pediatricians is important to ensure appropriate patient referral and care. In addition, because there are a variety of sequelae present in bone sarcoma survivors as a result of disease and treatment, understanding and awareness of such sequelae by nononcologist providers is important for long-term patient care.After completing this article, readers should be able to: Understand the incidence and general epidemiology of osteosarcoma and Ewing sarcoma, including genetic syndromes that increase the risk of developing sarcomas in children.Recognize the clinical presentation of osteosarcoma and Ewing sarcoma.Initiate an evaluation to further characterize a new bone or soft tissue lesion.Describe the prognostic factors associated with osteosarcoma and Ewing sarcoma.Describe the long-term complications associated with the treatment of osteosarcoma and Ewing sarcoma.Osteosarcoma and Ewing sarcoma represent the 2 most common cancers of bone seen in the pediatric population. Bone cancers as a group represent approximately 4% of the approximately 10,000 new pediatric cancer diagnoses made each year in the United States. (1) As with many pediatric tumors, although some cases can be attributed to environmental factors (such as ionizing radiation) or inherited genetic risk, most cases are believed to arise spontaneously. The anatomical location of the tumors shows differences between Ewing sarcoma and osteosarcoma, and Ewing sarcoma can also present as soft tissue masses. Patients commonly present with pain or swelling, leading to the identification of a mass by examination or imaging. Although treatment regimens differ between them, both sarcomas require therapy that includes both systemic chemotherapy and an element of local control, such as surgical resection or radiotherapy. For both sarcomas, survival decreases dramatically when the disease is determined to be metastatic, and the lungs are the most common site of metastases. In both cases, there are a variety of sequelae present in long-term survivors as a result of treatment or because of the location of the primary tumor, requiring special attention in survivorship care.Bone cancers in children rank in incidence behind multiple other types of cancers, including leukemias, lymphomas, and central nervous system tumors. Counting new diagnoses of osteosarcoma and Ewing sarcoma, there are approximately 800 newly diagnosed cases per year in the United States in the pediatric population, with approximately 450 cases in children (ages 0–14 years) and 350 cases in adolescents (ages 15–19 years). Osteosarcoma and Ewing sarcoma are rarely seen in the youngest group of children (ages 0–4 years) and have an incidence that rises with patient age, with the highest rate of diagnoses in adolescents aged 15 to 19 years. A second peak of osteosarcoma is seen in adults older than 65 years, oftentimes associated with Paget disease of bone. Both tumor types show a slight predominance in males: 55% of new diagnoses of osteosarcoma and 58% of diagnoses of Ewing sarcoma. (1)Most cases of bone tumors are sporadic, and few patients have predisposing genetic factors. Compared with Ewing sarcoma, osteosarcoma has a variety of associated syndromes that predispose to its development, including germline mutations in tumor suppressors such as TP53 (Li-Fraumeni syndrome) and RB1 (retinoblastoma). In addition, a variety of relatively rare syndromes that all seem to predispose to tumor development because of their role in genomic and DNA stability have been associated with increased risk of osteosarcoma (Table). (2)(3) However, all of these syndromes are rare in the population. Although not a genetic factor, ionizing radiation is a well-described risk factor for the later development of osteosarcoma, particularly in individuals with an underlying genetic predisposition. In contrast, the development of Ewing sarcoma has no known association with radiation or other named genetic disorders or syndromes. Although Ewing sarcoma does have a characteristic gene fusion present in the tumor cells (see the Diagnosis section), if there are genetic factors that predispose to such a fusion, they are currently unknown.Variations in incidence for both osteosarcoma and Ewing sarcoma have been described for individuals of different ancestry for reasons that remain unclear. Osteosarcoma is diagnosed at a higher rate in children with African and Hispanic ancestry compared with those of European descent, but this difference is reversed in the adult population with osteosarcoma. (4) In contrast, Ewing sarcoma is approximately 9 times more prevalent in individuals of European descent, with comparatively much lower rates in individuals of African descent. (5) This difference seems to be present across patient ages in Ewing sarcoma.Osteosarcoma has a variety of subtypes based on histologic characteristics and appearance. Subtyping based on tumor grading—ranked as low, intermediate, and high grade—has clinical implications for both treatment and outcomes, but further histologic designations within those categories do not. Tumors that have a subtype designation with relevance to management and outcome include the low-grade osteosarcomas, also known as parosteal osteosarcomas, and the intermediate-grade tumors, termed periosteal. (6) Most conventional osteosarcoma tumors are high grade and can be furthered classified into descriptive histologic subgroups such as osteoblastic, telangiectatic, and fibroblastic.For Ewing sarcoma and osteosarcoma, the initial presentation can be subtle, with complaints including nonspecific pain or swelling at the primary site of disease. Pain is present in approximately 70% of patients and is often associated with activity but is also seen at rest or at night. The initial complaint and the onset of symptoms are often associated with trauma, such as a sports-related injury, which can complicate making the diagnosis. (7) Although there is variability in presentation, pain that persists throughout both the day and night, is present for weeks to a month, and/or has no known association with trauma or vigorous activity should increase suspicion for a malignant process.This potential for a relatively subtle initial presentation in patients means that clinicians should hold a high index of suspicion and consider a more thorough evaluation in cases in which the diagnosis for a musculoskeletal complaint is unclear. A history of trauma, the acquisition of radiographs, and the presence of a palpable mass are all associated with shorter time to definitive diagnosis after initial presentation to a provider, but 1 study identified that 10% of patients with osteosarcoma and 28% of patients with Ewing sarcoma had a time to diagnosis that exceeded 6 months between initial presentation of symptoms and definitive diagnosis. (7) However, despite this potential for a delay in diagnosis, survival seems equivalent between patients who experience a delay and those who do not. (8)Sites of disease vary between the sarcomas. Osteosarcoma has a higher likelihood of being found in the appendicular skeleton. Ewing sarcoma is more likely to present in the axial skeleton (Fig 1). (9)(10) Interestingly, the presentation of osteosarcoma in the extremities has a tendency for specific localization within the involved bones; lower extremity lesions are more often localized close to the knee (eg, distal femur and proximal tibia), and lesions in the humerus are more likely to be proximal. The potential for Ewing sarcoma to involve axial structures also means that presentation of such tumors may be even more difficult to detect on history and physical examination given the lower likelihood of an easily detected palpable mass.For both osteosarcoma and Ewing sarcoma, diagnosis follows a similar trajectory: characterization via imaging of the primary site of disease, coupled with investigations to determine whether the disease is localized or metastatic. Biopsy for definitive pathological tissue diagnosis is essential.Initial imaging should be performed with standard radiography. Ewing sarcoma will frequently appear on such imaging with evidence of bony destruction, exhibiting indistinct lesional margins described as a moth-eaten appearance. There is also often evidence of cortical destruction and a soft tissue mass, and periosteal reaction can potentially give rise to such classic imaging findings as a sunburst pattern or onion skinning, (11) Osteosarcoma typically demonstrates a mixed appearance on imaging, with both lytic and radiodense aspects to the lesion. Frequently there is an accompanying soft tissue mass. As with Ewing sarcoma, findings of cortical destruction and a sunburst pattern can be present as a consequence of the tumor’s growth and infiltration, which can also result in a periosteal elevation that is termed the Codman triangle (Fig 2). (12)For bony lesions concerning for a sarcoma on plain films, more detailed magnetic resonance imaging of the affected body region and adjacent joint should be performed. This imaging permits characterization of soft tissue extension, detection of skip lesions that suggest local spread of the tumor in the bone of origin, and possible detection of any extension into adjacent joints or other important structures. Due to the risk of pulmonary metastases for both tumor types, computed tomography of the chest should be performed. In addition to assessing the lungs by computed tomography for any evidence of metastatic disease, fluorodeoxyglucose–positron emission tomography is frequently used to look for other sites of distant metastatic disease.The approach to detection of metastases to bone marrow differs between osteosarcoma and Ewing sarcoma because the likelihood of bone marrow metastases at diagnosis is very low in osteosarcoma compared with Ewing sarcoma. Although bone marrow biopsies are not routinely performed in osteosarcoma, bilateral bone marrow biopsies, typically from the iliac crests, are obtained at diagnosis to characterize the presence or absence of marrow disease in patients with Ewing sarcoma. The rate of metastatic marrow disease is approximately 5% in all patients with Ewing sarcoma, but it rises to nearly 20% in those with other metastatic disease sites. Interestingly, only 1.2% of Ewing sarcoma is metastatic to only the bone marrow. Although the role for positron emission tomography in the detection of metastatic Ewing sarcoma in bone marrow is still evolving, there is emerging data to suggest that it may be a safe alternative to bone marrow biopsy in patients with no other evidence of metastatic disease. (13)Although both osteosarcoma and Ewing sarcoma have certain typical characteristics from imaging, pathological diagnosis is essential to ensure proper treatment. The exact approach depends on the affected anatomical site and adjacent structures but should always be performed by a surgeon or interventional radiologist skilled in the management of sarcomas.Ewing sarcoma appears morphologically as a small round blue cell tumor (Fig 3A). For Ewing sarcoma, the tumors possess a gene fusion between the EWS gene and a member of the ETS gene family. This fusion results in the production of a tumor-specific transcription factor that is a key driver of Ewing sarcoma tumor biology. (14)(15)(16)(17) Given that the fusion is specific to tumor cells, molecular biological techniques such as next-generation sequencing, fluorescent in situ hybridization, or reverse transcription–polymerase chain reaction are used to confirm a presumptive histologic diagnosis. Evidence of osteoid production on a biopsy is pathognomonic for osteosarcoma (Fig 3B). The most critical piece for osteosarcoma is grading of the tumor to determine whether it is low-, intermediate-, or high-grade because that has direct implications for outcome and treatment.Laboratory tests are not helpful in making a definitive diagnosis of either Ewing sarcoma or osteosarcoma. If there is concern for a bone tumor, standard laboratory tests such as a basic metabolic panel, liver function tests, and a complete blood cell count with differential count should be performed, but normal results in no way exclude such a tumor. If they are measured, lactate dehydrogenase and alkaline phosphatase levels will typically be elevated at presentation, given the presence of bony destruction, but these enzyme elevations are relatively nonspecific and, therefore, cannot be used to make a definitive diagnosis.Before the introduction of chemotherapy, the treatment of osteosarcoma was surgical resection alone. Survival was less than 15% secondary to the development of metastatic disease, primarily in the lungs. This underscored the need for systemic therapy. (18) Early therapeutic trials established the efficacy of adjuvant (postoperative) chemotherapy, typically consisting of high-dose methotrexate, doxorubicin, and cisplatin (MAP). (19)(20) Studies from Sloan-Kettering showed an advantage to neoadjuvant (preoperative) chemotherapy. This allowed for limb-sparing surgical procedures and assessment of histologic response to chemotherapy, which has been found to have prognostic significance. Studies have shown that greater than 90% tumor necrosis at the time of resection is associated with improved outcomes. (21) These concepts led to development of the current model of treatment, including neoadjuvant chemotherapy with MAP, surgery to remove the primary tumor and sites of metastatic disease, and adjuvant chemotherapy.In the 1980s, the Multi-Institutional Osteosarcoma Study established the use of MAP as an effective treatment regimen in osteosarcoma. (21) Unfortunately, since that time, there has been little success in increasing overall survival. The most recent international trial, the European and American Osteosarcoma Study (EURAMOS), evaluated whether the addition of adjuvant high-dose ifosfamide and etoposide (IE) to the 3-drug therapy backbone improved outcome for patients with poor tumor necrosis. This trial also evaluated whether there was a role for maintenance therapy with adjuvant pegylated interferon in patients with good histologic response. The study completed in 2011, and neither the addition of IE nor maintenance therapy with pegylated interferon improved outcomes. This leaves neoadjuvant chemotherapy with MAP followed by surgery and adjuvant MAP as the standard of care. The standard chemotherapy management for metastatic osteosarcoma is similar to localized disease, with an emphasis on surgery to remove metastatic tumor where possible. Several recent trials using novel agents have not improved outcomes.Osteosarcoma is relatively radioresistant, and surgery is considered a mainstay of cure. The most important component is wide local excision, where both tumor and a normal tissue margin should be removed. Typically, surgical options include amputation, disarticulation (amputation through a joint), or limb salvage. Historically, more amputations were performed, but as surgical techniques have improved, limb-sparing surgeries have become more common. When either disarticulation or limb salvage is performed, reconstruction is necessary. Reconstruction can include osteoarticular allografts, an endoprosthesis made of different metals, or combinations of the two. More recently, for patients still growing, endoprosthetic devices that expand as the patient grows have been an attractive option. For large tumors of the distal femur or proximal tibia, a van Ness rotationplasty can be performed. In this procedure, the ankle joint becomes a knee joint by rotating the distal part of the lower leg 180° and reattaching to the proximal femur. A custom prosthesis is fitted to the rotated leg, which serves as a below-the-knee prosthesis (Fig 4). This option is attractive for younger patients and those who want to remain active in sports because other prostheses typically limit patients to low-impact activities. (19)(22)Osteosarcoma is thought to be relatively radioresistant, and radiotherapy is not used in the upfront setting. However, in circumstances in which tumors are unresectable or palliative symptom control is necessary, radiotherapy has been shown to be effective. Doses larger than 60 Gy are typically needed.For recurrent disease, treatment remains challenging. Metastatectomy of the lungs or bony sites can be curative in 20% of patients (23)(24) if disease is isolated to the lungs or to a bone amenable to resection. Many agents aimed at targeting some of the pathways known to drive osteosarcoma development have been trialed with mixed success. Agents that have shown some activity in recurrent osteosarcoma and that are often used include ifosfamide, IE, gemcitabine, and docetaxel, as well as tyrosine kinase inhibitors. (24)(25)(26)Patients with localized, completely resected disease have survival rates approaching 70%. Those with unresectable or metastatic disease fare much worse, with survival rates typically less than 25% (Fig 5). Despite many attempts to improve survival rates, these outcomes have remained unchanged for decades, and chemotherapy regimens remain the same.Unlike osteosarcoma, Ewing sarcoma is known to be radiation sensitive. Historically, when radiotherapy was solely used in the treatment of Ewing sarcoma, fewer than 10% survived, underscoring the need for systemic therapy. Most patients are now treated with neoadjuvant chemotherapy followed by local control with surgery or radiotherapy and adjuvant chemotherapy. Survival has increased dramatically with this multidisciplinary approach.In the 1980s, the North American Intergroup Ewing Sarcoma Study Group established the benefit of doxorubicin and higher-dose, intermittent cyclophosphamide in Ewing sarcoma therapy. (27)(28) Because of the dose-limiting cardiac toxic effects of doxorubicin, other alkylating agents were trialed, leading to the INT-0091 study, which established that the addition of IE to a doxorubicin-based backbone increased overall survival in nonmetastatic patients. Through INT-0091 and Children’s Oncology Group trial AEWS0031, the established standard of care is alternating cycles of vincristine, doxorubicin, cyclophosphamide, and IE every 2 weeks. (27)(29)Unfortunately, approximately 25% of newly diagnosed patients with Ewing sarcoma present with metastatic disease, primarily to the lungs, bone, and/or bone marrow. The prognosis for these patients remains poor. Intensified chemotherapy regimens and novel biological therapies have been tried but without major success. (30)(31) High-dose chemotherapy with autologous stem cell rescue is an approach used in certain patient populations in Europe but is not the standard approach in North America. (32)(33) Targeting the EWS fusion would seem attractive; however, to date there has been no clinical success. (34)The standard treatment approach is neoadjuvant chemotherapy followed by local control and adjuvant chemotherapy. The best option for local control is debated because there has never been a randomized controlled trial comparing the effectiveness of surgery versus radiotherapy. Retrospective evidence suggests that there are higher rates of local recurrence with radiotherapy alone, (35)(36) and there are concerns for secondary malignancies related to irradiation. Alternatively, surgery can lead to permanent deficits and morbidity.The most important aspect of surgical resection of the local tumor is the ability to obtain negative margins. This means that the entire tumor is removed along with a small border of normal tissue. Options include amputation and limb salvage with reconstruction. Reconstruction can consist of bone grafts, prosthetic devices, and combinations of the two, similar to surgeries for osteosarcoma. Ewing sarcoma of the pelvis is particularly challenging because the evidence is conflicting on whether surgery, radiotherapy, or a combination produces the best outcomes. (37) This underscores the importance of multidisciplinary discussions with surgeons, oncologists, and radiation oncologists for local treatment of pelvic Ewing sarcoma.Definitive radiotherapy can be used in select patients, including those in whom surgery would carry high morbidity. (35)(36) Definitive radiotherapy doses range from 55 to 60 Gy. In the postoperative setting, radiotherapy is used when there are positive margins after surgery or when there is evidence of tumor spill or rupture. In Europe, postoperative radiotherapy is used in patients with poor histologic response (<90% necrosis), although this is not routinely used in North America. (34)For metastatic disease to the lungs, whole lung radiotherapy is typically recommended during upfront (first-line) therapy. Due to the poor outcomes for patients with metastatic disease, clinical trials are the recommended treatment options. Unfortunately, to date, no trials have significantly improved survival for patients with metastatic disease.Up to 25% of those with initially localized disease will relapse. This number is even higher for those with metastatic disease at diagnosis. (38)(39) Of those who develop recurrent disease, 75% will show evidence of relapse within 2 years of the original diagnosis. Those who have isolated local relapse have a better prognosis. The approach for relapsed disease typically includes local control approaches (surgery or radiotherapy) with systemic therapy. Strategies that have shown efficacy include irinotecan/temodar, topotecan/cyclophosphamide, ifosfamide, tyrosine kinase inhibitors, or clinical trials. (40)(41)The most significant prognostic factor in Ewing sarcoma is the presence of metastatic disease. Patients with metastatic disease isolated to the lung fare better than those with metastatic disease elsewhere (Fig 5). (35)(42) Other factors that lead to a poorer prognosis include older age at diagnosis, tumor volume greater than 200 mL or largest diameter greater than 8 cm, multiple areas of bony involvement, bone marrow involvement, and tumors located in the axial skeleton. (42)Treatment-related late effects include secondary malignancies, cardiac and pulmonary conditions, and chronic conditions related to surgery. Secondary malignancy rates approach a cumulative incidence of 14% at 35 years from diagnosis. Secondary breast cancer and osteosarcoma in the radiation field are the most common solid tumors. (43) Exposure to alkylating agents (cyclophosphamide and ifosfamide) and etoposide increase the risk of secondary leukemia at a rate of 1% to 3%.Cardiac conditions are related to anthracycline (doxorubicin) exposures, particularly in cumulative doses higher than 450 mg/m2. The pathognomonic anthracycline-related cardiac condition is cardiomyopathy leading to progressive cardiac failure. Dexrazoxane is a cytoprotective drug used in conjunction with doxorubicin to try to mitigate cardiomyopathy risks. Lung irradiation is the prime causative agent in chronic lung conditions. Neurologic conditions such as peripheral and sometimes cranial neuropathies are common after surgery and exposure to vincristine. Cisplatin has been associated with ototoxicity in the form of hearing loss and/or tinnitus in survivors. Lifelong follow-up is needed to screen for and manage these conditions.Use of cryotherapy during chemotherapy infusions to reduce mucositis.Implementation of extended high-frequency testing and the ototoxicity grading scale to current ototoxic monitoring protocols in children with solid tumors.Education efforts regarding different local control options to help patients make the best informed decisions.You can find the teaching slides that accompany this article on the Views>Supplementary Data option in the online article toolbar.We thank our pathologist, Amy Treece, MD, Department of Pathology, University of Colorado School of Medicine, Aurora, CO, for her contribution to this article.

Pancreatic ductal cancer is one of the most aggressive malignancy with a high incidence of advanced stages at the time of diagnosis and unsatisfactory long-term treatment results. It is believed that pancreatic ductal cancer in the presence of distant metastases identified at the stage of intraoperative revision or before surgery is a contraindication to surgical treatment. There is currently renewed interest in surgical treatment of patients with oligometastatic pancreatic cancer.Material and Methods. The search for sources was carried out in the PubMed and Elibrary systems from January 1995 to January 2024. Of the 1321 sources found, 37 were used to write the review. Data from both retrospective and prospective clinical studies that focused on the results of combined modality treatment of pancreatic cancer with isolated liver metastases were included.Results. To date, a standard treatment strategy for patients with oligometastatic pancreatic cancer has not yet been established; there are no definitive criteria for selecting patients who may benefit from surgical treatment. The current selection criteria for surgery for metastatic pancreatic cancer are far from ideal, extremely heterogeneous and, as a rule, are based only on certain clinical and instrumental data. The starting point for developing selection criteria for surgical treatment of patients with metastatic pancreatic cancer is a common understanding of what “oligometastatic pancreatic cancer” is.